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1. Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control

Author

Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Stevenn Volant, Faroudy Boufassa, Pierre de Truchis, Morgane Marcou, Katia Bourdic, Laurence Weiss, Corinne Jung, Christine Bourgeois, Cécile Goujard, Laurence Meyer, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión, HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, 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), Hôpital Hôtel-Dieu [Paris], This work was funded by the ANRS, the NIH (UM1AI164562), co-funded by the National Heart, Lung and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Drug Abuse (NIDA), and the National Institute of Allergy and Infectious Diseases (NIAID). FPC was supported by the ANRS and a Pasteur-Roux-Cantarini fellowship from the Institut Pasteur. The authors thank Gilead for their financial support in acquiring the Fortessa cytometer., and Passaes, Caroline

Subjects
MESH: Humans, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adaptive immunity, Immunology, HIV Infections, General Medicine, Cellular immune response, MESH: HIV Infections, CD8-Positive T-Lymphocytes, MESH: CD8-Positive T-Lymphocytes, AIDS/HIV, MESH: HIV-1, Glycogen Synthase Kinase 3, HIV-1, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Viremia, Immunotherapy, MESH: Viremia, ComputingMilieux_MISCELLANEOUS, MESH: Glycogen Synthase Kinase 3
Abstract

International audience; Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.

Published
2022
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2. Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors

Author

Jessica Bertrand, Bernard Payrastre, N Gallay, Nathalie Vergnolle, Véronique Maguer-Satta, Mathieu Despeaux, Cécile Demur, Ezzeddine Bourogaa, S Joly, P Bonnevialle, F Louache, Claire Racaud-Sultan, ANDRA, Laboratoire d'Hématologie [Purpan], Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Equipe 11, 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 ), 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 Physiopathologie Toulouse Purpan, Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut Claudius Regaud-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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], 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), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud

Subjects
Male, MESH : Aged, Antigens, CD34, MESH : Blotting, Western, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Glycogen Synthase Kinase 3, 0302 clinical medicine, MESH : Indoles, MESH : Tumor Cells, Cultured, GSK-3, Tumor Cells, Cultured, Protein Phosphatase 2, MESH : GTP-Binding Proteins, Cells, Cultured, MESH: Glycogen Synthase Kinase 3, MESH: Etoposide, Etoposide, MESH: Indoles, MESH : Maleimides, Aged, 80 and over, MESH : Cell Survival, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH: Protein Phosphatase 2, Neoplasm Proteins, MESH: Cell Survival, MESH: Young Adult, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, RNA Interference, MESH: Cells, Cultured, MESH : Protein Phosphatase 2, MESH : Glycogen Synthase Kinase 3, MESH: Antineoplastic Agents, Phytogenic, Blotting, Western, MESH : Young Adult, Receptors, Cell Surface, MESH: Cell Adhesion, 03 medical and health sciences, MESH : Neoplasm Proteins, MESH: Sex Factors, Genetics, MESH: Blotting, Western, Humans, MESH : Middle Aged, MESH: Tumor Cells, Cultured, Progenitor cell, MESH : Aged, 80 and over, Clonogenic assay, education, Molecular Biology, Aged, MESH: Interleukin-3 Receptor alpha Subunit, MESH: Humans, Glycogen Synthase Kinase 3 beta, MESH : Hematopoietic Stem Cells, MESH : Humans, MESH : Leukemia, MESH: Adult, MESH: Antigens, CD34, Protein phosphatase 2, Hematopoietic Stem Cells, MESH: Neoplastic Stem Cells, Immunology, MESH: Female, MESH: Neoplasm Proteins, Cancer Research, Indoles, MESH : Receptors, Cell Surface, MESH : Interleukin-3 Receptor alpha Subunit, MESH : Antineoplastic Agents, Phytogenic, MESH: Hematopoietic Stem Cells, Maleimides, MESH: Aged, 80 and over, MESH : Female, MESH: Maleimides, MESH: Receptors, Cell Surface, MESH: Aged, Leukemia, Myeloid leukemia, MESH : Adult, Middle Aged, medicine.anatomical_structure, MESH : Antigens, CD34, Female, Stem cell, Adult, MESH: GTP-Binding Proteins, Cell Survival, MESH : Male, MESH : Sex Factors, MESH: RNA Interference, Population, Interleukin-3 Receptor alpha Subunit, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Etoposide, Biology, Receptors for Activated C Kinase, Young Adult, MESH : Neoplastic Stem Cells, Sex Factors, GTP-Binding Proteins, MESH: Leukemia, MESH : Cells, Cultured, Cell Adhesion, medicine, 030304 developmental biology, Antineoplastic Agents, Phytogenic, MESH: Male, MESH : Cell Adhesion, Cancer research, Bone marrow, MESH : RNA Interference
Abstract

International audience; Therapeutic resistance of acute myeloid leukemia stem cells, enriched in the CD34(+)38(-)123(+) progenitor population, is supported by extrinsic factors such as the bone marrow niche. Here, we report that when adherent onto fibronectin or osteoblast components, CD34(+)38(-)123(+) progenitors survive through an integrin-dependent activation of glycogen synthase kinase 3β (GSK3β) by serine 9-dephosphorylation. Strikingly, GSK3β-mediated survival was restricted to leukemic progenitors from female patients. GSK3β inhibition restored sensitivity to etoposide, and impaired the clonogenic capacities of adherent leukemic progenitors from female patients. In leukemic progenitors from female but not male patients, the scaffolding protein RACK1, activated downstream of α(5)β(1)-integrin engagement, was specifically upregulated and controlled GSK3β activation through the phosphatase protein phosphatase 2A (PP2A). In a mirrored manner, survival of adherent progenitors (CD34(+)38(-)) from male but not female healthy donors was partially dependent on this pathway. We conclude that the GSK3β-dependent survival pathway might be sex-specific in normal immature population and flip-flopped upon leukemogenesis. Taken together, our results strengthen GSK3β as a promising target for leukemic stem cell therapy and reveal gender differences as a new parameter in anti-leukemia therapy.

Published
2011
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3. β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites

Author

Lucie M. Laqueuvre, Eliette Bonnefoy, Charbel Massaad, Zeyni Mansuroglu, Jean-Jacques Panthier, Lionel Luron, Dominique Simon, Vasco Marcato, Sylvie Souès, Marie Flamand, Homéostasie cellulaire et cancer - Reprogrammation des réponses biologiques et thérapies alternatives (U1007), Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris Descartes - Paris 5 (UPD5), Génétique Fonctionnelle de la Souris, Institut Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Virologie Structurale, Toxicologie, Pharmacologie et Signalisation Cellulaire (U1124), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche (ANR)ANR-11-BSV3-007, Eliette Bonnefoy, Marie Flamand, Jean-Jacques Panthier.The DIM-Malinf project from Région Ile-de-France, Vasco Marcato, ANR-11-BSV3-0007, GenRift, Identification de voies cellulaires et de gènes clés pour la pathogénicité et la résistance au virus de la fièvre de la Vallée du Rift(2011), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virologie Structurale - Structural Virology, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-11-BSV3-0007,GenRift,Identification de voies cellulaires et de gènes clés pour la pathogénicité et la résistance au virus de la fièvre de la Vallée du Rift(2011), PANTHIER, Jean-Jacques, BLANC - Identification de voies cellulaires et de gènes clés pour la pathogénicité et la résistance au virus de la fièvre de la Vallée du Rift - - GenRift2011 - ANR-11-BSV3-0007 - BLANC - VALID, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
MESH: Signal Transduction, T-Lymphocytes, [SDV]Life Sciences [q-bio], MESH: beta Catenin, Glycogen Synthase Kinase 3, Mice, 0302 clinical medicine, GSK-3, MESH: Up-Regulation, MESH: Animals, Promoter Regions, Genetic, beta Catenin, MESH: Glycogen Synthase Kinase 3, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Wnt signaling pathway, Articles, 3. Good health, Cell biology, Up-Regulation, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Rift Valley fever virus, TCF Transcription Factors, Signal Transduction, Transcriptional Activation, T cell, Biology, Virus, 03 medical and health sciences, Immune system, Downregulation and upregulation, MESH: Promoter Regions, Genetic, medicine, Animals, Molecular Biology, MESH: Mice, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, Binding Sites, MESH: Interferon-beta, Cell Biology, Interferon-beta, Rift Valley fever virus, Virology, MESH: T-Lymphocytes, MESH: Binding Sites, MESH: Transcriptional Activation, IRF3, 030217 neurology & neurosurgery, MESH: TCF Transcription Factors, Interferon regulatory factors
Abstract

International audience; Rapid upregulation of interferon beta (IFN-β) expression following virus infection is essential to set up an efficient innate antiviral response. Biological roles related to the antiviral and immune response have also been associated with the constitutive production of IFN-β in naive cells. However, the mechanisms capable of modulating constitutive IFN-β expression in the absence of infection remain largely unknown. In this work, we demonstrate that inhibition of the kinase glycogen synthase kinase 3 (GSK-3) leads to the upregulation of the constitutive level of IFN-β expression in noninfected cells, provided that GSK-3 inhibition is correlated with the binding of β-catenin to the IFN-β promoter. Under these conditions, IFN-β expression occurred through the T-cell factor (TCF) binding sites present on the IFN-β promoter independently of interferon regulatory factor 3 (IRF3). Enhancement of the constitutive level of IFN-β per se was able to confer an efficient antiviral state to naive cells and acted in synergy with virus infection to stimulate virus-induced IFN-β expression. Further emphasizing the role of β-catenin in the innate antiviral response, we show here that highly pathogenic Rift Valley fever virus (RVFV) targets the Wnt/β-catenin pathway and the formation of active TCF/β-catenin complexes at the transcriptional and protein level in RVFV-infected cells and mice.

