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30 results on '"MESH : DNA-Binding Proteins"'

1. Peroxisome proliferator-activated receptor alpha deficiency impairs regulatory T cell functions: Possible application in the inhibition of melanoma tumor growth in mice

Author

François Ghiringhelli, Narcisse Zwetyenga, Naim Akhtar Khan, Kabirou Moutairou, Françoise Salvadori, Aziz Hichami, Akadiri Yessoufou, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Laboratoire de Biochimie et de Biologie Moléculaire (Université d'Abomey Calavi, Cotonou, Bénin) ( LBBM ), Université d'Abomey Calavi, French Ministry of Higher Education and Research, National Cancer Institute (1-23651-07), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire de Biochimie et de Biologie Moléculaire (Université d'Abomey Calavi, Cotonou, Bénin) (LBBM), University of Abomey Calavi (UAC), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)

Subjects
0301 basic medicine, Male, Adoptive cell transfer, MESH: Tumor Burden, B16 melanoma tumor, Melanoma, Experimental, MESH: T-Lymphocyte Subsets, CD4(+)CD25(+) regulatory T cells, Biochemistry, MESH: Mice, Knockout, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, PPARα, MESH : T-Lymphocytes, Regulatory, Cell Movement, T-Lymphocyte Subsets, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Cell Proliferation, MESH : Cell Movement, MESH: Animals, IL-2 receptor, MESH: PPAR alpha, MESH: Cell Movement, Cells, Cultured, Mice, Knockout, MESH : Melanoma, Experimental, biology, MESH : Tumor Burden, Reverse Transcriptase Polymerase Chain Reaction, MESH : Reverse Transcriptase Polymerase Chain Reaction, FOXP3, hemic and immune systems, General Medicine, MESH: Gene Expression Regulation, Neoplastic, 3. Good health, Tumor Burden, MESH: Melanoma, Experimental, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, MESH: Immunotherapy, Adoptive, Receptors, Chemokine, MESH : DNA-Binding Proteins, MESH: Cells, Cultured, medicine.medical_specialty, MESH : Receptors, Chemokine, MESH: Cell Line, Tumor, Regulatory T cell, MESH : Gene Expression Regulation, Neoplastic, T cell, MESH : Male, MESH : PPAR alpha, chemical and pharmacologic phenomena, MESH : Mice, Inbred C57BL, MESH : Clonal Anergy, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Cell Proliferation, Cell Line, Tumor, MESH : Cells, Cultured, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, PPAR alpha, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell Proliferation, Clonal Anergy, Perforin, MESH : Cell Line, Tumor, MESH: T-Lymphocytes, Regulatory, Molecular biology, MESH: Male, MESH : T-Lymphocyte Subsets, Granzyme B, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, MESH: Clonal Anergy, biology.protein, MESH : Mice, Knockout, MESH : Animals, MESH: Receptors, Chemokine, CD8, MESH: DNA-Binding Proteins, MESH : Immunotherapy, Adoptive
Abstract

International audience; Regulatory T (Treg) cells are important to induce and maintain immunological self-tolerance. Although the progress accomplished in understanding the functional mechanism of Treg cells, intracellular molecules that control the mechanisms of their suppressive capacity are still on investigation. The present study showed that peroxisome proliferator-activated receptor-alpha deficiency impaired the suppressive activity of Treg cells on CD4(+)CD25(-) and CD8(+) T cell proliferation. In Treg cells, PPARα gene deletion also induced a decrease of migratory abilities, and downregulated the expression of chemokine receptors (CCR-4, CCR-8 and CXCR-4) and p27(KIP1) mRNA. Treg cells from PPARα(-/-) mice also lost their anergic property. Since low Treg activity, as observed in PPARα(-/-) mice, is known to be associated with the inhibition of tumor growth, we inoculated these mice with B16 melanoma cells and assessed tumor proliferation. In PPARα(-/-) mice, cancer growth was significantly curtailed, and it was correlated with high expression of granzyme B and perforin mRNA in tumor bed. Degranulation of cytolytic molecules by CD8(+) T cells, assessed by a perforin-release marker CD107a expression, was higher in PPARα(-/-) mice than that in wild-type mice. Tumor-infiltrating lymphocytes (TIL) in melanoma tumors in PPARα(-/-) mice exhibited high pro-inflammatory Th1 phenotype. Consistently, adoptive transfer into lymphopenic RAG2(-/-) mice of total PPARα(-/-)splenic T cells inhibited more the growth rate of B16 tumor than the wild type splenic T cells. Our findings suggest that PPARα deficiency, by diminishing Treg cell functions and upregulating pro-inflammatory T cell phenotype, exerts an in vivo anti-cancer properties.

Published
2016

2. Genetic polymorphisms in ARID5B, CEBPE, IKZF1 and CDKN2A in relation with risk of acute lymphoblastic leukaemia in adults: a Group for Research on Adult Acute Lymphoblastic Leukaemia (GRAALL) study

Author

Eric Delabesse, Xavier Thomas, Véronique Lhéritier, Nicolas Pottier, Jean-Yves Cahn, Elizabeth Macintyre, Soizic Guihard, Nathalie Grardel, Meyling Cheok, Arnaud Pigneux, Céline Berthon, Hervé Dombret, Norbert Ifrah, Pauline Peyrouze, Marie C. Béné, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Service d'Immunologie [CHRU Nancy], Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Impact de l'Environnement Chimique sur la Santé Humain, PRES Université Lille Nord de France, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hospices Civils de Lyon ( HCL ), IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne-Université Paris 13 ( UP13 ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne

Subjects
Male, MESH : Transcription Factors, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: CCAAT-Enhancer-Binding Proteins, 0302 clinical medicine, CDKN2A, MESH : Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Female, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Hematology, MESH: Transcription Factors, MESH: Ikaros Transcription Factor, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Adult, 3. Good health, DNA-Binding Proteins, MESH : CCAAT-Enhancer-Binding Proteins, MESH: Young Adult, 030220 oncology & carcinogenesis, Female, MESH : DNA-Binding Proteins, Adult, MESH : Male, MESH : Young Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Ikaros Transcription Factor, Young Adult, MESH : Ikaros Transcription Factor, Humans, Genetic Predisposition to Disease, MESH : Middle Aged, 030304 developmental biology, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, MESH : Humans, MESH: Adult, CEBPE, MESH: Male, Immunology, CCAAT-Enhancer-Binding Proteins, Lymphoblastic leukaemia, MESH : Genetic Predisposition to Disease, MESH: Female, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

International audience

Published
2012

3. Virtual Screening and Biological Evaluation of Inhibitors Targeting the XPA-ERCC1 Interaction

Author

Charles Dumontet, David S. Wishart, Jacek A. Tuszynski, Rolando Perez-Pineiro, Khaled Barakat, Lars Petter Jordheim, University of Alberta, Equipe 14, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Alberta [Edmonton], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Genetics and Molecular Biology (all), DNA Repair, Colorectal cancer, MESH : DNA, Plasma protein binding, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH: Protein Conformation, Models, Drug Discovery, MESH: Ligands, MESH : Protein Conformation, MESH: Static Electricity, MESH: DNA Repair, MESH : Ligands, 0303 health sciences, Tumor, MESH: Models, Chemical, MESH : Protein Binding, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Medicine, Oncology Agents, MESH : DNA-Binding Proteins, MESH: Models, Molecular, Cell Line, Tumor, Culture Media, DNA, DNA-Binding Proteins, Endonucleases, Humans, Inhibitory Concentration 50, Kinetics, Ligands, Models, Chemical, Models, Molecular, Models, Statistical, Molecular Dynamics Simulation, Protein Binding, Protein Conformation, Solubility, Static Electricity, Ultraviolet Rays, Xeroderma Pigmentosum Group A Protein, Medicine (all), Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), endocrine system, Science, Biophysics, MESH : Molecular Dynamics Simulation, Chemical, DNA-binding protein, 03 medical and health sciences, Chemical Biology, MESH: Protein Binding, Biology, MESH: Humans, MESH : Solubility, MESH : Humans, Molecular, Computational Biology, medicine.disease, MESH: Solubility, chemistry, MESH : Culture Media, MESH: Models, Statistical, MESH : Models, Chemical, MESH : Static Electricity, Cancer Treatment, Bioinformatics, Biophysics Simulations, MESH: Xeroderma Pigmentosum Group A Protein, chemistry.chemical_compound, MESH : DNA Repair, MESH: Endonucleases, Molecular Cell Biology, Basic Cancer Research, MESH : Endonucleases, MESH: Molecular Dynamics Simulation, MESH: Inhibitory Concentration 50, Multidisciplinary, MESH: Kinetics, MESH : Models, Statistical, MESH: DNA, Statistical, MESH : Inhibitory Concentration 50, MESH : Kinetics, Research Article, MESH: Cell Line, Tumor, MESH : Models, Molecular, DNA repair, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Line, medicine, 030304 developmental biology, Virtual screening, MESH : Cell Line, Tumor, MESH : Ultraviolet Rays, Cancer research, MESH: Culture Media, MESH: Ultraviolet Rays, ERCC1, MESH : Xeroderma Pigmentosum Group A Protein, MESH: DNA-Binding Proteins, Nucleotide excision repair
Abstract

International audience; BACKGROUND: Nucleotide excision repair (NER) removes many types of DNA lesions including those induced by UV radiation and platinum-based therapy. Resistance to platinum-based therapy correlates with high expression of ERCC1, a major element of the NER machinery. The interaction between ERCC1 and XPA is essential for a successful NER function. Therefore, one way to regulate NER is by inhibiting the activity of ERCC1 and XPA. METHODOLOGY/PRINCIPAL FINDINGS: Here we continued our earlier efforts aimed at the identification and characterization of novel inhibitors of the ERCC1-XPA interaction. We used a refined virtual screening approach combined with a biochemical and biological evaluation of the compounds for their ability to interact with ERCC1 and to sensitize cells to UV radiation. Our findings reveal a new validated ERCC1-XPA inhibitor that significantly sensitized colon cancer cells to UV radiation indicating a strong inhibition of the ERCC1-XPA interaction. CONCLUSIONS: NER is a major factor in acquiring resistance to platinum-based therapy. Regulating the NER pathway has the potential of improving the efficacy of platinum treatments. One approach that we followed is to inhibit the essential interaction between the two NER elements, ERCC1 and XPA. Here, we performed virtual screening against the ERCC1-XPA interaction and identified novel inhibitors that block the XPA-ERCC1 binding. The identified inhibitors significantly sensitized colon cancer cells to UV radiation indicating a strong inhibition of the ERCC1-XPA interaction.

Published
2012

4. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters

Author

Marion Travert, Jean-Philippe Jais, Olivier A. Bernard, Tak W. Mak, Rob A. Cairns, Laurence Lamant, Thérèse Rousset, Marie Parrens, Lucile Couronné, François Lemonnier, Bettina Fabiani, Laurence de Leval, Philippe Gaulard, Christian Bastard, Olivier Tournillac, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génétique des tumeurs (U985), Institut Gustave Roussy (IGR)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service informatique médicale et biostatistique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'anatomie et cytologie pathologiques [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Thérapie ciblée combinatoire en Onco-Hématologie (EA3846), Université d'Auvergne - Clermont-Ferrand I (UdA), Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Laboratoire d'anatomie cytologie pathologiques, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Campbell Family Institute for Breast Cancer Research, University Health Network, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie Clinique, Université de Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This study was supported in part by grants from INCa (Institut National du Cancer), ARC (Association pour la Recherche contre le Cancer), Ligue Nationale Contre le Cancer (équipe labelisée), PHRC (Programme Hospitalier de Recherche Clinique), FRM (Fondation pour la Recherche Médicale, équipe labellisée) and the Cancer Plan research Programme (Belgium, LdL). FL was a M2 student, granted from ARC and MT, a post-doctorant granted by FRM., Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Génétique des tumeurs ( U985 ), Institut Gustave Roussy ( IGR ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Université Toulouse III - Paul Sabatier ( UPS ), Thérapie ciblée combinatoire en Onco-Hématologie ( EA3846 ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), CIC - Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Gui de Chauliac, Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Lausanne ( UNIL ) -Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ) -Institut Universitaire de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lausanne = University of Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie, Guellaen, Georges, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]

Subjects
Male, Myeloid, MESH : Recurrence, MESH : Aged, Chromosomal translocation, MESH : T-Lymphocytes, Helper-Inducer, Biochemistry, 0302 clinical medicine, International Prognostic Index, Recurrence, MESH : Female, MESH: Aged, 0303 health sciences, Not Otherwise Specified, Hematology, T-Lymphocytes, Helper-Inducer, MESH: Lymphoma, T-Cell, Peripheral, 3. Good health, DNA-Binding Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH : Proto-Oncogene Proteins, Female, MESH : DNA-Binding Proteins, MESH : Mutation, Angioimmunoblastic T-cell lymphoma, MESH: Mutation, T cell, MESH : Male, Immunology, Dioxygenases, 03 medical and health sciences, Proto-Oncogene Proteins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Clinical significance, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: T-Lymphocytes, Helper-Inducer, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Aged, MESH: Humans, business.industry, MESH : Lymphoma, T-Cell, Peripheral, MESH : Humans, Lymphoma, T-Cell, Peripheral, Cell Biology, medicine.disease, MESH: Male, Lymphoma, MESH: Recurrence, MESH: Proto-Oncogene Proteins, Mutation, business, MESH: Female, MESH: DNA-Binding Proteins
Abstract

Inactivating mutations of the Ten-Eleven Translocation 2 (TET2) gene were first identified in myeloid malignancies and more recently in peripheral T-cell lymphomas (PTCLs). In the present study, we investigated the presence of TET2 coding sequence mutations and their clinical relevance in a large cohort of 190 PTCL patients. TET2 mutations were identified in 40 of 86 (47%) cases of angioimmunoblastic T-cell lymphoma (AITL) and in 22 of 58 (38%) cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), but were absent in all other PTCL entities, with the exception of 2 of 10 cases of enteropathy-associated T-cell lymphoma. Among PTCL-NOS, a heterogeneous group of lymphoma-comprising cases likely to derive from Th follicular (TFH) cells similarly to AITL, TET2 mutations were more frequent when PTCL-NOS expressed TFH markers and/or had features reminiscent of AITL (58% vs 24%, P = .01). In the AITL and PTCL-NOS subgroups, TET2 mutations were associated with advanced-stage disease, thrombocytopenia, high International Prognostic Index scores, and a shorter progression-free survival.