Published
2015
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4. Synthesis of novel 5-substituted indirubins as protein kinases inhibitors

Author

Anne Beauchard, Olivier Lozach, Thierry Besson, Laurent Meijer, Mélina Blairvacq, Valérie Thiéry, Yoan Ferandin, Stéphane Frère, Institut national de recherches archéologiques préventives (Inrap), Mer et santé (MS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Molécules et cibles thérapeutiques (MCT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génie Protéique et Cellulaire (LGPC), Université de La Rochelle (ULR), La Rochelle Université (ULR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Indoles, Swine, Clinical Biochemistry, Cyclin B, Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Biochemistry, Glycogen Synthase Kinase 3, Starfish, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Drug Discovery, CDC2-CDC28 Kinases, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Swine, ComputingMilieux_MISCELLANEOUS, MESH: Glycogen Synthase Kinase 3, MESH: Indoles, MESH: Starfish, Molecular Structure, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Kinase, MESH: Molecular Weight, Stereoisomerism, 3. Good health, MESH: Cell Survival, Enzyme inhibitor, Molecular Medicine, MESH: Cell Line, Tumor, Cell Survival, MESH: Molecular Structure, 010402 general chemistry, Structure-Activity Relationship, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Cyclin-dependent kinase, Cell Line, Tumor, Animals, Humans, Structure–activity relationship, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein kinase A, MESH: CDC2-CDC28 Kinases, Protein Kinase Inhibitors, Molecular Biology, Cyclin-dependent kinase 1, MESH: Humans, 010405 organic chemistry, Organic Chemistry, [CHIM.CATA]Chemical Sciences/Catalysis, MESH: Stereoisomerism, 0104 chemical sciences, Molecular Weight, chemistry, biology.protein, Indirubin
Abstract

In an effort to identify new pharmacological inhibitors of disease-relevant protein kinases with increased potency and selectivity, we synthesized and evaluated new 5-substituted indirubins. The effects of 34 indirubin derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3, as well as on SH-SY5Y human neuroblastoma cell survival, were investigated.

Published
2006
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5. 7-Bromoindirubin-3′-oxime induces caspase-independent cell death

Author

Jacint Boix, Karima Bettayeb, Frank Totzke, Alexios-Leandros Skaltsounis, Jan Mester, Xènia Garrofé-Ochoa, Laurent Meijer, Panos Polychronopoulos, Yoan Ferandin, Prokopios Magiatis, Judit Ribas, Marie Knockaert, Christoph Schächtele, Departament de Quimica Inorgànica, Facultat de Quimica, Universitat de Barcelona (UB), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Swine, MESH: Cell Cycle, Apoptosis, Glycogen Synthase Kinase 3, Mice, Starfish, MESH: Structure-Activity Relationship, 0302 clinical medicine, Oximes, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Tumor Suppressor Protein p53, Càncer, MESH: Swine, MESH: Glycogen Synthase Kinase 3, Cancer, MESH: Indoles, 0303 health sciences, MESH: Starfish, Cell Cycle, MESH: STAT3 Transcription Factor, MESH: Oximes, MESH: CDC2 Protein Kinase, Cyclin-Dependent Kinases, 3. Good health, Cell biology, Cell Death Process, Caspases, 030220 oncology & carcinogenesis, MESH: Cell Nucleus, Cyclin-Dependent Kinase Inhibitor p21, Recombinant Fusion Proteins, bcl-X Protein, Cysteine Proteinase Inhibitors, Spodoptera, MESH: Cyclin-Dependent Kinase Inhibitor p21, Structure-Activity Relationship, 03 medical and health sciences, MESH: Recombinant Fusion Proteins, Genetics, Humans, Molecular Biology, MESH: Humans, MESH: Caspases, MESH: Phosphorylation, MESH: Amino Acid Chloromethyl Ketones, Apoptosi, Aryl hydrocarbon receptor, MESH: Cell Line, Proteïnes quinases, MESH: Proto-Oncogene Proteins c-bcl-2, chemistry, Indirubin, MESH: Female, MESH: Cell Death, Cancer Research, Indoles, Amino Acid Chloromethyl Ketones, chemistry.chemical_compound, Protein kinases, Phosphorylation, Caspase, MESH: Spodoptera, Cell Death, biology, MESH: Cyclin-Dependent Kinases, Proto-Oncogene Proteins c-bcl-2, Biochemistry, Mort cel·lular, Quinolines, Female, Indirubins, MESH: Quinolines, STAT3 Transcription Factor, Cell death, Programmed cell death, MESH: Cell Line, Tumor, Necroptosis, Kinases, MESH: bcl-X Protein, Cell Line, MESH: Cysteine Proteinase Inhibitors, Autofàgia, Cyclin-dependent kinase, Cell Line, Tumor, CDC2 Protein Kinase, Autophagy, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, Protein Kinase Inhibitors, 030304 developmental biology, Cell Nucleus, MESH: Male, MESH: Protein Processing, Post-Translational, biology.protein, Tumor Suppressor Protein p53, Protein Processing, Post-Translational
Abstract

Indirubin, an isomer of indigo, is a reported inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) as well as an agonist of the aryl hydrocarbon receptor (AhR). Indirubin is the active ingredient of a traditional Chinese medicinal recipe used against chronic myelocytic leukemia. Numerous indirubin analogs have been synthesized to optimize this promising kinase inhibitor scaffold. We report here on the cellular effects of 7-bromoindirubin-3'-oxime (7BIO). In contrast to its 5-bromo- and 6-bromo- isomers, and to indirubin-3'-oxime, 7BIO has only a marginal inhibitory activity towards CDKs and GSK-3. Unexpectedly, 7BIO triggers a rapid cell death process distinct from apoptosis. 7-Bromoindirubin-3'-oxime induces the appearance of large pycnotic nuclei, without classical features of apoptosis such as chromatin condensation and nuclear fragmentation. 7-Bromoindirubin-3'-oxime-induced cell death is not accompanied by cytochrome c release neither by any measurable effector caspase activation. Furthermore, the death process is not altered either by the presence of Q-VD-OPh, a broad-spectrum caspase inhibitor, or the overexpression of Bcl-2 and Bcl-XL proteins. Neither AhR nor p53 is required during 7BIO-induced cell death. Thus, in contrast to previously described indirubins, 7BIO triggers the activation of non-apoptotic cell death, possibly through necroptosis or autophagy. Although their molecular targets remain to be identified, 7-substituted indirubins may constitute a new class of potential antitumor compounds that would retain their activity in cells refractory to apoptosis.

Published
2006
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6. Inhibition of glycogen synthase kinase-3 increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of STAT3

Author

Vincenzo Federico, Maria Rosaria Ricciardi, Alessandra Soriani, Cinzia Fionda, Marco Cippitelli, Angela Santoni, Maria Teresa Petrucci, Alessandra Zingoni, Francesca Cecere, Maria Luisa Iannitto, Giulia Malgarini, Department of Molecular Medicine, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Division of Hematology, Department of Cellular Biotechnologies and Hematology, University of Rome, Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli studi di Napoli Federico II, and This work was supported by grants from the Italian Association for Cancer Research, 5x1000 AIRC, Ministero della Salute, Ateneo, Ministero dell'Istruzione dell'Università e della Ricerca (PRIN/2010NECHBX_004/Marco Cippitelli).