Published
2012

5. USF-1 is critical for maintaining genome integrity in response to UV-induced DNA photolesions

Author

Yorann Baron, Marie-Dominique Galibert, Sébastien Corre, Nicolas Mouchet, Sophie Vaulont, Sharon Prince, RTO - Régulation transcriptionnelle et oncogenèse, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Proclaim, Proclaim-Proclaim, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Biology, University of Cape Town, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud-CHU Pontchaillou [Rennes]-hôpital Sud, This work was supported by the Ligue National contre le Cancer-Comités Départementaux du Grand Ouest and the Association pour la Recherche contre le Cancer (ARC) foundations. YB has been successively supported by the Conseil Général Région Bretagne (ARED) and the ARC PhD fellowship programs. SC was supported by the CHU-research program and by CNRS., Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ) -Proclaim, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ) -Service de génétique clinique [Rennes], Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud-CHU Pontchaillou [Rennes]-Hôpital Sud, De Villemeur, Hervé, Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Proclaim, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud-CHU Pontchaillou [Rennes]-hôpital Sud, Faculty of Health Sciences, and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
DNA Repair, MESH : DNA, MESH : RNA, Small Interfering, Mice, 0302 clinical medicine, Small interfering RNAs, MESH: Animals, MESH: HSP70 Heat-Shock Proteins, Regulation of gene expression, MESH: DNA Repair, 0303 health sciences, MESH : Cell Survival, MESH : Gene Expression Regulation, MESH: Genomic Instability, MESH: Mitochondrial Proteins, Cell biology, MESH: DNA Repair Enzymes, MESH: Cell Survival, 030220 oncology & carcinogenesis, Medicine, MESH : DNA-Binding Proteins, MESH : Carrier Proteins, DNA damage, MESH: Carrier Proteins, Genomic Instability, 03 medical and health sciences, Transcription factors, Genetics, Humans, Biology, Molecular Biology, Ecology, Evolution, Behavior and Systematics, MESH : Mitochondrial Proteins, MESH: DNA Damage, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Humans, MESH : HSP70 Heat-Shock Proteins, DNA, DNA Repair Enzymes, chemistry, MESH : Biopsy, Gene expression, Carrier Proteins, [ SDV.MHEP.DERM ] Life Sciences [q-bio]/Human health and pathology/Dermatology, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Keratinocytes, Genome instability, Cancer Research, Biopsy, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Mice, Knockout, chemistry.chemical_compound, MESH: Biopsy, MESH : DNA Repair, Molecular Cell Biology, MESH: RNA, Small Interfering, RNA, Small Interfering, MESH : DNA Damage, Genetics (clinical), Mice, Knockout, MESH : Keratinocytes, MESH: DNA, MESH: Upstream Stimulatory Factors, MESH: Gene Expression Regulation, MESH: Keratinocytes, DNA-Binding Proteins, MESH : DNA Repair Enzymes, Research Article, lcsh:QH426-470, Cell Survival, Ultraviolet Rays, DNA repair, Dermatology, Mitochondrial Proteins, MESH : Mice, Immunoprecipitation, Animals, HSP70 Heat-Shock Proteins, Gene, Transcription factor, MESH: Mice, 030304 developmental biology, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, MESH : Upstream Stimulatory Factors, Gene regulation, lcsh:Genetics, Gene Expression Regulation, MESH : Ultraviolet Rays, Upstream Stimulatory Factors, MESH : Mice, Knockout, MESH: Ultraviolet Rays, MESH : Animals, MESH : Genomic Instability, MESH: DNA-Binding Proteins, DNA Damage, Nucleotide excision repair
Abstract

An important function of all organisms is to ensure that their genetic material remains intact and unaltered through generations. This is an extremely challenging task since the cell's DNA is constantly under assault by endogenous and environmental agents. To protect against this, cells have evolved effective mechanisms to recognize DNA damage, signal its presence, and mediate its repair. While these responses are expected to be highly regulated because they are critical to avoid human diseases, very little is known about the regulation of the expression of genes involved in mediating their effects. The Nucleotide Excision Repair (NER) is the major DNA–repair process involved in the recognition and removal of UV-mediated DNA damage. Here we use a combination of in vitro and in vivo assays with an intermittent UV-irradiation protocol to investigate the regulation of key players in the DNA–damage recognition step of NER sub-pathways (TCR and GGR). We show an up-regulation in gene expression of CSA and HR23A, which are involved in TCR and GGR, respectively. Importantly, we show that this occurs through a p53 independent mechanism and that it is coordinated by the stress-responsive transcription factor USF-1. Furthermore, using a mouse model we show that the loss of USF-1 compromises DNA repair, which suggests that USF-1 plays an important role in maintaining genomic stability., Author Summary UV is responsible for DNA damage and genetic alterations of key players of the Nucleotide Excision Repair (NER) machinery promote the development of UV-induced skin cancers. The NER is the major DNA–repair process involved in the recognition and removal of UV-mediated DNA damage. Different factors participating in this DNA repair are essential, and their mutations are associated with severe genetic diseases such as Cockayne Syndrome and Xeroderma Pigmentosum. Here, we show for the first time that the specific regulation of expression in response to UV of two NER factors CSA and HR23A is required to efficiently remove DNA lesions and to maintain genomic stability. We also implicate the USF-1 transcription factor in the regulation of the expression of these factors using in vitro and in vivo models. This finding is particularly important because UV is the major cause of skin cancers and dramatically compromises patients with highly sensitive genetic diseases.

Published
2012

6. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome

Author

Valérie, Bonadona, Bernard, Bonaïti, Sylviane, Olschwang, Sophie, Grandjouan, Laetitia, Huiart, Michel, Longy, Rosine, Guimbaud, Bruno, Buecher, Yves-Jean, Bignon, Olivier, Caron, Chrystelle, Colas, Catherine, Noguès, Sophie, Lejeune-Dumoulin, Laurence, Olivier-Faivre, Florence, Polycarpe-Osaer, Tan Dat, Nguyen, Françoise, Desseigne, Jean-Christophe, Saurin, Pascaline, Berthet, Dominique, Leroux, Jacqueline, Duffour, Sylvie, Manouvrier, Thierry, Frébourg, Hagay, Sobol, Christine, Lasset, Catherine, Bonaïti-Pellié, Qing, Wang, Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Troubles du comportement alimentaire de l'adolescent ( UMR_S 669 ), Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université ( AMU ), CHU Cochin [AP-HP], Service d'Oncologie Génétique, de Prévention et Dépistage, Département de pathologie, Institut Bergonié - CRLCC Bordeaux, Département d'oncologie médicale, Institut Claudius Regaud, Service de Génétique Oncologique, INSTITUT CURIE, Département d'Oncogénétique, Institut National de la Recherche Agronomique ( INRA ) -Réseau National Alimentation Cancer Recherche (réseau NACRe)-Centre Jean Perrin (CJP-EA 4233), Génétique oncologique ( GO - UMR 8125 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Santé Publique, INSTITUT CURIE-Hôpital René HUGUENIN (Saint-Cloud), Génétique épidémiologique et structures des populations humaines ( Inserm U535 ), Epidémiologie, sciences sociales, santé publique ( IFR 69 ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ), Consultation d'Oncogénétique, Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ), Service d'onco-hématologie et génétique, CHU Grenoble, Service de Génétique Clinique et Université Lille 2, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud )

Subjects
Male, MESH : Germ-Line Mutation, MESH : Aged, MESH : Genotype, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Colorectal Neoplasms, Hereditary Nonpolyposis, MESH : Female, MESH : Risk Assessment, MESH : Adaptor Proteins, Signal Transducing, Aged, 80 and over, Ovarian Neoplasms, Incidence, Age Factors, Nuclear Proteins, Middle Aged, MESH : Adult, MESH : Incidence, DNA-Binding Proteins, MutS Homolog 2 Protein, Female, France, MESH : Colorectal Neoplasms, MESH : DNA-Binding Proteins, Colorectal Neoplasms, MutL Protein Homolog 1, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Genotype, MESH : Male, MESH : Young Adult, Risk Assessment, Young Adult, Humans, Genetic Predisposition to Disease, MESH : Middle Aged, MESH : MutS Homolog 2 Protein, MESH : France, MESH : Aged, 80 and over, neoplasms, Germ-Line Mutation, Adaptor Proteins, Signal Transducing, Aged, MESH : Ovarian Neoplasms, MESH : Humans, nutritional and metabolic diseases, MESH : Nuclear Proteins, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Endometrial Neoplasms, MESH : Endometrial Neoplasms, MESH : Genetic Predisposition to Disease, MESH : Age Factors
Abstract

International audience; CONTEXT: Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. OBJECTIVE: To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. DESIGN, SETTING, AND PARTICIPANTS: Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed. MAIN OUTCOME MEASURE: Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias. RESULTS: Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations. CONCLUSIONS: MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.

Published
2011

7. Trade-off between bile resistance and nutritional competence drives Escherichia coli diversification in the mouse gut

Author

Nadine Cerf-Bensussan, Dominique Rainteau, François Taddei, Sabine Rakotobe, Marianne De Paepe, Valérie Gaboriau-Routhiau, Interactions de l'épithelium intestinal et du système immunitaire (UMR_S 793), Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Inflammation intestinale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Robustesse et évolvabilité de la vie (U1001), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), MDP was supported by the Fondation pour la Recherche Médicale (http://www.frm.org/)., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Recherche Agronomique (INRA), Interactions de l'épithelium intestinal et du système immunitaire ( UMR_S 793 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Recherche Agronomique ( INRA ), MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Robustesse et évolvabilité de la vie ( U1001 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), and Autard, Delphine

Subjects
Operon, Mutant, Genetic Fitness, MESH: Escherichia coli Proteins, Mice, MESH : Selection, Genetic, MESH: Animals, 0303 health sciences, MESH : Trans-Activators, MESH: Escherichia coli, Escherichia coli Proteins, Microbiology and Parasitology, Bacterial, SDV:GEN, MESH: Transcription Factors, MESH : Multienzyme Complexes, Microbiologie et Parasitologie, MESH : Phenotype, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Animals, Bacterial Outer Membrane Proteins, Bile Acids and Salts, Biodiversity, DNA-Binding Proteins, Escherichia coli, Flagella, Gastrointestinal Tract, Gene Expression Regulation, Immunity, Innate, Multienzyme Complexes, Mutation, Nutritional Physiological Phenomena, Phenotype, Selection, Genetic, Trans-Activators, Transcription Factors, MESH : DNA-Binding Proteins, MESH : Gene Expression Regulation, Bacterial, MESH: Phenotype, Microbiology, MESH: Flagella, MESH: Biodiversity, 03 medical and health sciences, Genetics, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Biology, Biology, Ecology, Evolution, Behavior and Systematics, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Genetic Fitness, 030306 microbiology, MESH: Bacterial Outer Membrane Proteins, Immunity, Innate, Colonisation, Regulon, MESH : Nutritional Physiological Phenomena, MESH: Gastrointestinal Tract, MESH : Gastrointestinal Tract, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Cancer Research, MESH : Escherichia coli, MESH : Transcription Factors, MESH: Selection, Genetic, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gut flora, medicine.disease_cause, MESH: Multienzyme Complexes, MESH: Genetic Fitness, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, MESH : Biodiversity, Genetics (clinical), 2. Zero hunger, Experimental evolution, MESH: Gene Expression Regulation, Bacterial, biology, MESH : Escherichia coli Proteins, MESH : Immunity, Innate, MESH: Immunity, Innate, MESH : Mutation, Research Article, MESH: Mutation, lcsh:QH426-470, MESH: Trans-Activators, MESH: Bile Acids and Salts, Model Organisms, MESH : Mice, medicine, Selection, Genetic, MESH: Nutritional Physiological Phenomena, MESH : Bacterial Outer Membrane Proteins, MESH: Mice, 030304 developmental biology, Evolutionary Biology, Gene Expression Regulation, Bacterial, biology.organism_classification, MESH : Bile Acids and Salts, lcsh:Genetics, bacteria, MESH : Animals, MESH : Flagella, MESH: DNA-Binding Proteins
Abstract

Bacterial diversification is often observed, but underlying mechanisms are difficult to disentangle and remain generally unknown. Moreover, controlled diversification experiments in ecologically relevant environments are lacking. We studied bacterial diversification in the mammalian gut, one of the most complex bacterial environments, where usually hundreds of species and thousands of bacterial strains stably coexist. Herein we show rapid genetic diversification of an Escherichia coli strain upon colonisation of previously germ-free mice. In addition to the previously described mutations in the EnvZ/OmpR operon, we describe the rapid and systematic selection of mutations in the flagellar flhDC operon and in malT, the transcriptional activator of the maltose regulon. Moreover, within each mouse, the three mutant types coexisted at different levels after one month of colonisation. By combining in vivo studies and determination of the fitness advantages of the selected mutations in controlled in vitro experiments, we provide evidence that the selective forces that drive E. coli diversification in the mouse gut are the presence of bile salts and competition for nutrients. Altogether our results indicate that a trade-off between stress resistance and nutritional competence generates sympatric diversification of the gut microbiota. These results illustrate how experimental evolution in natural environments enables identification of both the selective pressures that organisms face in their natural environment and the diversification mechanisms., Author Summary The mechanisms generating the huge biodiversity on earth are not entirely understood. Bacterial populations are powerful models to explore the mechanisms of evolution, owing to their big population size, rapid growth, and high mutation rate. One of the more complex bacterial community is the mammalian gut microbiota, and Escherichia coli is one of the first colonizers of the newborn intestine. Herein we studied diversification of an Escherichia coli strain in germ-free mice, a simplified though ecologically relevant system. We show rapid genetic diversification upon colonization, characterized by the systematic selection of mutations in three different pathways: in the global regulator EnvZ/OmpR controlling outer membrane permeability, in the flagellar operon, and in the maltose regulon. By combining in vivo and in vitro experiments, we show that the selective forces that drive E. coli diversification are the presence of bile salts and the competition for nutrients. Altogether our results indicate that a trade-off between stress resistance and nutritional competence is sufficient to mediate diversification of bacteria. These results illustrate how experimental evolution in natural environments allows the identification of the selective pressures that organisms face in their natural environment, as well as the diversification mechanisms.

Published
2011

8. Interactions of amphipathic CPPs with model membranes

Author

Deshayes , Sébastien, Konate , Karidia, Aldrian , Gudrun, Heitz , Frédéric, Divita , Gilles, Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en Biologie Cellulaire (CRBM), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)

Subjects
MESH : Molecular Sequence Data, MESH: Unilamellar Liposomes, Cell-Penetrating Peptides, MESH: Amino Acid Sequence, MESH : Hydrophobic and Hydrophilic Interactions, MESH: Circular Dichroism, MESH : Spectroscopy, Fourier Transform Infrared, MESH : Cell-Penetrating Peptides, Spectroscopy, Fourier Transform Infrared, Phospholipids, MESH: Cell-Penetrating Peptides, MESH: Peptides, MESH : Peptides, Air, Circular Dichroism, MESH : Amino Acid Sequence, MESH: Hydrophobic and Hydrophilic Interactions, MESH : Protein Binding, DNA-Binding Proteins, MESH : Water, MESH : Air, MESH : DNA-Binding Proteins, Hydrophobic and Hydrophilic Interactions, Protein Binding, Cysteamine, MESH : Cell Membrane, Molecular Sequence Data, Biophysics, MESH: Spectroscopy, Fourier Transform Infrared, MESH : Phospholipids, MESH: Water, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Unilamellar Liposomes, MESH: Biophysics, MESH: Phospholipids, MESH: Cysteamine, MESH: Molecular Sequence Data, Cell Membrane, Water, MESH : Unilamellar Liposomes, MESH : Biophysics, MESH : Circular Dichroism, MESH: Air, MESH : Cysteamine, Peptides, MESH: DNA-Binding Proteins, MESH: Cell Membrane
Abstract

International audience; Due to the poor permeability of the plasma membrane, several strategies are designed to enhance the transfer of therapeutics into cells. Over the last 20 years, small peptides called Cell-Penetrating Peptides (CPPs) have been widely developed to improve the cellular delivery of biomolecules. These small peptides derive from protein transduction domains, chimerical constructs, or model sequences. Several CPPs are primary or secondary amphipathic peptides, depending on whether the distribution of their hydrophobic and hydrophilic domains occurs from their amino-acid sequence or through α-helical folding. Most of the CPPs are able to deliver different therapeutics such as nucleic acids or proteins in vitro and in vivo. Although their mechanisms of internalization are varied and controversial, the understanding of the intrinsic features of CPPs is essential for future developments. This chapter describes several protocols for the investigation of biophysical properties of amphipathic CPPs. Surface physics approaches are specifically applied to characterize the interactions of amphipathic peptides with model membranes. Circular dichroism and infra-red spectroscopy allow the identification of their structural state. These methods are exemplified by the analyses of the main biophysical features of the cell-penetrating peptides MPG, Pep-1, and CADY.

Published
2011

9. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1

Author

Marie-Christine Alessi, Mark Lathrop, Simon Heath, Diana Zelenika, Jessy Brocheton, Jean-François Schved, Marine Germain, Pilar Galan, Ewa Ninio, Stefan Blankenberg, Thomas Münzel, Joseph Emmerich, Irene D. Bezemer, Christine Biron-Andreani, François Cambien, Aurélien Delluc, Noémie Saut, Tanja Zeller, David-Alexandre Trégouët, Ludovic Drouet, Frits R. Rosendaal, Laurence Tiret, Pierre-Emmanuel Morange, Viviane Nicaud, Hervé Durand, Stefan-Martin Brand-Herrmann, Gwenaelle Burgos, Lance A. Bare, Gilles Pernod, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Techniques pour l'Evaluation et la Modélisation des Actions de la Santé (TIMC-IMAG-ThEMAS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Service de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR6, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Department of Medicine II, Johannes Gutenberg - Universität Mainz (JGU), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Department of General and Interventional Cardiology, University Heart Center Hamburg, Risque Thrombotique et Mecanismes de l'Hemostase (U765), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Risque Thrombotique et Mécanismes de l'Hémostase (U765), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -CHU Saint-Eloi, ThEMAS, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-IFR6, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Département de Médecine Interne et Pneumologie [Brest] ( DMIP - Brest ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Johannes Gutenberg-University Mainz, Hôpital de la Timone [CHU - APHM] ( TIMONE ), Institut de Génomique d'Evry ( IG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Risque Thrombotique et Mecanismes de l'Hemostase ( U765 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-IFR6, Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
MESH : Transcription Factors, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, MESH : Chromosomes, Human, Pair 6, 0302 clinical medicine, Genetics(clinical), Genetics (clinical), Genetics, Venous Thrombosis, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, MESH: Follow-Up Studies, MESH: Transcription Factors, MESH : Venous Thrombosis, MESH: Case-Control Studies, DNA-Binding Proteins, Chromosomes, Human, Pair 6, MESH : DNA-Binding Proteins, Erratum, MESH : Genome-Wide Association Study, MESH : Case-Control Studies, MESH: Chromosomes, Human, Pair 6, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Genetic determinism, 03 medical and health sciences, Report, Genetic predisposition, Humans, Genetic Predisposition to Disease, Allele, Gene, 030304 developmental biology, MESH: Humans, [ SDV ] Life Sciences [q-bio], MESH : Humans, linking inflammation protein atherothrombosis sequence risk, Case-control study, Chromosome, MESH : Follow-Up Studies, Case-Control Studies, MESH: Genome-Wide Association Study, MESH: Venous Thrombosis, MESH : Genetic Predisposition to Disease, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Follow-Up Studies, Genome-Wide Association Study, Transcription Factors
Abstract

International audience; To identify genetic susceptibility factors conferring increased risk of venous thrombosis (VT), we conducted a multistage study, following results of a previously published GWAS that failed to detect loci for developing VT. Using a collection of 5862 cases with VT and 7112 healthy controls, we identified the HIVEP1 locus on chromosome 6p24.1 as a susceptibility locus for VT. Indeed, the HIVEP1 rs169713C allele was associated with an increased risk for VT, with an odds ratio of 1.20 (95% confidence interval 1.13-1.27, p = 2.86 x 10(-9)). HIVEP1 codes for a protein that participates in the transcriptional regulation of inflammatory target genes by binding specific DNA sequences in their promoter and enhancer regions. The current results provide the identification of a locus involved in VT susceptibility that lies outside the traditional coagulation/fibrinolysis pathway.

Published
2010

10. Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression

Author

Markus Aly, Stéphane Richard, Jeffrey P. MacKeigan, Viorel Vasiliu, Arnaud Mejean, Jeff Klomp, Magnus Nordenskjöld, Natalie M. Niemi, Yves Denoux, Peter Zickert, Sophie Giraud, Bin Tean Teh, Kyle A. Furge, Karl Dykema, David Petillo, Ximing J. Yang, Jindong Chen, Annika Sääf, Sophie Gad, L. Yonneau, Ulf S.R. Bergerheim, BMC, Ed., Laboratory of Computational Biology, Van Andel Institute [Grand Rapids], Laboratory of Cancer Genetics, Laboratory of Systems Biology, Division of Surgical Pathology, Northwestern University Feinberg School of Medicine, Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet [Stockholm], Department of Pathology, Karolinska University Hospital [Stockholm], Danderyds sjukhus = Danderyd University Hospital, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique, Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Références Cancers Rares (PREDIR), INCA, Service d'urologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Urologie, Hôpital Foch [Suresnes], NCCS-VARI Translational Research Laboratory, National Cancer Centre of Singapore, This work was supported by the French NCI (Institut National du Cancer, PNES rein) and the Ligue Nationale contre le Cancer (Comités du Cher et de l'Indre)., Division of Urology, Department of Surgery, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Sud - Paris 11 (UP11) - Institut Gustave Roussy (IGR) - Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL) - Hôpital Edouard Herriot [CHU - HCL], Université Paris-Sud - Paris 11 (UP11) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bicêtre, CHU Necker - Enfants Malades [AP-HP] - Assistance publique - Hôpitaux de Paris (AP-HP), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
MESH: Signal Transduction, MESH : Transcription Factors, Chromophobe Renal Cell Carcinoma, MESH: Heat-Shock Proteins, urologic and male genital diseases, Oxidative Phosphorylation, Birt-Hogg-Dube Syndrome, MESH : Carcinoma, Renal Cell, 0302 clinical medicine, Renal cell carcinoma, MESH: Up-Regulation, Adenoma, Oxyphilic, Genetics(clinical), Renal oncocytoma, MESH : Up-Regulation, Genetics (clinical), Heat-Shock Proteins, MESH: Estrone, 0303 health sciences, MESH : Genes, Mitochondrial, MESH: Mitochondrial Proteins, MESH: Transcription Factors, MESH: Carcinoma, Renal Cell, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Kidney Neoplasms, 3. Good health, Up-Regulation, DNA-Binding Proteins, Genes, Mitochondrial, MESH: Birt-Hogg-Dube Syndrome, 030220 oncology & carcinogenesis, MESH : Oxidative Phosphorylation, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH : DNA-Binding Proteins, Research Article, Signal Transduction, lcsh:Internal medicine, lcsh:QH426-470, Adenoma, MESH: Adenoma, Oxyphilic, Biology, MESH: Genes, Mitochondrial, Mitochondrial Proteins, 03 medical and health sciences, Germline mutation, MESH: Oxidative Phosphorylation, Proto-Oncogene Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH : Adenoma, Oxyphilic, Carcinoma, medicine, Genetics, Humans, Folliculin, lcsh:RC31-1245, Carcinoma, Renal Cell, MESH : Mitochondrial Proteins, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, Tumor Suppressor Proteins, MESH : Humans, MESH : Heat-Shock Proteins, medicine.disease, Human genetics, MESH : Kidney Neoplasms, lcsh:Genetics, MESH : Estrone, MESH : Birt-Hogg-Dube Syndrome, Cancer research, MESH: Kidney Neoplasms, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

Background Germline mutations in the folliculin (FLCN) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack FLCN mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied. Methods BHDS individuals were identified symptomatically and FLCN mutations were confirmed by DNA sequencing. Comparative gene expression profiling analyses were carried out on renal tumors isolated from individuals afflicted with BHDS and a panel of sporadic renal tumors of different subtypes using discriminate and clustering approaches. qRT-PCR was used to confirm selected results of the gene expression analyses. We further analyzed differentially expressed genes using gene set enrichment analysis and pathway analysis approaches. Pathway analysis results were confirmed by generation of independent pathway signatures and application to additional datasets. Results Renal tumors isolated from individuals with BHDS showed distinct gene expression and cytogenetic characteristics from sporadic renal oncocytoma and chromophobe RCC. The most prominent molecular feature of BHDS-derived kidney tumors was high expression of mitochondria-and oxidative phosphorylation (OXPHOS)-associated genes. This mitochondria expression phenotype was associated with deregulation of the PGC-1α-TFAM signaling axis. Loss of FLCN expression across various tumor types is also associated with increased nuclear mitochondrial gene expression. Conclusions Our results support a genetic distinction between BHDS-associated tumors and other renal neoplasias. In addition, deregulation of the PGC-1α-TFAM signaling axis is most pronounced in renal tumors that harbor FLCN mutations and in tumors from other organs that have relatively low expression of FLCN. These results are consistent with the recently discovered interaction between FLCN and AMPK and support a model in which FLCN is a regulator of mitochondrial function.