Subjects
Cytotoxicity, Immunologic, Fluorescent Antibody Technique, MESH: Multiple Myeloma, MESH: Flow Cytometry, Lymphocyte Activation, MESH: Histocompatibility Antigens Class I, Glycogen Synthase Kinase 3, 0302 clinical medicine, Transduction, Genetic, GSK-3, MESH: Reverse Transcriptase Polymerase Chain Reaction, Immunology and Allergy, MESH: Fluorescent Antibody Technique, MESH: Glycogen Synthase Kinase 3, MESH: Chromatin Immunoprecipitation, 0303 health sciences, biology, Reverse Transcriptase Polymerase Chain Reaction, Kinase, MESH: Real-Time Polymerase Chain Reaction, MESH: STAT3 Transcription Factor, Transfection, Flow Cytometry, MESH: Transduction, Genetic, Killer Cells, Natural, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Multiple Myeloma, STAT3 Transcription Factor, MESH: Killer Cells, Natural, Chromatin Immunoprecipitation, MESH: Cell Line, Tumor, nk, Blotting, Western, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Real-Time Polymerase Chain Reaction, multiple myeloma, gsk3, nkg2d, 03 medical and health sciences, Downregulation and upregulation, Cell Line, Tumor, Humans, MESH: Blotting, Western, MESH: Cytotoxicity, Immunologic, Glycogen synthase, MESH: Lymphocyte Activation, Transcription factor, 030304 developmental biology, MESH: Humans, MESH: Transfection, Histocompatibility Antigens Class I, NKG2D, Molecular biology, Cancer cell, biology.protein
Abstract

Engagement of NKG2D and DNAX accessory molecule-1 (DNAM-1) receptors on lymphocytes plays an important role for anticancer response and represents an interesting therapeutic target for pharmacological modulation. In this study, we investigated the effect of inhibitors targeting the glycogen synthase kinase-3 (GSK3) on the expression of NKG2D and DNAM-1 ligands in multiple myeloma (MM) cells. GSK3 is a pleiotropic serine–threonine kinase point of convergence of numerous cell-signaling pathways, able to regulate the proliferation and survival of cancer cells, including MM. We found that inhibition of GSK3 upregulates both MICA protein surface and mRNA expression in MM cells, with little or no effects on the basal expression of the MICB and DNAM-1 ligand poliovirus receptor/CD155. Moreover, exposure to GSK3 inhibitors renders myeloma cells more efficient to activate NK cell degranulation and to enhance the ability of myeloma cells to trigger NK cell–mediated cytotoxicity. We could exclude that increased expression of β-catenin or activation of the heat shock factor-1 (transcription factors inhibited by active GSK3) is involved in the upregulation of MICA expression, by using RNA interference or viral transduction of constitutive active forms. On the contrary, inhibition of GSK3 correlated with a downregulation of STAT3 activation, a negative regulator of MICA transcription. Both Tyr705 phosphorylation and binding of STAT3 on MICA promoter are reduced by GSK3 inhibitors; in addition, overexpression of a constitutively active form of STAT3 significantly inhibits MICA upregulation. Thus, we provide evidence that regulation of the NKG2D-ligand MICA expression may represent an additional immune-mediated mechanism supporting the antimyeloma activity of GSK3 inhibitors.

Published
2013
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7. Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation

Author

Guido Kroemer, Cécile Martel, Céline Henry, Catherine Brenner, Elena Fanelli, Maya Allouche, Joël Chopineau, Giuseppe Calamita, Davide Degli Esposti, Antoinette Lemoine, Céline Boursier, Université Joseph Fourier - Grenoble 1 (UJF), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Réponses cellulaires au microenvironnement et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Protéines et Nanotechnologies en Sciences Séparatives, Université Paris-Sud - Paris 11 (UP11), Centre Ressources Autisme de Bourgogne (CHU de Dijon) (CRAB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Nîmes (UNIMES), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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)-Centre National de la Recherche Scientifique (CNRS), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Microenvironnement et Physiopathologie de la Differenciation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry] (LabEx LERMIT), University of Paris Sud, Institut National pour le Cancer (INCa) [2008-1-PL BIO-04-CNRS ON1], LabEx LERMIT, PRES UniverSud Paris, Association pour la Recherche sur le Cancer, ANR [ANR-08PCVI-0008-01], MIUR [PRIN20089SRS2X_003], Fondazione Cassa di Risparmio di Puglia, Chopineau, Joel, Université Joseph Fourier - Grenoble 1 ( UJF ), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of Bari Aldo Moro ( UNIBA ), Université Paris-Sud - Paris 11 ( UP11 ), Centre Ressources Autisme de Bourgogne (CHU de Dijon) ( CRAB ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Nîmes ( UNIMES ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), Apoptose, cancer et immunité ( U848 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), PRES UniverSud ( CNRS UMR 8159 ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), University of Bari Aldo Moro (UNIBA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Male, MESH : Fatty Liver, MESH : Hepatocytes, Mitochondrion, ACTIVATION, MESH: Hepatocytes, Glycogen Synthase Kinase 3, Mice, MESH : Phosphorylation, 0302 clinical medicine, MESH: Mitochondrial Membranes, MESH : Lipid Metabolism, GSK-3, Voltage-Dependent Anion Channels, MESH : Female, MESH: Animals, Phosphorylation, MESH: Fatty Liver, Cells, Cultured, MESH: Glycogen Synthase Kinase 3, MESH: Lipid Metabolism, 0303 health sciences, INSULIN-RESISTANCE, biology, VDAC, MESH : Voltage-Dependent Anion Channels, NONALCOHOLIC STEATOHEPATITIS, Fatty liver, 3. Good health, Cell biology, APOPTOSIS, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Lipotoxicity, Biochemistry, 030220 oncology & carcinogenesis, MESH: Calcium, Mitochondrial Membranes, Female, MESH: Cells, Cultured, [ SDV.BBM.BP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Voltage-dependent anion channel, MESH : Glycogen Synthase Kinase 3, MESH : Male, bcl-X Protein, INHIBITION, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, MESH : Mice, Inbred C57BL, macromolecular substances, MESH: bcl-X Protein, 03 medical and health sciences, MESH : Mitochondrial Membranes, MESH: Mice, Inbred C57BL, LIVER STEATOSIS, MESH : Mice, MESH : Cells, Cultured, medicine, Animals, Humans, TRANSITION PORE, MODULATION, MESH : Calcium, MESH: Mice, 030304 developmental biology, MESH: Humans, Hepatology, MESH: Phosphorylation, MESH : bcl-X Protein, MESH : Humans, MESH: Voltage-Dependent Anion Channels, Lipid metabolism, Lipid Metabolism, medicine.disease, MESH: Male, Fatty Liver, Mice, Inbred C57BL, CELL-DEATH, Hepatocytes, biology.protein, Calcium, MESH : Animals, Steatosis, MESH: Female
Abstract

International audience; UNLABELLED: Nonalcoholic steatosis is a liver pathology characterized by fat accumulation and severe metabolic alterations involving early mitochondrial impairment and late hepatocyte cell death. However, mitochondrial dysfunction mechanisms remain elusive. Using four models of nonalcoholic steatosis, i.e., livers from patients with fatty liver disease, ob/ob mice, mice fed a high-fat diet, and in vitro models of lipotoxicity, we show that outer mitochondrial membrane permeability is altered and identified a posttranslational modification of voltage-dependent anion channel (VDAC), a membrane channel and NADH oxidase, as a cause of early mitochondrial dysfunction. Thus, in nonalcoholic steatosis VDAC exhibits reduced threonine phosphorylation, which increases the influx of water and calcium into mitochondria, sensitizes the organelle to matrix swelling, depolarization, and cytochrome c release without inducing cell death. This also amplifies VDAC enzymatic and channel activities regulation by calcium and modifies its interaction with proteic partners. Moreover, lipid accumulation triggers a rapid lack of VDAC phosphorylation by glycogen synthase kinase 3 (GSK3). Pharmacological and genetic manipulations proved GSK3 to be responsible for VDAC phosphorylation in normal cells. Notably, VDAC phosphorylation level correlated with steatosis severity in patients. CONCLUSION: VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis.

Published
2013
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8. A protocol to quantify mammary early common progenitors from long-term mammosphere culture

Author

Véronique Maguer-Satta, Emmanuel Delay, Elodie Bachelard-Cascales, Marion Chapellier, 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), 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 ) -Université Claude Bernard Lyon 1 ( UCBL ), and 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 )

Subjects
MESH: Neoplasm Proteins, Time Factors, Cellular differentiation, Cell Culture Techniques, MESH : Aged, MESH : Receptors, Cell Surface, MESH : Blotting, Western, MESH : Interleukin-3 Receptor alpha Subunit, MESH : Antineoplastic Agents, Phytogenic, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hematopoietic Stem Cells, Mice, 0302 clinical medicine, MESH: Aged, 80 and over, MESH : Indoles, MESH : Tumor Cells, Cultured, MESH : Female, MESH : GTP-Binding Proteins, MESH: Glycogen Synthase Kinase 3, MESH: Maleimides, MESH: Receptors, Cell Surface, MESH: Etoposide, MESH : Maleimides, MESH: Aged, MESH: Indoles, MESH : Cell Survival, 0303 health sciences, MESH: Middle Aged, Stem Cells, MESH: Protein Phosphatase 2, Cell Differentiation, General Medicine, MESH : Adult, Cell biology, MESH: Cell Survival, MESH: Young Adult, 030220 oncology & carcinogenesis, MESH : Antigens, CD34, Stem cell, MESH: Cells, Cultured, Adult, MESH: GTP-Binding Proteins, MESH : Protein Phosphatase 2, MESH : Glycogen Synthase Kinase 3, MESH : Male, MESH : Sex Factors, MESH: RNA Interference, MESH: Antineoplastic Agents, Phytogenic, MESH : Young Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Etoposide, Biology, MESH: Cell Adhesion, Colony-Forming Units Assay, 03 medical and health sciences, MESH : Neoplasm Proteins, MESH : Neoplastic Stem Cells, MESH: Sex Factors, Spheroids, Cellular, MESH : Cells, Cultured, MESH: Leukemia, Animals, Humans, MESH: Blotting, Western, MESH : Middle Aged, MESH: Tumor Cells, Cultured, Progenitor cell, Mammary Glands, Human, MESH : Aged, 80 and over, 030304 developmental biology, Progenitor, MESH: Interleukin-3 Receptor alpha Subunit, MESH: Humans, MESH : Hematopoietic Stem Cells, Stem cell population, MESH : Humans, MESH : Leukemia, MESH: Adult, Cell Biology, MESH: Antigens, CD34, MESH: Neoplastic Stem Cells, MESH: Male, MESH : Cell Adhesion, Cell culture, Immunology, NIH 3T3 Cells, MESH : RNA Interference, MESH: Female, Developmental Biology
Abstract