Published
2010

11. The expression of 16 genes related to the cell of origin and immune response predicts survival in elderly patients with diffuse large B-cell lymphoma treated with CHOP and rituximab

Author

Pierre Feugier, Eric Labouyrie, Hervé Tilly, Felix Reyes, A. de Reyniès, David S. Rickman, Françoise Berger, Corinne Haioun, Gilles Salles, Karen Leroy, Christian Gisselbrecht, Thierry Jo Molina, Christian Bastard, Bertrand Coiffier, J-P Jais, Josette Brière, P. Gaulard, Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Département de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 ( UPD5 ), Programme CIT, Ligue Nationale Contre le Cancer, Service d'Anatomo-Pathologie, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Hospices Civils de Lyon ( HCL ), Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'anatomo-pathologie [Paris], Institut Mondor de recherche biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Département de pathologie [Mondor], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service d'Anatomie et Cytologie Pathologiques, Service d'Hématologie, CRLCC Henri Becquerel, Service de génétique oncologique, Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Guellaen, Georges, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Ligue Nationale Contre le Cancer (LNCC), Hospices Civils de Lyon (HCL), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]

Subjects
Oncology, Male, Cellular immunity, MESH: Cytoskeletal Proteins, MESH : Antineoplastic Combined Chemotherapy Protocols, MESH: Metalloproteins, MESH : Aged, MESH: Antibodies, Monoclonal, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, 80 and over, MESH : Cytidine Deaminase, Aged, 80 and over, 0303 health sciences, Hematology, MESH: Middle Aged, MESH : Reverse Transcriptase Polymerase Chain Reaction, Antibodies, Monoclonal, LIM Domain Proteins, Diffuse, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Vincristine, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, Rituximab, MESH : DNA-Binding Proteins, MESH : Vincristine, medicine.medical_specialty, Article, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Doxorubicin, MESH: Forkhead Transcription Factors, Large B-Cell, Humans, MESH : Middle Aged, MESH : Aged, 80 and over, Cyclophosphamide, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Aged, MESH: Humans, MESH : Gene Expression Profiling, MESH : Humans, MESH: Cyclophosphamide, MESH : Prednisone, MESH : Cytoskeletal Proteins, medicine.disease, Lymphoma, Cytoskeletal Proteins, rab GTP-Binding Proteins, Immunology, Diffuse large B-cell lymphoma, MESH: Female, MESH: Prednisone, Cancer Research, MESH : rab GTP-Binding Proteins, APOBEC-3G Deaminase, CHOP, MESH : Lymphoma, Large B-Cell, Diffuse, Antibodies, Monoclonal, Murine-Derived, International Prognostic Index, MESH: Aged, 80 and over, MESH : Metalloproteins, immune system diseases, MESH: Reverse Transcriptase Polymerase Chain Reaction, hemic and lymphatic diseases, Monoclonal, MESH : Female, MESH : Cyclophosphamide, MESH: Aged, Reverse Transcriptase Polymerase Chain Reaction, Forkhead Transcription Factors, Middle Aged, DNA-Binding Proteins, MESH : Forkhead Transcription Factors, MESH : Antibodies, Monoclonal, Female, Lymphoma, Large B-Cell, Diffuse, MESH : Repressor Proteins, medicine.drug, MESH : Male, MESH: Vincristine, Biology, Antibodies, MESH: Multivariate Analysis, Proto-Oncogene Proteins, Internal medicine, Cytidine Deaminase, Metalloproteins, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Doxorubicin, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Cytidine Deaminase, Gene Expression Profiling, MESH : Multivariate Analysis, MESH: Male, Repressor Proteins, MESH: rab GTP-Binding Proteins, Doxorubicin, Multivariate Analysis, Prednisone, MESH: Lymphoma, Large B-Cell, Diffuse, MESH: DNA-Binding Proteins
Abstract

International audience; Gene expression profiles have been associated with clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-containing chemotherapy. Using Affymetrix HU133A microarrays, we analyzed the lymphoma transcriptional profile of 30 patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and 23 patients treated with rituximab (R)-CHOP in the Groupe d'Etude des Lymphomes de l'Adulte clinical centers. We used this data set to select transcripts showing an association with progression-free survival in all patients or showing a differential effect in the two treatment groups. We performed real-time quantitative reverse transcription-PCR in the 23 R-CHOP samples of the screening set and an additional 44 R-CHOP samples set to evaluate the prognostic significance of these transcripts. In these 67 patients, the level of expression of 16 genes and the cell-of-origin classification were significantly associated with overall survival, independently of the International Prognostic Index. A multivariate model comprising four genes of the cell-of-origin signature (LMO2, MME, LPP and FOXP1) and two genes related to immune response, identified for their differential effects in R-CHOP patients (APOBEC3G and RAB33A), demonstrated a high predictive efficiency in this set of patients, suggesting that both features affect outcome in DLBCL patients receiving immunochemotherapy.

Published
2008

12. Distinct effects of DNA-PKcs and Artemis inactivation on signal joint formation in vivo

Author

Evelyne Jouvin-Marche, Cédric Touvrey, Serge M. Candéias, Chrystelle Couedel, Jean-Pierre de Villartay, Maria Jasin, Pauline Soulas, Rachel Couderc, Patrice N. Marche, Contrôle moléculaire de la réponse immune specifique, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Biology Program, Memorial Sloane Kettering Cancer Center [New York], Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Memorial Sloan Kettering Cancer Center, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Lésions des Acides Nucléiques ( LAN ), Service de Chimie Inorganique et Biologique ( SCIB - UMR E3 ), Institut Nanosciences et Cryogénie ( INAC ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Grenoble Alpes ( UGA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut Nanosciences et Cryogénie ( INAC ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Grenoble Alpes ( UGA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ), Candéias, Serge, Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
Protein kinase complex, MESH : Molecular Sequence Data, MESH : DNA, MESH : Lymphocytes, DNA-Activated Protein Kinase, Mice, SCID, MESH: Base Sequence, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Artemis, Mice, 0302 clinical medicine, MESH: Endonucleases, MESH : Antigens, Nuclear, MESH : Endonucleases, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, Lymphocytes, MESH: Mice, SCID, MESH : DNA-Activated Protein Kinase, DNA-PKcs, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, V(D)J recombination, MESH: DNA, Nuclear Proteins, Antigens, Nuclear, T cell receptor genes, Junctional diversity, DNA-Binding Proteins, Non-homologous end joining, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA-Binding Proteins, MESH: Enzyme Activation, [SDV.IMM] Life Sciences [q-bio]/Immunology, Molecular Sequence Data, Immunology, MESH : Mice, Inbred C57BL, 03 medical and health sciences, MESH: Mice, Inbred C57BL, signal joints, MESH : Mice, Animals, Protein kinase A, MESH: Antigens, Nuclear, MESH: Mice, Ku Autoantigen, Molecular Biology, 030304 developmental biology, Nuclease, MESH: Molecular Sequence Data, Base Sequence, MESH : Nuclear Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DNA, Endonucleases, Molecular biology, MESH : Mice, SCID, Enzyme Activation, Mice, Inbred C57BL, MESH: DNA-Activated Protein Kinase, biology.protein, MESH: Lymphocytes, MESH : Base Sequence, MESH : Animals, Homologous recombination, MESH : Enzyme Activation, MESH: Nuclear Proteins, MESH: DNA-Binding Proteins, 030217 neurology & neurosurgery
Abstract

International audience; The assembly of functional immune receptor genes via V(D)J recombination in developing lymphocytes generates DNA double-stranded breaks intermediates that are repaired by non-homologous end joining (NHEJ). This repair pathway requires the sequential recruitment and activation onto coding and signal DNA ends of several proteins, including the DNA-dependent protein kinase and the nuclease Artemis. Artemis activity, triggered by the DNA-dependent protein kinase, is necessary to process the genes hairpin-sealed coding ends but appears dispensable for the ligation of the reciprocal phosphorylated, blunt-ended signal ends into a signal joint. The DNA-dependent protein kinase is however present on signal ends and could potentially recruit and activate Artemis during signal joint formation. To determine whether Artemis plays a role during the resolution of signal ends during V(D)J recombination, we analyzed the structure of signal joints generated in developing thymocytes during the rearrangement of T cell receptor genes in wild type mice and mice mutated for NHEJ factors. These joints exhibit junctional diversity resulting from N nucleotide polymerization by the terminal nucleotidyl transferase and nucleotide loss from one or both of the signal ends before they are ligated. Our results show that Artemis participates in the repair of signal ends in vivo. Furthermore, our results also show that while the DNA-dependent protein kinase complex protects signal ends from processing, including deletions, Artemis seems on the opposite to promote their accessibility to modifying enzymes. In addition, these data suggest that Artemis might be the nuclease responsible for nucleotide loss from signal ends during the repair process.

Published
2008

13. The Hsp90 chaperone controls the biogenesis of L7Ae RNPs through conserved machinery

Author

Nathalie Marmier-Gourrier, Tamás Kiss, Edouard Bertrand, Beáta E. Jády, Bruno Charpentier, Christina Pescia, Séverine Boulon, Céline Verheggen, Bérengère Pradet-Balade, Alain Krol, Benjamin Rothé, Barbara Bardoni, Laurence Wurth, Christine Allmang, Christiane Branlant, Marie-Cécile Robert, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Maturation des ARN et enzymologie moléculaire (MAEM), Cancéropôle du Grand Est-Université Henri Poincaré - Nancy 1 (UHP)-IFR111-Centre National de la Recherche Scientifique (CNRS), Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie moléculaire eucaryote (LBME), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Maturation des ARN et enzymologie moléculaire ( MAEM ), Cancéropôle du Grand Est-Université Henri Poincaré - Nancy 1 ( UHP ) -IFR111-Centre National de la Recherche Scientifique ( CNRS ), Architecture et réactivité de l'ARN ( ARN ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de biologie moléculaire eucaryote du CNRS ( LBME ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3)

Subjects
MESH: Signal Transduction, Protein Folding, MESH : Saccharomyces cerevisiae, MESH: DNA Helicases, Cell Cycle Proteins, MESH : Cell Cycle Proteins, MESH: Saccharomyces cerevisiae Proteins, Heterogeneous-Nuclear Ribonucleoprotein L, MESH : DNA Helicases, RUVBL2, MESH : Cell Proliferation, Conserved Sequence, Research Articles, MESH: Evolution, Molecular, Ribonucleoprotein, Adenosine Triphosphatases, 0303 health sciences, MESH: Conserved Sequence, biology, 030302 biochemistry & molecular biology, Nuclear Proteins, RNA-Binding Proteins, MESH : Protein Binding, MESH : HSP90 Heat-Shock Proteins, Hsp90, MESH: Saccharomyces cerevisiae, Cell biology, DNA-Binding Proteins, MESH : Heterogeneous-Nuclear Ribonucleoprotein L, MESH : DNA-Binding Proteins, MESH: Molecular Chaperones, Protein Binding, Signal Transduction, MESH : Protein Folding, Ribosomal Proteins, Saccharomyces cerevisiae Proteins, animal structures, MESH: Protein Folding, MESH : RNA-Binding Proteins, Saccharomyces cerevisiae, Article, Evolution, Molecular, MESH : Saccharomyces cerevisiae Proteins, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH : Conserved Sequence, MESH: Cell Proliferation, MESH: Adenosine Triphosphatases, MESH: HSP90 Heat-Shock Proteins, MESH: Heterogeneous-Nuclear Ribonucleoprotein L, MESH: Protein Binding, snRNP, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, HSP90 Heat-Shock Proteins, MESH : Evolution, Molecular, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, R2TP complex, Cell Proliferation, MESH : Signal Transduction, MESH : Adenosine Triphosphatases, DNA Helicases, MESH : Molecular Chaperones, RNA, MESH : Nuclear Proteins, Cell Biology, MESH: RNA-Binding Proteins, Chaperone (protein), biology.protein, MESH: Nuclear Proteins, Biogenesis, MESH: DNA-Binding Proteins, Molecular Chaperones, Transcription Factors
Abstract

International audience; RNA-binding proteins of the L7Ae family are at the heart of many essential ribonucleoproteins (RNPs), including box C/D and H/ACA small nucleolar RNPs, U4 small nuclear RNP, telomerase, and messenger RNPs coding for selenoproteins. In this study, we show that Nufip and its yeast homologue Rsa1 are key components of the machinery that assembles these RNPs. We observed that Rsa1 and Nufip bind several L7Ae proteins and tether them to other core proteins in the immature particles. Surprisingly, Rsa1 and Nufip also link assembling RNPs with the AAA + adenosine triphosphatases hRvb1 and hRvb2 and with the Hsp90 chaperone through two conserved adaptors, Tah1/hSpagh and Pih1. Inhibition of Hsp90 in human cells prevents the accumulation of U3, U4, and telomerase RNAs and decreases the levels of newly synthesized hNop58, hNHP2, 15.5K, and SBP2. Thus, Hsp90 may control the folding of these proteins during the formation of new RNPs. This suggests that Hsp90 functions as a master regulator of cell proliferation by allowing simultaneous control of cell signaling and cell growth.

Published
2008

14. Analysis of human papillomavirus type 16 (HPV16) DNA load and physical state for identification of HPV16-infected women with high-grade lesions or cervical carcinoma

Author

Sylvain Monnier-Benoit, Frédéric Mauny, Christiane Mougin, Jean-Luc Prétet, Didier Riethmuller, Véronique Dalstein, Elisabeth Schwarz, Jenny Briolat, Maëlle Saunier, Bernadette Kantelip, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Service d'Anatomie pathologique [CHRU Besançon], and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)

Subjects
Oncology, Pathology, Statistics as Topic, MESH : Statistics as Topic, Uterine Cervical Neoplasms, MESH: Papillomavirus Infections, Polymerase Chain Reaction, law.invention, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, chemistry.chemical_compound, 0302 clinical medicine, law, MESH : Female, MESH : DNA, Viral, MESH : Polymerase Chain Reaction, Polymerase chain reaction, MESH: Human papillomavirus 16, Cervical cancer, MESH : Papillomavirus Infections, Human papillomavirus 16, 0303 health sciences, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH : Oncogene Proteins, Viral, 3. Good health, DNA-Binding Proteins, MESH: Uterine Cervical Neoplasms, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, Female, MESH : DNA Primers, MESH : DNA-Binding Proteins, medicine.symptom, MESH : Repressor Proteins, Viral load, Microbiology (medical), MESH: DNA Primers, medicine.medical_specialty, MESH : Uterine Cervical Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Virus, Lesion, 03 medical and health sciences, Virology, Internal medicine, medicine, Humans, Gene, MESH: Statistics as Topic, DNA Primers, 030304 developmental biology, MESH: Humans, Papillomavirus Infections, MESH : Humans, MESH : Human papillomavirus 16, Cancer, MESH: Polymerase Chain Reaction, Oncogene Proteins, Viral, medicine.disease, MESH: DNA, Viral, Repressor Proteins, chemistry, DNA, Viral, MESH: Oncogene Proteins, Viral, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Female, DNA, MESH: DNA-Binding Proteins
Abstract

Integration of human papillomavirus (HPV) DNA into the host cell genome is a frequent event in cervical carcinogenesis, even though this phenomenon does not seem to be mandatory for cervical cancer development. Our objective was to describe the load and physical state of HPV type 16 (HPV16) DNA in a series of cervical samples representative of the natural history of cervical cancer. We used a combination of three real-time PCR assays targeting E6, E2, and albumin genes to calculate HPV16 load (E6 and albumin) and the E2/E6 ratio as a surrogate of integration. This method was applied to 173 HPV16-positive cervical samples. Results show that viral load increases with the lesion grade (from 102 HPV16 DNA copies per 10 3 cells in normal samples up to 56,354 copies per 10 3 cells in cancers), while E2/E6 ratio decreases (from 1 in normal samples down to 0.36 in cancers). We propose that, according to this technique, an HPV16 viral load of higher than 22,000 copies/10 3 cells or an E2/E6 ratio of lower than 0.50 allows the identification of women with prevalent high-grade lesions or worse with a high specificity. In conclusion, both viral load and E2/E6 ratio, used in combination with an appropriate cutoff value, are suitable to screen women with prevalent cervical intraepithelial neoplasia grade 2 or 3 or cancer. Therefore, these assays would be useful in addition to routine HPV testing to more accurately identify women with (pre)cancerous lesions.

Published
2008

15. The mycobacterial DNA-binding protein 1 (MDP1) from Mycobacterium bovis BCG influences various growth characteristics

Author

Fabienne Bon, Ralph Kunisch, Astrid Lewin, Daniela Baus, Michaela K. Adonopoulou, Katharina Eich, Sven Maurischat, Elisabeth Kamal, Dr Lewin, PG2, Robert Koch Insitut, Robert Koch Institut, SANOFI-AVENTIS GERMANY GmbH, TD Metabolism, SANOFI-AVENTIS GERMANY, Laboratoire Interactions Muqueuses Agents Transmissibles ( LIMA ), Université de Bourgogne ( UB ), and We wish to thank Bernd Appel (Federal Institute for Risk Assessment, Berlin, Germany) and Hubert Schäfer (Robert Koch Institute, Berlin, Germany) for general support of the project. We furthermore thank Barbara Freytag (Federal Institute for Risk Assessment, Berlin, Germany) and Beate Meister (Robert Koch Institute) for their technical support. The study was funded by the Robert Koch Institute in Berlin, Germany.

Subjects
Microbiology (medical), MESH : Cell Line, MESH : Oxygen, lcsh:QR1-502, Oligonucleotides, Virulence, Gene Expression, Biology, Microbiology, lcsh:Microbiology, law.invention, Cell Line, Mice, Plasmid, Bacterial Proteins, law, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Gene expression, MESH : Mice, MESH : Ampicillin, Animals, Humans, MESH : Bacterial Proteins, Antisense, MESH : Macrophages, MESH : Mycobacterium bovis, Mycobacterium bovis, Strain (chemistry), Macrophages, MESH : Oligonucleotides, Antisense, MESH : Humans, Oligonucleotides, Antisense, biology.organism_classification, DNA-Binding Proteins, Oxygen, MESH : Gene Expression, Cell culture, MESH : Plasmids, Recombinant DNA, MDP1, Ampicillin, MESH : Animals, MESH : DNA-Binding Proteins, Bacteria, Research Article, Plasmids
Abstract

Background Pathogenic mycobacteria such as M. tuberculosis, M. bovis or M. leprae are characterised by their extremely slow growth rate which plays an important role in mycobacterial virulence and eradication of the bacteria. Various limiting factors influence the generation time of mycobacteria, and the mycobacterial DNA-binding protein 1 (MDP1) has also been implicated in growth regulation. Our strategy to investigate the role of MDP1 in mycobacterial growth consisted in the generation and characterisation of a M. bovis BCG derivative expressing a MDP1-antisense gene. Results The expression rate of the MDP1 protein in the recombinant M. bovis BCG containing the MDP1-antisense plasmid was reduced by about 50% compared to the reference strain M. bovis BCG containing the empty vector. In comparison to this reference strain, the recombinant M. bovis BCG grew faster in broth culture and reached higher cell masses in stationary phase. Likewise its intracellular growth in mouse and human macrophages was ameliorated. Bacterial clumping in broth culture was reduced by the antisense plasmid. The antisense plasmid increased the susceptibility of the bacteria towards Ampicillin. 2-D protein gels of bacteria maintained under oxygen-poor conditions demonstrated a reduction in the number and the intensity of many protein spots in the antisense strain compared to the reference strain. Conclusion The MDP1 protein has a major impact on various growth characteristics of M. bovis BCG. It plays an important role in virulence-related traits such as aggregate formation and intracellular multiplication. Its impact on the protein expression in a low-oxygen atmosphere indicates a role in the adaptation to the hypoxic conditions present in the granuloma.

Published
2008

16. Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination

Author

Pierre Charneau, Christelle Olivier-Martin, Jean-Pierre de Villartay, Gwenaël Le Guyader, Paola Rivera-Munoz, Vincent Abramowski, Pauline Soulas-Sprauel, Cécile Goujet-Zalc, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Transgenèse et archivage d'animaux modèles (TAAM), Centre National de la Recherche Scientifique (CNRS), Virologie moléculaire et Vectorologie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Transgenèse et archivage d'animaux modèles ( TAAM ), Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
DNA Repair, medicine.disease_cause, MESH: Mice, Knockout, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH : DNA Repair, Immunology and Allergy, MESH: Animals, MESH: Lentivirus, Mice, Knockout, MESH: DNA Repair, B-Lymphocytes, 0303 health sciences, Mutation, Articles, DNA repair protein XRCC4, MESH : Mice, Transgenic, DNA-Binding Proteins, Non-homologous end joining, MESH : Lentivirus, 030220 oncology & carcinogenesis, MESH: Immunoglobulin Class Switching, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA-Binding Proteins, MESH : Mutation, MESH: Mutation, DNA repair, MESH: Mice, Transgenic, Immunology, Mice, Transgenic, chemical and pharmacologic phenomena, Biology, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Article, Immunoglobulin Class Switch Recombination, MESH : B-Lymphocytes, 03 medical and health sciences, MESH: B-Lymphocytes, MESH : Mice, medicine, Animals, MESH : Immunoglobulin Class Switching, MESH: Mice, 030304 developmental biology, Lentivirus, DNA Repair Pathway, Immunoglobulin Class Switching, Molecular biology, chemistry, Immunoglobulin class switching, MESH : Genes, Lethal, MESH : Mice, Knockout, Genes, Lethal, MESH : Animals, MESH: Genes, Lethal, DNA, MESH: DNA-Binding Proteins
Abstract

International audience; V(D)J recombination and immunoglobulin class switch recombination (CSR) are two somatic rearrangement mechanisms that proceed through the introduction of double-strand breaks (DSBs) in DNA. Although the DNA repair factor XRCC4 is essential for the resolution of DNA DSB during V(D)J recombination, its role in CSR has not been established. To bypass the embryonic lethality of XRCC4 deletion in mice, we developed a conditional XRCC4 knockout (KO) using LoxP-flanked XRCC4 cDNA lentiviral transgenesis. B lymphocyte restricted deletion of XRCC4 in these mice lead to an average two-fold reduction in CSR in vivo and in vitro. Our results connect XRCC4 and the nonhomologous end joining DNA repair pathway to CSR while reflecting the possible use of an alternative pathway in the repair of CSR DSB in the absence of XRCC4. In addition, this new conditional KO approach should be useful in studying other lethal mutations in mice.

Published
2007

17. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates

Author

Cyril Boyault, Benoit Gilquin, Yu Zhang, Carmen Garrido, Cécile Caron, Patrick Matthias, Saadi Khochbin, So Hee Kwon, Claire Vourc'h, Sabrina Fritah, Tso-Pang Yao, Souchier, Catherine, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Friedrich Miescher Institute for Biomedical Research (FMI), Novartis Research Foundation, Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology and Cancer Biology, Duke University [Durham], INSERM U823, équipe 10 (Stress et Dynamique de l'Organisation du Génome), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 6 (Epigénétique et Signalisation Cellulaire), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Friedrich Miescher Institute for Biomedical Research ( FMI ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Duke university [Durham], and Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Protein Folding, MESH : Transcription Factors, MESH: 3T3 Cells, Leupeptins, Cell Cycle Proteins, MESH: Tubulin, Protein aggregation, Histone Deacetylase 6, Mice, MESH : Cell Cycle Proteins, 0302 clinical medicine, Heat Shock Transcription Factors, MESH : Leupeptins, Tubulin, Valosin Containing Protein, MESH: Animals, Nuclear protein, HSF1, MESH: HSP70 Heat-Shock Proteins, MESH : Ubiquitin, Adenosine Triphosphatases, 0303 health sciences, MESH : Histone Deacetylases, Nuclear Proteins, MESH : Protein Binding, Acetylation, 3T3 Cells, MESH: Transcription Factors, MESH : Tubulin, MESH : HSP90 Heat-Shock Proteins, MESH : Heat-Shock Response, Hsp90, Cell biology, DNA-Binding Proteins, Aggresome, 030220 oncology & carcinogenesis, MESH : DNA-Binding Proteins, MESH: Molecular Chaperones, MESH: Acetylation, MESH : Protein Folding, MESH : 3T3 Cells, Protein Binding, Research Paper, MESH: Ubiquitin, MESH: Protein Folding, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH : Acetylation, Histone Deacetylases, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH : Mice, Genetics, MESH: Adenosine Triphosphatases, MESH: HSP90 Heat-Shock Proteins, Animals, MESH: Protein Binding, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Cell Cycle Protein, Transcription factor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, MESH : Adenosine Triphosphatases, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Ubiquitin, MESH : Molecular Chaperones, MESH : Nuclear Proteins, MESH : HSP70 Heat-Shock Proteins, MESH: Leupeptins, HDAC6, MESH: Histone Deacetylases, MESH: Heat-Shock Response, biology.protein, MESH : Animals, MESH: Nuclear Proteins, Heat-Shock Response, MESH: DNA-Binding Proteins, Molecular Chaperones, Transcription Factors, Developmental Biology
Abstract

International audience; A cellular defense mechanism counteracts the deleterious effects of misfolded protein accumulation by eliciting a stress response. The cytoplasmic deacetylase HDAC6 (histone deacetylase 6) was previously shown to be a key element in this response by coordinating the clearance of protein aggregates through aggresome formation and their autophagic degradation. Here, for the first time, we demonstrate that HDAC6 is involved in another crucial cell response to the accumulation of ubiquitinated protein aggregates, and unravel its molecular basis. Indeed, our data show that HDAC6 senses ubiquitinated cellular aggregates and consequently induces the expression of major cellular chaperones by triggering the dissociation of a repressive HDAC6/HSF1 (heat-shock factor 1)/HSP90 (heat-shock protein 90) complex and a subsequent HSF1 activation. HDAC6 therefore appears as a master regulator of the cell protective response to cytotoxic protein aggregate formation.

Published
2007

18. Partial defects in transcriptional activity of two novel DAX-1 mutations in childhood-onset adrenal hypoplasia congenita

Author

Paul Laissue, Silvia Copelli, Marc Fellous, Gabriel Barrio, César Bergadá, Sinan Karaboga, Jean Marie Wurtz, Reiner A. Veitia, Ignacio Bergadá, Enzo Lalli, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Departamento de Ciencias Biologicas, Universidad CAECE, Centro de Investigaciones Endocrinológicas (CEDIE), Hospital de Niños 'Ricardo Gutiérrez', Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur - Strasbourg I - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (UNS), and Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA) - Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Transcription, Genetic, MESH : Hela Cells, Receptors, Retinoic Acid, Endocrinology, Diabetes and Metabolism, MESH : Immunohistochemistry, DNA Mutational Analysis, Mutant, MESH : Child, Preschool, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Endocrinology, MESH: Structure-Activity Relationship, MESH : Child, MESH: Child, Adrenal Glands, MESH : Structure-Activity Relationship, MESH: Adrenal Glands, MESH: DNA Mutational Analysis, Child, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH : Infant, Transfection, Immunohistochemistry, Protein subcellular localization prediction, MESH: Infant, MESH : Receptors, Retinoic Acid, DNA-Binding Proteins, MESH: Repressor Proteins, Child, Preschool, MESH: Adrenal Insufficiency, MESH : DNA-Binding Proteins, MESH : Mutation, MESH : Repressor Proteins, MESH : Transfection, MESH : Protein Structure, Tertiary, medicine.medical_specialty, MESH: Mutation, MESH : Male, 030209 endocrinology & metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, Biology, MESH : Adrenal Glands, Structure-Activity Relationship, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, X-linked adrenal hypoplasia congenita, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epigenetics, Gene, 030304 developmental biology, MESH: Receptors, Retinoic Acid, MESH: Humans, DAX-1 Orphan Nuclear Receptor, MESH: Transcription, Genetic, MESH: Transfection, MESH : Humans, MESH: Child, Preschool, Infant, MESH : Transcription, Genetic, MESH: Immunohistochemistry, MESH : Adrenal Insufficiency, medicine.disease, MESH: Male, Protein Structure, Tertiary, Repressor Proteins, MESH: Hela Cells, Nuclear receptor, Mutation, DAX1, MESH: DNA-Binding Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Adrenal Insufficiency, HeLa Cells
Abstract

OBJECTIVE: Mutations in DAX-1, an X-linked gene encoding an orphan nuclear receptor, have been associated with adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Here we describe two novel DAX-1 mutations, Y214X and I361T, associated with childhood-onset primary adrenal failure. We aimed at analysing their effects on protein localization, transcriptional activity and propose a structural-function relationship. DESIGN: We have directly sequenced the DAX-1 gene from PCR-amplified DNA. The effect of the mutations on protein localization was assessed by immunocytochemistry in transfected cells. The impact of mutations on transcriptional activity was determined by transfection using a StAR promoter-luciferase reporter system. RESULTS: The mutation Y214X produces a protein lacking the C-terminal half of DAX-1. The other one, I361T, affects a highly conserved amino acid within the putative ligand-binding domain. The mutant Y214X displayed a wild-type subcellular localization while I361T was partially retained in the cytoplasm. Both mutants retained subtantial transcriptional repressive activity, compared to mutants producing early onset adrenal failure. Interestingly, I361T displayed similar in vitro transcriptional repressive activity to the mutant I439S previously described in a case of late-onset AHC. This shows that molecular alterations of DAX-1 leading to similar in vitro activities may result in very different ages of onset of adrenal failure, which suggests that additional genetic and epigenetic factors are important in determining the clinical course of AHC. CONCLUSIONS: Our results help the understanding of structure-function relationships in the DAX-1 molecule, suggesting that the N-terminal domain is relatively autonomous and add credence to presumed molecular interactions within ligand binding domain of the protein.