International audience; Here we describe a protocol established in our laboratory to quantify early common progenitors/stem cells grown as spheres in non-adherent culture conditions. This protocol is based on the combination of two functional tests: the mammosphere assay to maintain and enrich early mammary progenitors/stem cells, and the epithelial colony-forming cells (E-CFC) assay to identify and quantify further differentiated epithelial progenitors. Primary spheres mainly contain progenitors and rare stem/early common progenitor cells while secondary and tertiary spheres contain progenitor cells derived from the early common progenitor/stem cell population maintained through passages and partially differentiated. Spheres are enzymatically and mechanically dissociated; the derived cells are subsequently plated on irradiated NIH-3T3 fibroblasts for further processing, as in the E-CFC assay. The principle of this assay is to quantify the number of epithelial colonies generated by cells present in the different sequential spheres. This assay has therefore been named ECP-DC, standing for Early Common Progenitor-Derived Colonies assay.

Published
2012
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9. Switching reversibility to irreversibility in glycogen synthase kinase 3 inhibitors: clues for specific design of new compounds

Author

Carmen Gil, Pablo D. Dans, Ana Martínez, F. Javier Luque, Santiago Conde, Concepción Pérez, Valle Palomo, Daniel I. Perez, Instituto de Quimica Médica (CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), Departamento de Fisicoquímica e Instituto de Biomedicina, Facultad de farmacia-Universidad de Barcelona, and Financial support from MICINN and ISCiii (projects nos. SAF2009-13015-CO2-01, SAF2008-05595, SAF2006-01249 and RD07-0060/0015) and computational facilities from the CESCA are also acknowledged. D. I. P. acknowledges a postdoctoral grant to the CSIC (JAEDoc program) and V. P. a predoctoral grant (JAEPre program).

Subjects
Models, Molecular, MESH: Neurons, Plasma protein binding, MESH: Ketones, Pharmacology, MESH: Drug Design, 01 natural sciences, MESH: Receptors, Neurotransmitter, MESH: Neurodegenerative Diseases, Glycogen Synthase Kinase 3, Mice, Adenosine Triphosphate, MESH: Structure-Activity Relationship, GSK-3, Cerebellum, Drug Discovery, MESH: Adenosine Triphosphate, MESH: Animals, Phosphorylation, Receptor, MESH: Glycogen Synthase Kinase 3, Neurons, 0303 health sciences, Chemistry, Neurodegenerative Diseases, Stereoisomerism, Ketones, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Receptors, Neurotransmitter, 3. Good health, MESH: tau Proteins, MESH: Cattle, medicine.anatomical_structure, Biochemistry, Molecular Medicine, Signal transduction, MESH: Models, Molecular, Protein Binding, MESH: Rats, Central nervous system, tau Proteins, In Vitro Techniques, Structure-Activity Relationship, 03 medical and health sciences, medicine, Animals, Humans, Structure–activity relationship, MESH: Protein Binding, Binding site, MESH: Mice, 030304 developmental biology, Binding Sites, MESH: Humans, MESH: Phosphorylation, 010405 organic chemistry, MESH: Central Nervous System Agents, MESH: Stereoisomerism, MESH: Cerebellum, Rats, 0104 chemical sciences, MESH: Binding Sites, Drug Design, Cattle, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Central Nervous System Agents
Abstract

Development of kinase-targeted therapies for central nervous system (CNS) diseases is a great challenge. Glycogen synthase kinase 3 (GSK-3) offers a great potential for severe CNS unmet diseases, being one of the inhibitors on clinical trials for different tauopathies. Following our hypothesis based on the enhanced reactivity of residue Cys199 in the binding site of GSK-3, we examine here the suitability of phenylhalomethylketones as irreversible inhibitors. Our data confirm that the halomethylketone unit is essential for the inhibitory activity. Moreover, addition of the halomethylketone moiety to reversible inhibitors turned them into irreversible inhibitors with IC50 values in the nanomolar range. Overall, the results point out that these compounds might be useful pharmacological tools to explore physiological and pathological processes related to signaling pathways regulated by GSK-3 opening new avenues for the discovery of novel GSK-3 inhibitors. © 2011 American Chemical Society.

Published
2011
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10. Protein tyrosine kinase 7 has a conserved role in Wnt/beta-catenin canonical signalling

Author

Anne Catherine Lhoumeau, Edwige Belotti, Sylvie Marchetto, Michael Sebbagh, Frédérique Lembo, Seung Taek Lee, Francesca Puppo, Akanksha Gangar, Jean-Paul Borg, Virginie Thomé, Marie Cibois, Laurent Kodjabachian, Thomas Prebet, Won Sik Shin, Patrick Lécine, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM / U891 Inserm), Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, Embryo, Nonmammalian, MESH: beta Catenin, Xenopus Proteins, Biochemistry, MESH: Mice, Knockout, Glycogen Synthase Kinase 3, Mice, Xenopus laevis, 0302 clinical medicine, GSK-3, MESH: Animals, MESH: Organizers, Embryonic, MESH: Xenopus Proteins, beta Catenin, ComputingMilieux_MISCELLANEOUS, MESH: Glycogen Synthase Kinase 3, Mice, Knockout, 0303 health sciences, Wnt signaling pathway, LRP6, LRP5, Cell biology, MESH: Wnt Proteins, 030220 oncology & carcinogenesis, MESH: Cell Adhesion Molecules, MESH: Receptor Protein-Tyrosine Kinases, PTK7, Signal transduction, Tyrosine kinase, Signal Transduction, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Two-Hybrid System Techniques, 03 medical and health sciences, MESH: Xenopus laevis, Two-Hybrid System Techniques, MESH: Homeodomain Proteins, Genetics, Animals, Humans, Molecular Biology, MESH: Mice, 030304 developmental biology, Homeodomain Proteins, MESH: Humans, Scientific Reports, Organizers, Embryonic, MESH: Embryo, Mammalian, Receptor Protein-Tyrosine Kinases, MESH: Embryo, Nonmammalian, Embryo, Mammalian, Molecular biology, Wnt Proteins, Catenin, Cell Adhesion Molecules
Abstract

International audience; The receptor protein tyrosine kinase 7 (PTK7) was recently shown to participate in noncanonical Wnt/planar cell polarity signalling during mouse and frog embryonic development. In this study, we report that PTK7 interacts with β-catenin in a yeast two-hybrid assay and mammalian cells. PTK7-deficient cells exhibit weakened β-catenin/T-cell factor transcriptional activity on Wnt3a stimulation. Furthermore, Xenopus PTK7 is required for the formation of Spemann's organizer and for Siamois promoter activation, events that require β-catenin transcriptional activity. Using epistatic assays, we demonstrate that PTK7 functions upstream from glycogen synthase kinase 3. Taken together, our data reveal a new and conserved role for PTK7 in the Wnt canonical signalling pathway.

Published
2011
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11. Commitment of mouse embryonic stem cells to the adipocyte lineage requires retinoic acid receptor beta and active GSK3

Author

Catherine Iehle, Nathalie Billon, Miguel Caetano Monteiro, Christian Dani, Brigitte Wdziekonski, Cécile Vernochet, Phi Villageois, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
MESH: Signal Transduction, Receptors, Retinoic Acid, Glycogen Synthase Kinase 3, Mice, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Adipocytes, MESH: Animals, MESH: Embryonic Stem Cells, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Glycogen Synthase Kinase 3, 0303 health sciences, Adipogenesis, Cell Differentiation, Hematology, Cell biology, MESH: Wnt Proteins, Stem cell, Signal transduction, Signal Transduction, MESH: Cell Differentiation, medicine.medical_specialty, Lineage (genetic), animal structures, Tretinoin, Biology, Cell Line, 03 medical and health sciences, Internal medicine, medicine, Animals, Cell Lineage, MESH: Mice, Embryonic Stem Cells, MESH: Adipocytes, 030304 developmental biology, MESH: Receptors, Retinoic Acid, MESH: Tretinoin, Cell Biology, MESH: Cell Lineage, Embryonic stem cell, MESH: Cell Line, Wnt Proteins, Retinoic acid receptor, Endocrinology, chemistry, MESH: Adipogenesis, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; Key events leading to terminal differentiation of preadipocytes into adipocytes have been identified in recent years. However, signaling pathways involved in the decision of stem cells to follow the adipogenic lineage have not yet been characterized. We have previously shown that differentiating mouse embryonic stem (mES) cells give rise to functional adipocytes upon an early treatment with retinoic acid (RA). The goal of this work was to identify regulators of RA-induced commitment of mES cells to the adipocyte lineage. First, we investigated the role of RA receptor (RAR) isotypes in the induction of mES cell adipogenesis. Using synthetic retinoids selective of RAR isotypes, we show that RARbeta activation is both sufficient and necessary to trigger commitment of mES cells to adipocytes. Then, we performed a small-scale drug screening to find signaling pathways involved in RARbeta-induced mES cell adipogenesis. We show that pharmacological inhibitors of glycogen synthase kinase (GSK) 3, completely inhibit RARbeta-induced adipogenesis in mES cells. This finding uncovers the requirement of active GSK3 in RARbeta-induced commitment of mES cells toward the adipocyte lineage. Finally, we investigated the role of the Wnt pathway, in which GSK3 is a critical negative regulator, in adipocyte commitment by analyzing Wnt pathway activity in RA- and RARbeta-induced mES cell adipogenesis. Our results suggest that although RARbeta and active GSK3 are required for RA-induced adipogenesis, they might be acting through a Wnt pathway-independent mechanism.