Published
2006

19. Tsg101 and Alix interact with murine leukemia virus Gag and cooperate with Nedd4 ubiquitin ligases during budding

Author

Christine Chatellard-Causse, Christina Pescia, Edouard Bertrand, Rémy Sadoul, Eugenia Basyuk, Carolina Segura-Morales, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Neurodegenerescence et Plasticite, Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fraboulet, Sandrine, and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : Cell Line, MESH : Transcription Factors, Nedd4 Ubiquitin Protein Ligases, viruses, MESH : Gene Products, gag, NEDD4, MESH: Calcium-Binding Proteins, Virus Replication, Biochemistry, Mice, Ubiquitin, MESH : Calcium-Binding Proteins, Murine leukemia virus, TSG101, MESH: Animals, MESH : Ubiquitin, 0303 health sciences, biology, MESH : Rats, 030302 biochemistry & molecular biology, MESH: Leukemia Virus, Murine, MESH: Transcription Factors, MESH : Mutagenesis, Site-Directed, DNA-Binding Proteins, Leukemia Virus, Murine, MESH : Virus Replication, MESH: Mutagenesis, Site-Directed, MESH: Gene Products, gag, MESH : DNA-Binding Proteins, MESH : Transfection, MESH : Carrier Proteins, MESH : Leukemia Virus, Murine, MESH: Ubiquitin, MESH: Rats, Endosome, Ubiquitin-Protein Ligases, Gene Products, gag, MESH: Carrier Proteins, macromolecular substances, Transfection, Cell Line, 03 medical and health sciences, MESH : Mice, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Binding site, MESH: Mice, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Binding Sites, MESH: Humans, Endosomal Sorting Complexes Required for Transport, MESH: Transfection, Calcium-Binding Proteins, MESH: Virus Replication, MESH : Humans, Cell Biology, biology.organism_classification, MESH: Ubiquitin-Protein Ligases, Virology, Rats, MESH: Cell Line, MESH: Binding Sites, Viral replication, Mutagenesis, Site-Directed, biology.protein, MESH : Animals, MESH : Ubiquitin-Protein Ligases, Carrier Proteins, MESH: DNA-Binding Proteins, MESH : Binding Sites, Transcription Factors
Abstract

International audience; Retroviruses use endosomal machinery to bud out of infected cells, and various Gag proteins recruit this machinery by interacting with either of three cellular factors as follows: ubiquitin ligases of the Nedd4 family, Tsg101, or Alix/Aip1. Here we show that the murine leukemia virus Gag has the unique ability to interact with all three factors. Small interfering RNAs against Tsg101 or Alix and dominant-negative forms of Nedd4 can all reduce production of virus-like particles. However, inactivating the Nedd4-binding site abolishes budding, whereas disrupting Tsg101 or Alix binding has milder effects. Nedd4 ubiquitin ligases are therefore essential, and Tsg101 and Alix play auxiliary roles. Most interestingly, overexpression of Alix can stimulate the release of Gag, and this occurs independently of most Alix partners Tsg101, Cin85, Alg-2, and endophilins. In addition, Gag mutants that do not bind Tsg101 or Alix concentrate on late endosomes and become very sensitive to dominant-negative forms of Nedd4 that do not conjugate ubiquitin. This suggests that the direct interaction of Gag with Tsg101 and Alix favors budding from the plasma membrane and relieves a requirement for ubiquitination by Nedd4.1. Other Nedd4-dependent Gag proteins also contain binding sites for Tsg101 or Alix, suggesting that this could be a common feature of retroviruses.

Published
2005

20. Normal immune system development in mice lacking the Deltex-1 RING finger domain

Author

Pierre Ferrier, Florence Bernex, Claude-Agnès Reynaud, Christophe Verthuy, Sébastien Storck, Frédéric Delbos, Catherine Thirion-Delalande, Nicolas Stadler, Jean-Claude Weill, Génétique Moléculaire et Cellulaire (UGMC), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Développement du Systeme Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), This work was supported by grants from the Ministère de la Recherche (ACI Biologie du Développement et Physiologie Intégrative) and the Fondation Princesse Grace. S.S was supported by grants from the Ministère de l'Education Nationale de la Recherche et de la Technologie and Association pour la Recherche contre le Cancer., Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA) - Ecole Nationale Vétérinaire d'Alfort, Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Haon, Marie Laure, and École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)

Subjects
Antigens, Differentiation, T-Lymphocyte, MESH : Molecular Sequence Data, MESH: Sequence Homology, Amino Acid, MESH: Spleen, T-Lymphocytes, [SDV]Life Sciences [q-bio], MESH: Flow Cytometry, MESH: Amino Acid Sequence, medicine.disease_cause, MESH: Mice, Knockout, VOIE DE SIGNALISATION NOTCH, 0302 clinical medicine, MESH: Gene Expression Regulation, Developmental, Mammalian Genetic Models with Minimal or Complex Phenotypes, MESH: Animals, Mice, Knockout, Regulation of gene expression, B-Lymphocytes, 0303 health sciences, Mutation, biology, MESH : Amino Acid Sequence, Gene Expression Regulation, Developmental, Flow Cytometry, Antigens, T-Independent, MESH : Sequence Homology, Amino Acid, Ubiquitin ligase, DNA-Binding Proteins, RING finger domain, MESH : Antigens, T-Independent, MESH : Antigens, Differentiation, T-Lymphocyte, medicine.anatomical_structure, Deltex-4, [SDV.IMM]Life Sciences [q-bio]/Immunology, NOTCH SIGNALING PATHWAY, MESH : DNA-Binding Proteins, MESH : Mutation, Deltex-1, MESH : Spleen, Notch, MESH: Mutation, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : Flow Cytometry, Ubiquitin-Protein Ligases, Molecular Sequence Data, Notch signaling pathway, Deltex, lymphocyte development, Cell fate determination, ubiquitin ligase, MESH : B-Lymphocytes, 03 medical and health sciences, MESH: B-Lymphocytes, MESH : Mice, medicine, Ring finger, Animals, Amino Acid Sequence, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH : T-Lymphocytes, MESH: Molecular Sequence Data, Sequence Homology, Amino Acid, LIGNAGE T, Germinal center, Cell Biology, Molecular biology, MICE, MESH: T-Lymphocytes, MESH: Antigens, Differentiation, T-Lymphocyte, germinal center, T CELL LINEAGE, biology.protein, MESH: Antigens, T-Independent, MESH : Mice, Knockout, marginal zone, MESH : Animals, MESH : Gene Expression Regulation, Developmental, Spleen, MESH: DNA-Binding Proteins, 030215 immunology
Abstract

The Notch signaling pathway controls several cell fate decisions during lymphocyte development, from T-cell lineage commitment to the peripheral differentiation of B and T lymphocytes. Deltex-1 is a RING finger ubiquitin ligase which is conserved from Drosophila to humans and has been proposed to be a regulator of Notch signaling. Its pattern of lymphoid expression as well as gain-of-function experiments suggest that Deltex-1 regulates both B-cell lineage and splenic marginal-zone B-cell commitment. Deltex-1 was also found to be highly expressed in germinal-center B cells. To investigate the physiological function of Deltex-1, we generated a mouse strain lacking the Deltex-1 RING finger domain, which is essential for its ubiquitin ligase activity. Deltex-1(Delta/Delta) mice were viable and fertile. A detailed histological analysis did not reveal any defects in major organs. T- and B-cell development was normal, as were humoral responses against T-dependent and T-independent antigens. These data indicate that the Deltex-1 ubiquitin ligase activity is dispensable for mouse development and immune function. Possible compensatory mechanisms, in particular those from a fourth Deltex gene identified during the course of this study, are also discussed.

Published
2005

21. DNA-binding proteins: LC-MS to identify key domains in RNA polymerase-promoter interactions

Author

Malcolm Buckle, Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), and Buckle, Malcolm

Subjects
Time Factors, MESH : DNA, MESH : Chromatography, Liquid, F-box protein, Mass Spectrometry, MESH : Spectrophotometry, Ultraviolet, chemistry.chemical_compound, Non-histone protein, MESH: Spectrophotometry, Ultraviolet, RNA polymerase, Promoter Regions, Genetic, Chromatography, High Pressure Liquid, 0303 health sciences, biology, Chemistry, 030302 biochemistry & molecular biology, Peripheral membrane protein, MESH: DNA, DNA-Directed RNA Polymerases, DNA-Binding Proteins, MESH: Promoter Regions (Genetics), Biochemistry, Electrophoresis, Polyacrylamide Gel, MESH : DNA-Binding Proteins, MESH : Time Factors, Signal peptide, MESH : Electrophoresis, Polyacrylamide Gel, DNA-binding protein, 03 medical and health sciences, MESH : Chromatography, High Pressure Liquid, MESH : Mass Spectrometry, MESH : DNA-Directed RNA Polymerases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Chromatography, High Pressure Liquid, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 14-3-3 protein, 030304 developmental biology, MESH: Mass Spectrometry, MESH: Time Factors, DNA, MESH : Promoter Regions (Genetics), MESH: DNA-Directed RNA Polymerases, Membrane protein, biology.protein, Spectrophotometry, Ultraviolet, MESH: Chromatography, Liquid, MESH: DNA-Binding Proteins, Chromatography, Liquid, MESH: Electrophoresis, Polyacrylamide Gel
Published
2004

22. Truncation of C-mip (Tc-mip), a new proximal signaling protein, induces c-maf Th2 transcription factor and cytoskeleton reorganization

Author

Sabine Le gouvelo, Asta Valanciuté, Philippe Grimbert, Georges Guellaen, Albert Bensman, Djillali Sahali, André Pawlak, Philippe Lang, Vincent Audard, Patrick Niaudet, Régulation des gènes et signalisation cellulaire, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de néphrologie et transplantation, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de néphrologie et pédiatrie générale, CHU Trousseau [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie et pédiatrie générale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Maillochon, Franck

Subjects
[ SDV.MHEP.UN ] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Nephrotic Syndrome, MESH: Cytoskeletal Proteins, T-Lymphocytes, 030232 urology & nephrology, MESH: Base Sequence, Polymerase Chain Reaction, Jurkat cells, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Recombinant Proteins, Jurkat Cells, MESH : Cytoskeleton, 0302 clinical medicine, MESH : Child, T-Lymphocyte Subsets, MESH: Child, MESH: Jurkat Cells, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Interferon gamma, Child, MESH : Polymerase Chain Reaction, Cytoskeleton, MESH : Jurkat Cells, Sequence Deletion, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Kinase, MESH : Adult, Recombinant Proteins, DNA-Binding Proteins, Pleckstrin homology domain, medicine.anatomical_structure, lipoid nephrosis, Proto-Oncogene Proteins c-maf, MESH : Proto-Oncogene Proteins, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA Primers, MESH : DNA-Binding Proteins, MESH: Proto-Oncogene Proteins c-maf, signal transduction, medicine.drug, Proto-oncogene tyrosine-protein kinase Src, Adult, MESH: DNA Primers, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : Recombinant Proteins, T cell, MESH : Nephrotic Syndrome, Immunology, T lymphocytes, MESH : Researc, MESH : Proto-Oncogene Proteins c-maf, Biology, Transfection, Article, src Homology Domains, 03 medical and health sciences, Th2 Cells, Proto-Oncogene Proteins, medicine, MESH: Cytoskeleton, Humans, Transcription factor, Interleukin 4, Adaptor Proteins, Signal Transducing, DNA Primers, 030304 developmental biology, pleckstrin domain, MESH: Humans, Base Sequence, MESH : Humans, MESH: Researc, MESH: Adult, MESH: Polymerase Chain Reaction, MESH : Cytoskeletal Proteins, Molecular biology, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Proto-Oncogene Proteins, Cytoskeletal Proteins, MESH : Base Sequence, MESH: Nephrotic Syndrome, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

Several arguments suggest that minimal change nephrotic syndrome (MCNS) results from yet unknown systemic disorder of T cell function. By screening a cDNA library from T cell relapse, we identified a new pleckstrin homology (PH) domain-containing protein encoded by a gene located on chromosome 16q24. Two alternative transcripts were identified. The first species (c-mip) was expressed in fetal liver, kidney, and peripheral blood mononuclear cells (PBMCs), but weakly detected in PBMCs from MCNS patients. The second form (Tc-mip, standing for truncated c-maf inducing protein), corresponds to subtracted transcript and lacks the NH2-terminal PH domain. The expression of Tc-mip was restricted to fetal liver, thymus, and MCNS PBMCs where it was specifically recruited in CD4+ T cells subset. Overexpression of Tc-mip in T cell Jurkat induced c-maf, transactivated the interleukin 4 gene and down-regulated the interferon γ expression, characteristic of a Th2 commitment. Moreover, the overexpression of Tc-mip induced Src phosphorylation, T cell clustering, and a cellular redistribution of the cytoskeleton-associated L-plastin, by a PI3 kinase independent pathway. Tc-mip represents therefore the first identified protein, which links proximal signaling to c-maf induction.