Published
2009
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12. Inhibition of glycogen synthase kinase-3beta downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A

Author

Amandine Magnaudeix, Faraj Terro, Ludovic Martin, Françoise Esclaire, Catherine Yardin, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service d'Histologie, cytologie, cytogénétique, biologie cellulaire [CHU Limoges], CHU Limoges, Equipe de Recherche Médicale Appliquée (ERMA), and Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges

Subjects
Indoles, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, MESH: Okadaic Acid, Glycogen Synthase Kinase 3, 0302 clinical medicine, GSK-3, Oximes, MESH: Animals, Protein Phosphatase 2, Enzyme Inhibitors, Phosphorylation, Cells, Cultured, MESH: Glycogen Synthase Kinase 3, MESH: Indoles, Neurons, 0303 health sciences, biology, Chemistry, General Neuroscience, MESH: Protein Phosphatase 2, Calcineurin, Neurodegeneration, MESH: Lithium Chloride, MESH: Purines, MESH: Oximes, MESH: tau Proteins, MESH: Enzyme Inhibitors, MESH: Calcineurin, MESH: Cells, Cultured, MESH: Cyclin-Dependent Kinase 5, MESH: Rats, Tau protein, Blotting, Western, Calcineurin Inhibitors, tau Proteins, macromolecular substances, Tacrolimus, 03 medical and health sciences, MESH: Analysis of Variance, mental disorders, Okadaic Acid, medicine, MESH: Tacrolimus, Roscovitine, MESH: Blotting, Western, Animals, Rats, Wistar, Glycogen synthase, Molecular Biology, GSK3B, 030304 developmental biology, Analysis of Variance, Glycogen Synthase Kinase 3 beta, MESH: Phosphorylation, Cyclin-dependent kinase 5, Cyclin-Dependent Kinase 5, Protein phosphatase 2, MESH: Rats, Wistar, medicine.disease, Molecular biology, Rats, enzymes and coenzymes (carbohydrates), Purines, biology.protein, Neurology (clinical), Lithium Chloride, 030217 neurology & neurosurgery, Developmental Biology
Abstract

ERMA; International audience; In tauopathies such as Alzheimer's disease (AD), the molecular mechanisms of tau protein aggregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration remain not understood. It was recently demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration. Therefore, reduction of tau levels might represent a mechanism of neuroprotection. Glycogen synthase kinase-3beta (GSK3beta) and protein phosphatase-2A (PP2A) are key enzymes involved in the regulation of tau phosphorylation, and have been suggested to be involved in the abnormal tau phosphorylation and aggregation in AD. Connections between PP2A and GSK3beta signaling have been reported. We have previously demonstrated that exposure of cultured cortical neurons to lithium decreased tau protein expression and provided neuroprotection against Abeta. Since lithium is not a specific inhibitor of GSK3beta (ID50=2.0 mM), whether or not the lithium-induced tau decrease involves GSK3beta remained to be determined. For that purpose, cultured cortical neurons were exposed to 6-bromo-indirubin-3'-oxime (6-BIO), a more selective and potent GSK3beta inhibitor (ID50=1.5 microM) or to lithium. Analysis of tau levels and phosphorylation by western-blot assays showed that lithium and 6-BIO dose-dependently decreased both tau protein levels and tau phosphorylation. Conversely, inhibition of cyclin-dependent kinase-5 (CDK5) by roscovitine decreased phosphorylated tau but failed to alter tau protein levels. These data indicate that GSK3beta might be selectively involved in the regulation of tau protein levels. Moreover, inhibition of PP2A by okadaic acid, but not that of PP2B (protein phosphatase-2B)/calcineurin by FK506, dose-dependently reversed lithium-induced tau decrease. These data indicate that GSK3beta regulates both tau phosphorylation and total tau levels through PP2A.

Published
2008
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13. Butyrolactone I derivatives from Aspergillus terreus carrying an unusual sulfate moiety

Author

Isabel Sattler, Olivier Lozach, Xuemei Niu, Klaus-Dieter Menzel, Hans-Martin Dahse, Laurent Meijer, Susanne Grabley, Grit Walther, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Swine, Cyclin B, Pharmaceutical Science, 01 natural sciences, Analytical Chemistry, HeLa, chemistry.chemical_compound, Glycogen Synthase Kinase 3, Starfish, 4-Butyrolactone, Drug Discovery, Moiety, Aspergillus terreus, MESH: Animals, Cytotoxicity, MESH: Swine, MESH: Glycogen Synthase Kinase 3, chemistry.chemical_classification, biology, MESH: Starfish, Chemistry, Sulfates, MESH: Drug Screening Assays, Antitumor, Brain, Biological activity, Protein-Tyrosine Kinases, MESH: CDC2 Protein Kinase, Aspergillus, MESH: Aspergillus, Molecular Medicine, Lactone, MESH: Cyclin-Dependent Kinase 5, Stereochemistry, Antineoplastic Agents, Protein Serine-Threonine Kinases, MESH: Protein-Tyrosine Kinases, MESH: Protein-Serine-Threonine Kinases, MESH: Oocytes, MESH: Brain, CDC2 Protein Kinase, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phenols, Pharmacology, MESH: Humans, 010405 organic chemistry, Organic Chemistry, Cyclin-Dependent Kinase 5, biology.organism_classification, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Complementary and alternative medicine, biology.protein, Oocytes, MESH: 4-Butyrolactone, MESH: Antineoplastic Agents, Drug Screening Assays, Antitumor, MESH: Sulfates
Abstract

In our ongoing search for new bioactive metabolites from microbial resources, Aspergillus terreus (HKI0499) was examined by chemical metabolite profiling. Together with the known butyrolactone I ( 3), the unusual sulfate derivatives butyrolactone I 3-sulfate ( 1) and butyrolactone I 4''-sulfate ( 2) were discovered. The chemical structures were determined by NMR and MS data analyses. All compounds were tested on CDK1/cyclin B, CDK5/p25, DYRK1A, CK1, and GSK-3alpha/beta kinases; compounds 2 and 3 were also evaluated for their cytotoxic and antiproliferative activities. Butyrolactone I 3-sulfate ( 1) exhibited specific inhibitory activity against CDK1/cyclin B and CDK5/p25, yet 15-30-fold less than butyrolactone I ( 3). Likewise, butyrolactone I 3-sulfate ( 1) exhibited moderate cytotoxicity solely against HeLa cells (CC 50 = 80.7 microM).

Published
2008
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14. Lithium down-regulates tau in cultured cortical neurons: a possible mechanism of neuroprotection

Author

A. Rametti, Françoise Esclaire, Faraj Terro, Catherine Yardin, N. Cogné, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Equipe de Recherche Médicale Appliquée (ERMA), Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Lithium (medication), MESH: Neurons, Apoptosis, MESH: Lithium Compounds, MESH: Down-Regulation, MESH: Dose-Response Relationship, Drug, Glycogen Synthase Kinase 3, 0302 clinical medicine, Antimanic Agents, MESH: Animals, Cells, Cultured, MESH: Glycogen Synthase Kinase 3, Cerebral Cortex, Neurons, 0303 health sciences, biology, Chemistry, General Neuroscience, Neurodegeneration, Neurofibrillary Tangles, MESH: Antimanic Agents, MESH: Neuroprotective Agents, MESH: Amyloid beta-Peptides, MESH: tau Proteins, Neuroprotective Agents, medicine.anatomical_structure, Lithium Compounds, [SDV.IMM]Life Sciences [q-bio]/Immunology, Alzheimer's disease, medicine.drug, MESH: Cells, Cultured, Amyloid, MESH: Rats, Tau protein, Down-Regulation, tau Proteins, Neuroprotection, 03 medical and health sciences, Alzheimer Disease, mental disorders, medicine, Animals, RNA, Messenger, Rats, Wistar, GSK3B, 030304 developmental biology, MESH: RNA, Messenger, Amyloid beta-Peptides, Glycogen Synthase Kinase 3 beta, Dose-Response Relationship, Drug, MESH: Apoptosis, MESH: Rats, Wistar, medicine.disease, MESH: Cerebral Cortex, Rats, MESH: Cytoprotection, Cytoprotection, biology.protein, Neuron, Neuroscience, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, MESH: Neurofibrillary Tangles
Abstract

ERMA; International audience; In tauopathies such as Alzheimer's disease (AD), the moleccular mechanisms of tau protein agregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration are not fully understood. Recent studies indirectly demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration, especially that induced by the amyloid (Abeta) pathology. Lithium is a medication for bipolar mood disorders. Its therapeutic mechanism of action remains unclear, in part because of the large number of biochemical effects attributed to lithium. Since lithium directly inhibits glycogen synthase kinase-3beta (GSK3beta), a key enzyme involved in tau phosphorylation, it was suggested that the therapeutic use of lithium could be expanded from mood disorders to neurodegenerative conditions. Lithium has been also reported to protect cultured neurons against Abeta toxicity, and to prevent NFTs accumulation and cognitive impairments in transgenic models of tauopathies. However, the exact mechanism of neuroprotection provided by lithium remains unknown. Here, we show that exposure of cultured cortical neurons to lithium decreased tau protein levels. This decrease was not linked to the activation of proteolytic processes including calpains, caspases and proteasome or to neuronal loss, but was rather associated with a reduction in tau mRNA levels. Moreover, prior exposure to lithium, at concentrations effective in reducing tau protein levels, markedly reduced pre-aggregated Abeta-induced neuronal apoptosis. Our findings raise the possibility that lithium could exert its neuroprotective effect against Abeta toxicity through the downregulation of tau proteins and that, at least, by acting at the level of tau mRNA.