Published
2003

23. The H-NS dimerization domain defines a new fold contributing to DNA recognition

Author

Vanessa Bloch, Marie Thérèse Augé, Bruno Robert, Stefan T. Arold, Yinshan Yang, Sylvie Rimsky, Emmanuel Margeat, Alain Chavanieu, Michel Kochoyan, Centre de Biochimie Structurale [Montpellier] ( CBS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Bioénergétique, Métalloprotéines et Stress ( LBMS ), Département Biochimie, Biophysique et Biologie Structurale ( B3S ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Bioénergétique Membranaire et Stress (LBMS), Département Biochimie, Biophysique et Biologie Structurale (B3S), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Protein Folding, Magnetic Resonance Spectroscopy, MESH : Molecular Sequence Data, Protein Conformation, MESH : DNA, MESH: Amino Acid Sequence, MESH: Protein Structure, Tertiary, chemistry.chemical_compound, MESH: Protein Conformation, Structural Biology, MESH : Bacterial Proteins, MESH: Peptide Fragments, MESH: Bacterial Proteins, Conserved Sequence, MESH : Protein Conformation, 0303 health sciences, MESH: Conserved Sequence, MESH : Amino Acid Sequence, MESH: DNA, DNA-Binding Proteins, Biochemistry, MESH : Dimerization, MESH : DNA-Binding Proteins, MESH : Mutation, Dimerization, MESH : Protein Structure, Tertiary, MESH: Models, Molecular, Binding domain, MESH : Protein Folding, MESH: Mutation, HMG-box, MESH : Models, Molecular, MESH: Protein Folding, Molecular Sequence Data, Fluorescence Polarization, Computational biology, Biology, DNA-binding protein, 03 medical and health sciences, Bacterial Proteins, MESH : Conserved Sequence, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, B3 domain, Molecular Biology, Gene, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Fluorescence Polarization, MESH: Molecular Sequence Data, MESH: Magnetic Resonance Spectroscopy, 030306 microbiology, Circular bacterial chromosome, MESH : Peptide Fragments, DNA, Peptide Fragments, Protein Structure, Tertiary, MESH: Dimerization, Heteronuclear molecule, chemistry, Mutation, MESH : Fluorescence Polarization, MESH : Magnetic Resonance Spectroscopy, MESH: DNA-Binding Proteins
Abstract

International audience; H-NS, a protein found in Gram-negative bacteria, is involved in structuring the bacterial chromosome and acts as a global regulator for the expression of a wide variety of genes. These functions are correlated with both its DNA-binding and oligomerization properties. We have identified the minimal dimerization domain of H-NS, a 46 amino acid-long N-terminal fragment, and determined its structure using heteronuclear NMR spectroscopy. The highly intertwined structure of the dimer, reminiscent of a handshake, defines a new structural fold, which may offer a possibility for discriminating prokaryotic from eukaryotic proteins in drug design. Using mutational analysis, we also show that this N-terminal domain actively contributes to DNA binding, conversely to the current paradigm. Together, our data allows us to propose a model for the action of full length H-NS.

Published
2003

24. Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p

Author

Philippe Froguel, Kazuo Hara, Kazuki Yasuda, Shuichi Otabe, Cécile Lecoeur, Takashi Kadowaki, Kazuyuki Tobe, Céline Populaire, Philippe Boutin, Emmanuelle Durand, Terumasa Okada, Christian Dina, Yasumichi Mori, Vincent Vatin, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé - Centre National de la Recherche Scientifique (CNRS), Science et Ingénierie des Matériaux et Procédés (SIMaP), Université Joseph Fourier - Grenoble 1 (UJF) - Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP) - Institut National Polytechnique de Grenoble (INPG) - Centre National de la Recherche Scientifique (CNRS) - Université Grenoble Alpes (UGA), Physique, Aucune, Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS), Développement artériel, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Mercator Océan, Société Civile CNRS Ifremer IRD Météo-France SHOM, Itoh laboratory, Division of Materials Physics, Osaka University [Osaka] - School of Engineering Science, Section of Genomic Medicine, Imperial College London, Genome Centre, Imperial College London - Hammersmith campus, Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université de Bordeaux (UB), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Osaka University [Osaka]-School of Engineering Science, Imperial College London-Hammersmith campus, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)

Subjects
MESH : Chromosomes, Human, Pair 20, MESH : Transcription Factors, Genetic Linkage, MESH: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Endocrinology, Diabetes and Metabolism, Chromosomes, Human, Pair 20, MESH : Japan, Type 2 diabetes, MESH: Genetic Markers, MESH : Chromosomes, Human, Pair 3, Genome, MESH : Chromosomes, Human, Pair 1, MESH : Chromosomes, Human, Pair 7, 0302 clinical medicine, Japan, MESH : Diabetes Mellitus, Type 2, MESH: Chromosomes, Human, Pair 20, MESH : Genetic Markers, Age of Onset, MESH: Japan, Genetics, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH: Nuclear Family, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, MESH: Genetic Predisposition to Disease, Chromosome Mapping, MESH: Transcription Factors, Middle Aged, MESH : Adult, MESH : Chromosomes, Human, Pair 15, 3. Good health, MESH : Age of Onset, DNA-Binding Proteins, Hepatocyte Nuclear Factor 4, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 3, MESH: Hepatocyte Nuclear Factor 4, MESH : DNA-Binding Proteins, MESH : Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Chromosomes, Human, Pair 7, MESH: Diabetes Mellitus, Type 2, Adult, Genetic Markers, MESH : Genome, Human, MESH: Chromosomes, Human, Pair 7, MESH: Chromosomes, Human, Pair 1, MESH: Age of Onset, Population, MESH: Chromosomes, Human, Pair 3, 030209 endocrinology & metabolism, Susceptibility gene, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phosphoproteins, Nuclear Family, 03 medical and health sciences, MESH : Hepatocyte Nuclear Factor 4, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, MESH : Middle Aged, education, Gene, MESH: Genome, Human, 030304 developmental biology, Linkage (software), Chromosomes, Human, Pair 15, MESH: Humans, Genome, Human, MESH : Humans, Chromosome, MESH: Adult, medicine.disease, Phosphoproteins, Sib pairs, Diabetes Mellitus, Type 2, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH : Genetic Predisposition to Disease, MESH : Nuclear Family, MESH : Phosphoproteins, MESH: Chromosome Mapping, MESH: Linkage (Genetics), MESH: DNA-Binding Proteins, MESH : Linkage (Genetics), MESH : Chromosome Mapping, Transcription Factors, MESH: Chromosomes, Human, Pair 15
Abstract

The genetic background that predisposes the Japanese population to type 2 diabetes is largely unknown. Therefore, we conducted a 10-cM genome-wide scan for type 2 diabetes traits in the 359 affected individuals from 159 families, yielding 224 affected sib-pairs of Japanese origin. Nonparametric multipoint linkage analyses performed in the whole population showed one suggestive linked region on 11p13-p12 (maximum logarithm of odds score [MLS] 3.08, near Pax6) and seven potentially linked regions (MLS >1.17) at 1p36-p32, 2q34, 3q26-q28, 6p23, 7p22-p21, 15q13-q21, and 20q12-q13 (near the gene for hepatocyte nuclear factor-4α [HNF-4α]). Subset analyses according to maximal BMI and early age at diagnosis added suggestive evidence of linkage with type 2 diabetes at 7p22-p21 (MLS 3.51), 15q13-q21 (MLS 3.91), and 20q12-q13 (MLS 2.32). These results support previous indication for linkage found on chromosome 3q, 15q, and 20q in other populations and identifies two new potential loci on 7p and 11p that may confer genetic risk for type 2 diabetes in the Japanese population.

Published
2002

25. Adenovirus-mediated overexpression of sterol regulatory element binding protein-1c mimics insulin effects on hepatic gene expression and glucose homeostasis in diabetic mice

Author

Isabelle Hainault, Dalila Azzout-Marniche, Pascal Ferré, Lydia Bertry-Coussot, Dominique Bécard, Fabienne Foufelle, Physiologie de la Nutrition et du Comportement Alimentaire ( PNCA ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Azzout-Marniche, Dalila, AgroParisTech-Institut National de la Recherche Agronomique (INRA), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)

Subjects
Male, MESH : RNA, Messenger, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH: CCAAT-Enhancer-Binding Proteins, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, Homeostasis, Insulin, Glucose homeostasis, MESH: Animals, 0303 health sciences, MESH: Mice, Inbred CBA, Glycogen, Gene Transfer Techniques, MESH: Adenoviridae, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], MESH: Transcription Factors, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Genetic Vectors, 3. Good health, MESH : DNA-Binding Proteins, MESH : Diabetes Mellitus, Experimental, Sterol Regulatory Element Binding Protein 1, medicine.medical_specialty, MESH: Gene Expression, MESH: Gene Transfer Techniques, MESH: Insulin, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Adenoviridae, MESH: Sterol Regulatory Element Binding Protein 1, 03 medical and health sciences, MESH : Sterol Regulatory Element Binding Protein 1, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], RNA, Messenger, MESH : Gene Transfer Techniques, MESH : Injections, Intraperitoneal, MESH : Glucose, Glucokinase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH : Gene Expression, Glucose, Endocrinology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], chemistry, CCAAT-Enhancer-Binding Proteins, Mice, Inbred CBA, MESH: Liver, Transcription Factors, MESH : Transcription Factors, MESH : Insulin, MESH : Mice, Inbred CBA, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Gene Expression, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, chemistry.chemical_compound, MESH: Genetic Vectors, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Diabetes Mellitus, Experimental, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Recombinant Proteins, MESH: Glucose, DNA-Binding Proteins, Liver, MESH : CCAAT-Enhancer-Binding Proteins, MESH: Homeostasis, MESH : Homeostasis, Phosphoenolpyruvate carboxykinase, MESH: Injections, Intraperitoneal, Injections, Intraperitoneal, MESH : Recombinant Proteins, MESH : Male, Genetic Vectors, 030209 endocrinology & metabolism, Biology, Diabetes Mellitus, Experimental, [ SDV.BC.IC ] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [ SDV.BBM.MN ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Diabetes mellitus, Internal medicine, MESH : Mice, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Internal Medicine, medicine, Animals, MESH : Adenoviridae, MESH: Mice, Transcription factor, MESH: RNA, Messenger, 030304 developmental biology, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH : Liver, Metabolism, MESH: Male, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, MESH : Animals, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: DNA-Binding Proteins
Abstract

International audience; In vitro, the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) mimics the positive effects of insulin on hepatic genes involved in glucose utilization, such as glucokinase (GK) and enzymes of the lipogenic pathway, suggesting that it is a key factor in the control of hepatic glucose metabolism. Decreased glucose utilization and increased glucose production by the liver play an important role in the development of the hyperglycemia in diabetic states. We thus reasoned that if SREBP-1c is indeed a mediator of hepatic insulin action, a hepatic targeted overexpression of SREBP-1c should greatly improve glucose homeostasis in diabetic mice. This was achieved by injecting streptozotocin-induced diabetic mice with a recombinant adenovirus containing the cDNA of the mature, transcriptionally active form of SREBP-1c. We show here that overexpressing SREBP-1c specifically in the liver of diabetic mice induces GK and lipogenic enzyme gene expression and represses the expression of phosphoenolpyruvate carboxykinase, a key enzyme of the gluconeogenic pathway. This in turn increases glycogen and triglyceride hepatic content and leads to a marked decrease in hyperglycemia in diabetic mice. We conclude that SREBP-1c has a major role in vivo in the long-term control of glucose homeostasis by insulin.

Published
2001

26. The stress proteome of Enterococcus faecalis

Author

J C, Giard, J M, Laplace, A, Rincé, V, Pichereau, A, Benachour, C, Leboeuf, S, Flahaut, Y, Auffray, A, Hartke, Laboratoire de Microbiologie de l’Environnement (LME), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Laboratoire des Sciences de l'Environnement Marin (LEMAR) (LEMAR), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut de Recherche pour le Développement (IRD)-Institut Universitaire Européen de la Mer (IUEM), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Université de Brest (UBO)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Microbiologie de l’Environnement ( LME ), Institut National de la Recherche Agronomique ( INRA ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Laboratoire des Sciences de l'Environnement Marin (LEMAR) ( LEMAR ), Institut de Recherche pour le Développement ( IRD ) -Institut Français de Recherche pour l'Exploitation de la Mer ( IFREMER ) -Université de Brest ( UBO ) -Institut Universitaire Européen de la Mer ( IUEM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université de Brest ( UBO ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université de Brest ( UBO ) -Centre National de la Recherche Scientifique ( CNRS ), and Institut de Recherche pour le Développement (IRD)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : Oxidative Stress, MESH : Molecular Sequence Data, Proteome, MESH: Sequence Homology, Amino Acid, MESH : Enzymes, Sequence Homology, MESH : Blotting, Western, MESH: Amino Acid Sequence, [ SDV.MP.BAC ] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH : Mercuric Chloride, MESH: Silver Staining, Cadmium Chloride, Enterococcus faecalis, MESH : Bacterial Proteins, MESH : Silver Staining, Electrophoresis, Gel, Two-Dimensional, MESH : Enterococcus faecalis, Databases, Protein, MESH: Bacterial Proteins, MESH: Cadmium Chloride, Gel, MESH: Gene Expression Regulation, Bacterial, MESH: Oxidative Stress, Blotting, MESH : Amino Acid Sequence, Bacterial, Sodium Dodecyl Sulfate, MESH : Sequence Homology, Amino Acid, Enzymes, DNA-Binding Proteins, MESH: Glucose, MESH: Proteome, Amino Acid, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Repressor Proteins, Two-Dimensional, Mercuric Chloride, MESH: Hydrogen Peroxide, MESH : DNA-Binding Proteins, MESH : Repressor Proteins, Western, MESH : Gene Expression Regulation, Bacterial, Electrophoresis, MESH: Sodium Dodecyl Sulfate, MESH: Databases, Protein, Silver Staining, MESH: Enterococcus faecalis, MESH: Terminology as Topic, MESH : Cadmium Chloride, Blotting, Western, Detergents, Molecular Sequence Data, MESH : Acids, MESH: Enzymes, MESH : Proteome, MESH : Open Reading Frames, MESH: Bile Acids and Salts, MESH: Acids, Bile Acids and Salts, Databases, Open Reading Frames, Bacterial Proteins, Terminology as Topic, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Blotting, Western, Amino Acid Sequence, MESH : Databases, Protein, MESH: Mercuric Chloride, MESH : Sodium Dodecyl Sulfate, MESH: Molecular Sequence Data, Sequence Homology, Amino Acid, MESH : Glucose, Protein, Gene Expression Regulation, Bacterial, MESH : Detergents, MESH : Electrophoresis, Gel, Two-Dimensional, Hydrogen Peroxide, MESH: Open Reading Frames, MESH: Electrophoresis, Gel, Two-Dimensional, MESH : Terminology as Topic, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH : Bile Acids and Salts, Repressor Proteins, Oxidative Stress, Glucose, Gene Expression Regulation, MESH : Hydrogen Peroxide, Acids, MESH: DNA-Binding Proteins, MESH: Detergents
Abstract

International audience; Enterococcus faecalis is a resident bacterium of the intestinal tract of humans and animals. This bacterium can be responsible for serious diseases and is one of the largest causes of hospital-based infections. This hardy organism resists many kinds of stresses and is used as a major indicator of the hygienic quality of food, milk, and drinking water. On the other side, enterococci seem to have beneficial role in the development of cheese aroma and are added in certain starter cultures. Since ten years, our laboratory has used the two-dimensional electrophoresis (2-DE) technique to study the response of E. faecalis to physical or chemical stresses as well as to glucose and total starvation. Twenty-seven protein spots on 2-D gels have been identified by N-terminal sequencing or Western blotting which make up the first proteome database of this species. The proteins were classified in four different groups according to their function and their regulation. The first group comprises well-characterized proteins with known protective functions towards stresses. The second group contains enzymes of catabolic pathways. Their implication in stress resistance seems not obvious. A third group are proteins induced in glucose-starved cells belonging to the CcpA regulon. Induction of these enzymes under starvation may serve to increase the scavenging capacity of the cells for nutrients or may be important to mobilize endogenous energetic reserves. Lastly, nine N-terminal amino acid sequences or open reading frames (ORF) showed no homologies with sequences in databases. A comprehensive description of stress proteins of E. faecalis and analysis of their patterns of expression under different environmental conditions would greatly increase our understanding of the molecular mechanisms underlying the extraordinary capacity of this bacterium to survive under hostile conditions.