Published
2008
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15. CDK/GSK-3 inhibitors as therapeutic agents for parenchymal renal diseases

Author

S.H. Obligado, Anna Zuk, Peter J. Nelson, O. Ibraghimov-Beskrovnaya, L. Meijer, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Oregon State University (OSU)

Subjects
Nephrology, medicine.medical_specialty, proliferation, Lupus nephritis, End stage renal disease, immunology, Glycogen Synthase Kinase 3, Mice, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Polycystic kidney disease, Animals, Humans, MESH: Protein Kinase Inhibitors, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Kinase Inhibitors, MESH: Mice, 030304 developmental biology, MESH: Glycogen Synthase Kinase 3, 0303 health sciences, Kidney, MESH: Kidney Diseases, end-stage renal disease, MESH: Humans, business.industry, Acute kidney injury, apoptosis, MESH: Biological Markers, medicine.disease, Cyclin-Dependent Kinases, 3. Good health, medicine.anatomical_structure, MESH: Cyclin-Dependent Kinases, 030220 oncology & carcinogenesis, Immunology, Cancer research, Mesangial proliferative glomerulonephritis, Kidney Diseases, business, Biomarkers, chronic kidney disease, Kidney disease
Abstract

Drug discovery to lessen the burden of chronic renal failure and end-stage renal disease remains a principle goal of translational research in nephrology. In this review, we provide an overview of the current development of small molecule cyclin-dependent kinase (CDK)/glycogen synthase kinase-3 (GSK-3) inhibitors as therapeutic agents for parenchymal renal diseases. The emergence of this drug family has resulted from the recognition that CDKs and GSK-3s play critical roles in the progression and regression of many kidney diseases. CDK/GSK-3 inhibitors suppress pathogenic proliferation, apoptosis, and inflammation, and promote regeneration of injured tissue. Preclinical efficacy has now been demonstrated in mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, polycystic kidney diseases, diabetic nephropathy, and several forms of acute kidney injury. Novel biomarkers of therapy are aiding the process of drug development. This review will highlight these advancements in renal therapeutics.

Published
2008
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16. The role of GSK-3 in synaptic plasticity

Author

Peineau, S, Bradley, C, Taghibiglou, C, Doherty, A, Bortolotto, Z A, Wang, Y T, Collingridge, G L, Peineau, Stephane, Department of Anatomy, University Walk-MRC Centre for Synaptic Plasticity-School of Medical and Sciences, and Supported by the MRC, Wellcome Trust and CIHR. SP was supported by a fellowship from FRM. CT was supported by fellowships from CIHR and MSFHR. GLC is a Royal Society- Wolfson Merit Award Holder. YTW is a HHMI international scholar

Subjects
MESH: Receptors, N-Methyl-D-Aspartate, Neuronal Plasticity, MESH: Humans, Review, Receptors, N-Methyl-D-Aspartate, MESH: Synapses, Glycogen Synthase Kinase 3, Synapses, Animals, Humans, MESH: Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Neuronal Plasticity, MESH: Glycogen Synthase Kinase 3
Abstract

International audience; Glycogen synthase kinase-3 (GSK-3), an important component of the glycogen metabolism pathway, is highly expressed in the CNS. It has been implicated in major neurological disorders including Alzheimer's disease, schizophrenia and bipolar disorders. Despite its central role in these conditions it was not known until recently whether GSK-3 has neuronal-specific functions under normal conditions. However recent work has shown that GSK-3 is involved in the regulation of, and cross-talk between, two major forms of synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and NMDAR-dependent long-term depression (LTD). The present article summarizes this recent work and discusses its potential relevance to the treatment of neurological disorders.

Published
2008
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17. LTP inhibits LTD in the hippocampus via regulation of GSK3beta

Author

Peineau, Stéphane, Taghibiglou, Changiz, Bradley, Clarrisa, Wong, Tak Pan, Liu, Lidong, Lu, Jie, Lo, Edmond, Wu, Dongchuan, Saule, Emilia, Bouschet, Tristan, Matthews, Paul, Isaac, John, Bortolotto, Zuner, Wang, Yu Tian, Collingridge, Graham, Department of Anatomy, University Walk-MRC Centre for Synaptic Plasticity-School of Medical and Sciences, Brain Research Center, Department of Medicine-UBC Hospital-University of British Columbia (UBC), National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), and This work was supported by the MRC, Wellcome Trust, CIHR, and NINDS. S.P. was supported by a fellowship from FRM (Fondation pour la Recherche Médicale). C.T. was supported by fellowships from CIHR and MSFHR. G.L.C. is a Royal Society-Wolfson Merit Award Holder. Y.T.W. is an HHMI international scholar.

Subjects
MESH: Signal Transduction, MESH: Enzyme Activation, MESH: Hippocampus, MESH: Long-Term Synaptic Depression, endocrine system diseases, MESH: Rats, macromolecular substances, glycogen synthase kinase, PI3K, MESH: Dendritic Spines, MESH: Long-Term Potentiation, MESH: Protein Kinase Inhibitors, long-term depression, MESH: Animals, MESH: Excitatory Postsynaptic Potentials, MESH: Glycogen Synthase Kinase 3, MESH: Maleimides, synaptic plasticity, MESH: Proto-Oncogene Proteins c-akt, Akt, MESH: Aminophenols, MESH: Organ Culture Techniques, nervous system, NMDA, MESH: Phosphatidylinositol 3-Kinases, MESH: Receptors, AMPA, Long-term potentiation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information.

Published
2007
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18. LTP inhibits LTD in the hippocampus via regulation of GSK3beta

Author

Peineau, Stéphane, Taghibiglou, Changiz, Bradley, Clarrisa, Wong, Tak Pan, Liu, Lidong, Lu, Jie, Lo, Edmond, Wu, Dongchuan, Saule, Emilia, Bouschet, Tristan, Matthews, Paul, Isaac, John, Bortolotto, Zuner, Wang, Yu Tian, Collingridge, Graham, Department of Anatomy, University Walk-MRC Centre for Synaptic Plasticity-School of Medical and Sciences, Brain Research Center, Department of Medicine-UBC Hospital-University of British Columbia (UBC), National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), This work was supported by the MRC, Wellcome Trust, CIHR, and NINDS. S.P. was supported by a fellowship from FRM (Fondation pour la Recherche Médicale). C.T. was supported by fellowships from CIHR and MSFHR. G.L.C. is a Royal Society-Wolfson Merit Award Holder. Y.T.W. is an HHMI international scholar., and Peineau, Stephane

Subjects
MESH: Signal Transduction, MESH: Enzyme Activation, MESH: Hippocampus, MESH: Long-Term Synaptic Depression, endocrine system diseases, MESH: Rats, macromolecular substances, glycogen synthase kinase, PI3K, MESH: Dendritic Spines, MESH: Long-Term Potentiation, MESH: Protein Kinase Inhibitors, long-term depression, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Excitatory Postsynaptic Potentials, MESH: Glycogen Synthase Kinase 3, MESH: Maleimides, synaptic plasticity, MESH: Proto-Oncogene Proteins c-akt, Akt, MESH: Aminophenols, MESH: Organ Culture Techniques, nervous system, NMDA, MESH: Phosphatidylinositol 3-Kinases, MESH: Receptors, AMPA, Long-term potentiation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information.

Published
2007
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19. CDK/GSK-3 inhibitors as a new approach for the treatment of proliferative renal diseases

Author

Laurent Meijer, Peter J. Nelson, Timothy J. Soos, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Mer et santé (MS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Anti-Inflammatory Agents, Lupus nephritis, macromolecular substances, Nephropathy, Glycogen Synthase Kinase 3, 03 medical and health sciences, 0302 clinical medicine, Cyclin-dependent kinase, GSK-3, MESH: Cell Proliferation, medicine, Animals, Humans, MESH: Protein Kinase Inhibitors, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Kinase Inhibitors, Cell Proliferation, 030304 developmental biology, MESH: Glycogen Synthase Kinase 3, 0303 health sciences, Kidney, MESH: Kidney Diseases, MESH: Humans, biology, Kinase, MESH: Biological Markers, medicine.disease, Cyclin-Dependent Kinases, 3. Good health, medicine.anatomical_structure, MESH: Cyclin-Dependent Kinases, MESH: Anti-Inflammatory Agents, Immunology, Cancer research, biology.protein, Mesangial proliferative glomerulonephritis, Kidney Diseases, Biomarkers, 030217 neurology & neurosurgery, Kidney disease
Abstract

Proliferation of specific renal cell types leads to the development of many types of kidney disease. Given the central role that both cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) play in promoting aberrant proliferation within the kidney, these paralogous serine/threonine kinases are being explored as therapeutic molecular targets in proliferative renal diseases. CDK/GSK-3 inhibitors have now demonstrated efficacy in preclinical models of mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, proliferative lupus nephritis and collapsing glomerulopathy. Moreover, they have recently entered human clinical trials in IgA nephropathy. Since the pathogenesis of most proliferative renal diseases is multifactorial, there is the belief that CDK/GSK-3 inhibitors, as inherently promiscuous drugs, may have several modes of action. This is supported by recent studies in systems research delineating the antiinflammatory profile of CDK/GSK-3 inhibitors compared with other immunomodulators. Thus, CDK/GSK-3 inhibitors may emerge as effective drugs for proliferative renal diseases due to their integrative properties across several aspects of disease pathogenesis. This brief mini-review will highlight these issues.

Published
2006
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20. Synthesis, anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activity evaluation of benzimidazole/benzoxazole derivatives and some Schiff's bases

Author

Olivier Lozach, Laurent Meijer, Nirupma Singh, Ashok Kumar, Sham M. Sondhi, European Organization for Nuclear Research (CERN), Center for Visual Information Technology [Hyderabad] (CVIT), International Institute of Information Technology, Hyderabad [Hyderabad] (IIIT-H), Massachusetts Institute of Technology (MIT), Department of Biochemistry and Molecular Biology, University of Washington [Seattle], Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Analgesics, Clinical Biochemistry, Drug Evaluation, Preclinical, Pharmaceutical Science, 01 natural sciences, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Glycogen Synthase Kinase 3, Mice, MESH: Structure-Activity Relationship, Drug Discovery, Imidazole, MESH: Animals, MESH: Glycogen Synthase Kinase 3, Analgesics, Benzoxazoles, biology, Anti-Inflammatory Agents, Non-Steroidal, Benzoxazole, MESH: Anti-Inflammatory Agents, Non-Steroidal, MESH: CDC2 Protein Kinase, 3. Good health, Enzyme inhibitor, Molecular Medicine, MESH: Drug Evaluation, Preclinical, Female, MESH: Benzoxazoles, Benzimidazole, MESH: Cyclin-Dependent Kinase 5, MESH: Enzyme Activation, MESH: Rats, Stereochemistry, Imine, 010402 general chemistry, Structure-Activity Relationship, Cyclin-dependent kinase, CDC2 Protein Kinase, Structure–activity relationship, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Schiff Bases, Rats, Wistar, Molecular Biology, MESH: Mice, MESH: Protein Kinases, Schiff Bases, 010405 organic chemistry, Organic Chemistry, Cyclin-Dependent Kinase 5, MESH: Rats, Wistar, 0104 chemical sciences, Rats, Enzyme Activation, chemistry, biology.protein, Benzimidazoles, MESH: Benzimidazoles, Protein Kinases, MESH: Female
Abstract

A series of N-(acridin-9-yl)-4-(benzo[d]imidazol/oxazol-2-yl) benzamides has been synthesized by the condensation of 9-aminoacridine derivatives with benzimidazole or benzoxazole derivatives. Condensation of 2-hydroxy naphthaldehyde with functionalized diamines leads to the formation of Schiff's bases and not imidazole derivatives. All these compounds were characterized by correct FT-IR, (1)H NMR, MS and elemental analyses. These compounds were screened for anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activities. Compounds 11 and 7e(f) showed good anti-inflammatory (35.8% at 50 mg/kg po) activity and good analgesic activity (60% at 50 mg/kg po), respectively. Compound 3b showed significant in vitro activity against CDK-5 (IC(50)=4.6 microM) and CDK-1(IC(50)=7.4 microM) and compound 3a showed moderate CDK-5 inhibitory activity (IC(50)=7.5 microM). The other compounds showed moderate anti-inflammatory and analgesic activities.

Published
2006
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21. Synthesis and biological evaluation of novel phenylcarbazoles as potential anticancer agents

Author

Jean-Yves Mérour, Olivier Lozach, Laurent Meijer, Nathalie Dias, Amélie Lansiaux, Christian Bailly, Sylvain Routier, Génétique moléculaire et approches thérapeutiques des hémopathies malignes, IRCL-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Mécanique des Structures Industrielles Durables (LAMSID - UMR 8193), EDF R&D (EDF R&D), EDF (EDF)-EDF (EDF)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-EDF R&D (EDF R&D), EDF (EDF)-EDF (EDF), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Indoles, MESH: Cell Cycle, 01 natural sciences, Chemical synthesis, Maleimides, chemistry.chemical_compound, Glycogen Synthase Kinase 3, MESH: Structure-Activity Relationship, Drug Discovery, Moiety, Cytotoxicity, Maleimide, MESH: Glycogen Synthase Kinase 3, MESH: Maleimides, MESH: Indoles, biology, Cell Cycle, MESH: Drug Screening Assays, Antitumor, MESH: DNA, MESH: CDC2 Protein Kinase, MESH: Drug Resistance, Neoplasm, Molecular Medicine, medicine.symptom, MESH: Cyclin-Dependent Kinase 5, MESH: Cell Line, Tumor, Stereochemistry, Carbazoles, Antineoplastic Agents, 010402 general chemistry, Structure-Activity Relationship, Cell Line, Tumor, CDC2 Protein Kinase, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Indole test, MESH: Humans, 010405 organic chemistry, Topoisomerase, Cyclin-Dependent Kinase 5, DNA, 0104 chemical sciences, chemistry, Mechanism of action, Drug Resistance, Neoplasm, biology.protein, MESH: Antineoplastic Agents, Drug Screening Assays, Antitumor, Topoisomerase I Inhibitors, MESH: Carbazoles, MESH: DNA Topoisomerases, Type I
Abstract

We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole and hydroxyindole were used to generate three scaffolds that were successively exploited to introduce various substituents on the maleimide moiety. The synthesis includes a final intramolecular key Heck-type reaction, which was carried out with a triflate derivative or with a bromophenyl derivative. Each step was optimized and the complete chemical strategy is detailed. Several compounds showed a marked cytotoxicity against CEM human leukemia cells with IC(50) values in the 10-100 nM range. Precise structure-activity relationships were delineated. Cell cycle analysis, topoisomerase I inhibition, and interaction with DNA were evaluated, and inhibition of CDK activity was also investigated. Although binding of the drugs to DNA likely contributes to the cytotoxic action, the exact molecular targets of these molecules remain undiscovered. The efficient chemical routes reported here for the design of highly cytotoxic compounds provide novel opportunities to identify antitumor agents in the phenylcarbazole series.

Published
2006
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22. Synthesis and evaluation of the antiproliferative activity of novel thiazoloquinazolinone kinases inhibitors

Author

Thierry Besson, Jean-Marie Piot, Olivier Lozach, Laurent Meijer, Mélina Blairvacq, Alexandra Testard, Valérie Thiéry, Laurent Picot, Laurence Murillo, LIttoral ENvironnement et Sociétés (LIENSs), La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Phophorylation de protéines et Pathologies Humaines (P3H), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Cell Line, Tumor, MESH: Molecular Structure, Drug Evaluation, Preclinical, MESH: Microwaves, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Glycogen Synthase Kinase 3, Structure-Activity Relationship, MESH: Structure-Activity Relationship, Cyclin-dependent kinase, GSK-3, Cell Line, Tumor, MESH: Cell Proliferation, Drug Discovery, Structure–activity relationship, Humans, Enzyme Inhibitors, Microwaves, 030304 developmental biology, Cell Proliferation, MESH: Glycogen Synthase Kinase 3, Pharmacology, 0303 health sciences, MESH: Humans, biology, Molecular Structure, 010405 organic chemistry, Kinase, Chemistry, [SDV.BA]Life Sciences [q-bio]/Animal biology, General Medicine, Cyclin-Dependent Kinases, 0104 chemical sciences, 3. Good health, MESH: Quinazolines, MESH: Cyclin-Dependent Kinases, Biochemistry, Cell culture, MESH: Enzyme Inhibitors, biology.protein, Quinazolines, MESH: Drug Evaluation, Preclinical, Lead compound
Abstract

International audience; The microwave-assisted synthesis of a family of 2,8-substituted thiazoloquinazolinones is described. The preliminary evaluation of the antiproliferative activity and the capacity of these molecules to inhibit CDKs and GSK-3 are reported. A lead compound was identified, constituting a scaffold from which more potent inhibitors could be designed.