Published
2001

27. Surface plasmon resonance applied to DNA-protein complexes

Author

Buckle , Malcolm, Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), and École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : DNA, MESH : Nucleic Acid Conformation, MESH: Streptavidin, MESH : Oligodeoxyribonucleotides, Ligands, Polymerase Chain Reaction, MESH : Indicators and Reagents, MESH: Ligands, Biotinylation, MESH: Biotinylation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Polymerase Chain Reaction, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, MESH : Ligands, MESH: Kinetics, MESH: DNA, MESH: Indicators and Reagents, MESH : Biotinylation, MESH: Polymerase Chain Reaction, DNA, Surface Plasmon Resonance, MESH: Surface Plasmon Resonance, MESH : Streptavidin, DNA-Binding Proteins, Kinetics, MESH: Nucleic Acid Conformation, Oligodeoxyribonucleotides, MESH: Oligodeoxyribonucleotides, Nucleic Acid Conformation, Indicators and Reagents, Streptavidin, MESH : DNA-Binding Proteins, MESH : Surface Plasmon Resonance, MESH : Kinetics, MESH: DNA-Binding Proteins
Abstract

International audience

Published
2001

28. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes

Author

Dalila Azzout-Marniche, Marc Foretz, Fabienne Foufelle, Pascal Ferré, Colette Guichard, Dominique Bécard, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), AgroParisTech-Institut National de la Recherche Agronomique (INRA), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie de la Nutrition et du Comportement Alimentaire ( PNCA ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) ( EMD ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)

Subjects
MESH: Protein Precursors, Transcription, Genetic, medicine.medical_treatment, MESH : Hepatocytes, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, MESH: CCAAT-Enhancer-Binding Proteins, MESH: Hepatocytes, 0302 clinical medicine, Insulin receptor substrate, Insulin, MESH: Animals, Enzyme Inhibitors, MESH : Immunoblotting, Cells, Cultured, Protein Synthesis Inhibitors, 0303 health sciences, MESH : Cell Nucleus, MESH : Glucokinase, MESH: Immunoblotting, food and beverages, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], MESH: Glucokinase, MESH: Transcription Factors, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030220 oncology & carcinogenesis, MESH : DNA-Binding Proteins, Sterol Regulatory Element Binding Protein 1, MESH: Cells, Cultured, MESH: Cell Nucleus, MESH: Enzyme Activation, MESH : Cell Membrane, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Insulin, digestive system, 03 medical and health sciences, MESH: Sterol Regulatory Element Binding Protein 1, MESH : Sterol Regulatory Element Binding Protein 1, MESH: Blotting, Northern, Protein Precursors, Molecular Biology, Dose-Response Relationship, Drug, Glucokinase, Endoplasmic reticulum, Cell Membrane, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sterol regulatory element-binding protein, Enzyme Activation, MESH: Phosphatidylinositol 3-Kinases, CCAAT-Enhancer-Binding Proteins, MESH: Female, Transcription Factors, MESH: Signal Transduction, Time Factors, MESH : Transcription Factors, MESH : Insulin, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, MESH : Dose-Response Relationship, Drug, Endoplasmic Reticulum, MESH: Dose-Response Relationship, Drug, Phosphatidylinositol 3-Kinases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], polycyclic compounds, MESH : Female, Cycloheximide, MESH: Cycloheximide, MESH : Protein Precursors, MESH : Endoplasmic Reticulum, MESH : Rats, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH : Blotting, Northern, DNA-Binding Proteins, Fatty acid synthase, MESH : CCAAT-Enhancer-Binding Proteins, MESH: Enzyme Inhibitors, Female, lipids (amino acids, peptides, and proteins), MESH : Time Factors, Research Article, Signal Transduction, MESH: Rats, Immunoblotting, Biology, [ SDV.BC.IC ] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [ SDV.BBM.MN ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], MESH: Endoplasmic Reticulum, MESH : Cycloheximide, MESH : Cells, Cultured, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, MESH : Protein Synthesis Inhibitors, Transcription factor, 030304 developmental biology, MESH : Signal Transduction, Cell Nucleus, MESH : Enzyme Inhibitors, MESH: Protein Synthesis Inhibitors, MESH: Transcription, Genetic, MESH: Time Factors, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH : Transcription, Genetic, MESH : Phosphatidylinositol 3-Kinases, Cell Biology, Blotting, Northern, Rats, biology.protein, Hepatocytes, MESH : Animals, MESH : Enzyme Activation, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: DNA-Binding Proteins, MESH: Cell Membrane
Abstract

International audience; The transcription factor sterol regulatory-element-binding protein-1c (SREBP-1c) plays a major role in the effect of insulin on the transcription of hepatic genes such as glucokinase and fatty acid synthase. We show here in cultured rat hepatocytes that insulin, through activation of the phosphatidylinositol 3-kinase pathway increases the abundance of the precursor form of SREBP-1c in endoplasmic reticulum. This precursor form is then rapidly cleaved, possibly irrespective of the continuous presence of insulin, leading to an increased content of the nuclear mature form of SREBP-1c. Nevertheless, the increased amount of the mature form of SREBP-1c in the nucleus is not a prerequisite for the rapid effect of insulin on the transcription of genes such as glucokinase, suggesting that additional actions of the hormone are involved, such as the activation of the nuclear form of SREBP-1c or of an unidentified SREBP-1c partner.

Published
2000

29. Glutamate Induces Phosphorylation of Elk-1 and CREB, Along with c -fos Activation, via an Extracellular Signal-Regulated Kinase-Dependent Pathway in Brain Slices

Author

Marie-Jo Besson, Peter Vanhoutte, Jean-Vianney Barnier, Jocelyne Caboche, Robert A. Hipskind, Christiane Pagès, Bernard Guibert, Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Institut Alfred Fessard, Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences (IDN), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ), Institut de Neurobiologie Alfred Fessard ( INAF ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), and Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
MAPK/ERK pathway, Male, MESH : Proto-Oncogene Proteins c-raf, MESH : Transcription Factors, Mitogen-Activated Protein Kinase 3, MESH : Corpus Striatum, MAP Kinase Kinase 1, MESH : MAP Kinase Kinase 1, Mitogen-activated protein kinase kinase, MESH : Ca(2+)-Calmodulin Dependent Protein Kinase, Rats, Sprague-Dawley, MESH : Phosphorylation, 0302 clinical medicine, MESH : Glutamic Acid, MESH : Trans-Activation (Genetics), Phosphorylation, Cyclic AMP Response Element-Binding Protein, Cell Growth and Development, MESH : Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinase 1, 0303 health sciences, MESH : Mitogen-Activated Protein Kinase 1, biology, MESH : Mitogen-Activated Protein Kinase 3, MESH : Gene Expression Regulation, Kinase, MESH : Rats, MESH : Cyclic AMP Response Element-Binding Protein, Brain, Protein-Tyrosine Kinases, DNA-Binding Proteins, MESH : Proto-Oncogene Proteins, Proto-Oncogene Proteins c-raf, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : DNA-Binding Proteins, Signal transduction, MESH : Kinetics, Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-fos, Signal Transduction, MESH : Protein-Serine-Threonine Kinases, Transcriptional Activation, MESH : Male, Glutamic Acid, Protein Serine-Threonine Kinases, CREB, MESH : Extracellular Space, 03 medical and health sciences, Proto-Oncogene Proteins, MESH : Protein-Tyrosine Kinases, Animals, Protein kinase A, Molecular Biology, 030304 developmental biology, ets-Domain Protein Elk-1, MESH : Signal Transduction, Mitogen-Activated Protein Kinase Kinases, MESH : Mitogen-Activated Protein Kinases, Cell Biology, Molecular biology, MESH : Rats, Sprague-Dawley, Corpus Striatum, Rats, Kinetics, MESH : Proto-Oncogene Proteins c-fos, MESH : Brain, Gene Expression Regulation, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Calcium-Calmodulin-Dependent Protein Kinases, biology.protein, MESH : Animals, MESH : ets-Domain Protein Elk-1, Extracellular Space, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; In cell culture systems, the TCF Elk-1 represents a convergence point for extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) subclasses of mitogen-activated protein kinase (MAPK) cascades. Its phosphorylation strongly potentiates its ability to activate transcription of the c-fos promoter through a ternary complex assembled on the c-fos serum response element. In rat brain postmitotic neurons, Elk-1 is strongly expressed (V. Sgambato, P. Vanhoutte, C. Pagès, M. Rogard, R. A. Hipskind, M. J. Besson, and J. Caboche, J. Neurosci. 18:214-226, 1998). However, its physiological role in these postmitotic neurons remains to be established. To investigate biochemically the signaling pathways targeting Elk-1 and c-fos in mature neurons, we used a semi-in vivo system composed of brain slices stimulated with the excitatory neurotransmitter glutamate. Glutamate treatment leads to a robust, progressive activation of the ERK and JNK/SAPK MAPK cascades. This corresponds kinetically to a significant increase in Ser383-phosphorylated Elk-1 and the appearance of c-fos mRNA. Glutamate also causes increased levels of Ser133-phosphorylated cyclic AMP-responsive element-binding protein (CREB) but only transiently relative to Elk-1 and c-fos. ERK and Elk-1 phosphorylation are blocked by the MAPK kinase inhibitor PD98059, indicating the primary role of the ERK cascade in mediating glutamate signaling to Elk-1 in the rat striatum in vivo. Glutamate-mediated CREB phosphorylation is also inhibited by PD98059 treatment. Interestingly, KN62, which interferes with calcium-calmodulin kinase (CaM-K) activity, leads to a reduction of glutamate-induced ERK activation and of CREB phosphorylation. These data indicate that ERK functions as a common component in two signaling pathways (ERK/Elk-1 and ERK/?/CREB) converging on the c-fos promoter in postmitotic neuronal cells and that CaM-Ks act as positive regulators of these pathways.

Published
1999

30. Stat3 and Gfi-1 Transcription Factors Control Th17 Cell Immunosuppressive Activity via the Regulation of Ectonucleotidase Expression

Author

Bernhard Ryffel, Simon C. Robson, Sylvain Ladoire, Jean René Pallandre, François Ghiringhelli, Lionel Apetoh, Frédérique Végran, Aziz Hichami, Angélique Chevriaux, Gérard Eberl, Christophe Borg, Julie Vincent, Cédric Rébé, Grégoire Mignot, David Masson, Fanny Chalmin, Valentin Derangère, Mélanie Bruchard, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Department of Medicine and Surgery, Harvard Medical School [Boston] ( HMS ) -Beth Israel Deaconess Medical Centre-Liver Center and Transplantation Institute, Développement des Tissus Lymphoïdes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Immunologie et embryologie moléculaires ( IEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Centre-Liver Center and Transplantation Institute, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
Adoptive cell transfer, MESH : Transcription Factors, Cellular differentiation, MESH: Th17 Cells, T-Lymphocytes, Cell, MESH : Promoter Regions, Genetic, MESH : RNA, Small Interfering, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Transforming Growth Factor beta, MESH: RNA, Small Interfering, MESH : STAT3 Transcription Factor, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Ectonucleotidase, MESH: Animals, RNA, Small Interfering, STAT3, MESH: Lymphocytes, Tumor-Infiltrating, Promoter Regions, Genetic, MESH: Antigens, CD, 5'-Nucleotidase, Regulation of gene expression, Mice, Knockout, 0303 health sciences, MESH : Gene Expression Regulation, Apyrase, MESH: STAT3 Transcription Factor, MESH: Transcription Factors, MESH: Gene Expression Regulation, MESH : Mice, Transgenic, Cell biology, MESH : Lymphocytes, Tumor-Infiltrating, DNA-Binding Proteins, MESH : Apyrase, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA-Binding Proteins, MESH: Apyrase, STAT3 Transcription Factor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : Interleukin-6, MESH: Mice, Transgenic, T cell, Immunology, Mice, Transgenic, MESH : Mice, Inbred C57BL, Biology, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, MESH: Mice, Inbred C57BL, Antigens, CD, MESH: Promoter Regions, Genetic, MESH : 5'-Nucleotidase, MESH : Mice, medicine, MESH : Antigens, CD, MESH : Th17 Cells, Animals, Transcription factor, MESH: Mice, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH : T-Lymphocytes, Binding Sites, Interleukin-6, MESH: Interleukin-6, Mice, Inbred C57BL, MESH: T-Lymphocytes, MESH : Transforming Growth Factor beta, MESH: Binding Sites, Gene Expression Regulation, biology.protein, MESH : Mice, Knockout, Th17 Cells, MESH : Animals, MESH: 5'-Nucleotidase, MESH: DNA-Binding Proteins, MESH : Binding Sites, 030215 immunology, Transcription Factors
Abstract

International audience; Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.

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