Published
2005
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23. Inhibition of HMC-1 mast cell proliferation by vitamin E: involvement of the protein kinase B pathway

Author

Kempná, Petra, Reiter, Elke, Arock, Michel, Azzi, Angelo, Zingg, Jean-Marc, Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Mécanique Appliquée, Université des sciences et de la Technologie d'Oran Mohamed Boudiaf [Oran] (USTO MB), Unité de Recherche Matériaux et Energies Renouvelables (URMER), and Université Aboubekr Belkaid - University of Belkaïd Abou Bekr [Tlemcen]

Subjects
MESH: Signal Transduction, Time Factors, MESH: Piperazines, Tocopherols, Apoptosis, Piperazines, MESH: Dose-Response Relationship, Drug, Glycogen Synthase Kinase 3, Phosphatidylinositol 3-Kinases, MESH: Vitamin E, Vitamin E, Mast Cells, Enzyme Inhibitors, Phosphorylation, MESH: Tocopherols, MESH: Glycogen Synthase Kinase 3, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, MESH: Oxidative Stress, MESH: Mast Cells, U937 Cells, MESH: Enzyme Inhibitors, Benzamides, Imatinib Mesylate, MESH: Hydrogen Peroxide, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Mitogen-Activated Protein Kinase 3, MESH: ras Proteins, Signal Transduction, MESH: Mitogen-Activated Protein Kinase 1, MESH: Cell Line, Tumor, Blotting, Western, Protein Serine-Threonine Kinases, MESH: U937 Cells, Models, Biological, MESH: Protein-Serine-Threonine Kinases, Cell Line, Tumor, Proto-Oncogene Proteins, MESH: Cell Proliferation, Humans, MESH: Blotting, Western, Cell Proliferation, Glycogen Synthase Kinase 3 beta, MESH: Humans, Dose-Response Relationship, Drug, MESH: Phosphorylation, MESH: Proto-Oncogene Proteins c-akt, MESH: Apoptosis, Cell Membrane, MESH: Time Factors, MESH: Models, Biological, Hydrogen Peroxide, MESH: 1-Phosphatidylinositol 3-Kinase, MESH: Proto-Oncogene Proteins, Oxidative Stress, Pyrimidines, MESH: Pyrimidines, ras Proteins, Proto-Oncogene Proteins c-akt, MESH: Cell Membrane
Abstract

The effects of four natural tocopherols on the proliferation and signaling pathways were examined in the human mastocytoma cell line (HMC-1). The four tocopherols inhibited HMC-1 cell proliferation with different potency (delta > alpha = gamma > beta). Growth inhibition correlated with the reduction of PKB (protein kinase B) phosphorylation by the different tocopherols. The reduction of PKB phosphorylation led to a decrease of its activity, as judged from a parallel reduction of GSKalpha/beta phosphorylation. The translocation of PKB to the membrane, as a response to receptor stimulation by NGFbeta, is also prevented by treatment with tocopherols. In the presence of PKC or PP2A inhibitors, the reduction of PKB phosphorylation by tocopherols was still observed, thus excluding the direct involvement of these enzymes. Other pathways, such as the Ras-stimulated ERK1/2 (extracellular signal responsive kinase) pathway, were not affected by tocopherol treatment. The tocopherols did not significantly change oxidative stress in HMC-1 cells, suggesting that the observed effects are not the result of a general reduction of oxidative stress. Thus, the tocopherols interfere with PKB phosphorylation and reduce proliferation of HMC-1 cells, possibly by modulating either phosphatidylinositol 3-kinase, a kinase phosphorylating PKB (PDK1/2), or a phosphatase that dephosphorylates it. Inhibition of proliferation and PKB signaling in HMC-1 cells by vitamin E suggests a role in preventing diseases with mast cell involvement, such as allergies, atherosclerosis, and tumorigenesis.

Published
2004
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24. Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells

Author

Pierre Savatier, Stéphanie Gobert-Gosse, Suzy Markossian, Marielle Afanassieff, Ludmila Jirmanova, Unité mixte de recherche biologie moléculaire de la cellule, École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de Biologie Moléculaire et Cellulaire, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, MESH: Cyclin D1, Cyclin D, [SDV]Life Sciences [q-bio], Cyclin A, Cyclin B, S Phase, Glycogen Synthase Kinase 3, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Cyclin D1, MESH: Animals, Enzyme Inhibitors, Phosphorylation, ComputingMilieux_MISCELLANEOUS, Cyclin, MESH: Glycogen Synthase Kinase 3, 0303 health sciences, biology, Stem Cells, MESH: S Phase, Cell Differentiation, MESH: Ca(2+)-Calmodulin Dependent Protein Kinase, MESH: Gene Expression Regulation, Cell biology, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, MESH: Immunosuppressive Agents, Mitogen-Activated Protein Kinases, Immunosuppressive Agents, MESH: Cell Differentiation, Blotting, Western, Antineoplastic Agents, Tretinoin, MESH: Stem Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: G1 Phase, 03 medical and health sciences, Cyclin-dependent kinase, Genetics, Animals, MESH: Blotting, Northern, MESH: Blotting, Western, RNA, Messenger, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Sirolimus, MESH: Tretinoin, MESH: Phosphorylation, MESH: Embryo, G1 Phase, G1/S transition, MESH: 1-Phosphatidylinositol 3-Kinase, Blotting, Northern, Embryo, Mammalian, MESH: Mitogen-Activated Protein Kinases, Gene Expression Regulation, Calcium-Calmodulin-Dependent Protein Kinases, Cancer research, biology.protein, MESH: Antineoplastic Agents, MESH: Sirolimus, Cyclin A2
Abstract

Mouse embryonic stem (ES) cells are known to express D-type cyclins at very low levels and these levels increase dramatically during in vitro and in vivo differentiation. Here, we investigate some of the signalling pathways regulating expression of cyclin D1 and progression to S phase, the Ras/Extracellular signal-regulated protein kinase (ERK) pathway and the phosphatidylinositol 3-kinase (PI3-kinase) pathway. We demonstrate that ERK phosphorylation is fully dispensable for the regulation of cyclin D1 level and for the progression from G1 to S phase in ES cells. By contrast, PI3-kinase activity is required for both. Differentiation induced by retinoic acid results in the gain of ERK-dependent control of cyclin D1 expression and of S phase progression. Differentiation is also paralleled by an increase in PI3-kinase activity. This leads (a) to an increase in the p70 S6 kinase-dependent regulation of the steady-state level of cyclin D1, and (b) to a concomitant decrease in the GSK3beta-dependent rate of cyclin D1 degradation. Altogether, these multiple pathways account for the dramatic increase in the level of cyclin D1 protein which parallels ES cell differentiation. Our studies suggest that PI3-kinase is an important regulator of the ES cell cycle and that its activity is not regulated by mitogen stimulation.

Published
2002
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25. Effects of GSK3 inhibitors on in vitro expansion and differentiation of human adipose-derived stem cells into adipocytes

Author

Christian Dani, Pascal Peraldi, Laure-Emmanuelle Zaragosi, Brigitte Wdziekonski, Coralie Fontaine, Phi Villageois, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Male, Cellular differentiation, Adipose tissue, Glycogen Synthase Kinase 3, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Adipocytes, MESH: Protein Kinase Inhibitors, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Cells, Cultured, MESH: Glycogen Synthase Kinase 3, Stem cell transplantation for articular cartilage repair, 0303 health sciences, Adipogenesis, lcsh:Cytology, Stem Cells, Cell Differentiation, MESH: Lithium Chloride, Immunohistochemistry, MESH: Infant, Cell biology, Adipose Tissue, Child, Preschool, 030220 oncology & carcinogenesis, Stem cell, MESH: Adipose Tissue, Research Article, MESH: Cells, Cultured, Adult stem cell, MESH: Cell Differentiation, Adipose tissue macrophages, MESH: Stem Cells, macromolecular substances, Biology, 03 medical and health sciences, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:QH573-671, Protein Kinase Inhibitors, MESH: Adipocytes, 030304 developmental biology, MESH: Humans, MESH: Child, Preschool, Infant, MESH: Immunohistochemistry, 3T3-L1, Cell Biology, MESH: Male, chemistry, Lithium Chloride, MESH: Adipogenesis
Abstract

Background Multipotent stem cells exist within adipose tissue throughout life. An abnormal recruitment of these adipose precursor cells could participate to hyperplasia of adipose tissue observed in severe obesity or to hypoplasia of adipose tissue observed in lipodystrophy. Therefore, pharmacological molecules that control the pool of stem cells in adipose tissue are of great interest. Glycogen Synthase Kinase (GSK) 3 has been previously described as involved in differentiation of preadipose cells and might be a potential therapeutic target to modulate proliferation and differentiation of adipocyte precursors. However, the impact of GSK3 inhibition on human adipose-derived stem cells remained to be investigated. The aim of this study was to investigate GSK3 as a possible target for pharmacological inhibition of stem cell adipogenesis. To reach this goal, we studied the effects of pharmacological inhibitors of GSK3, i.e. lithium chloride (LiCl) and BIO on proliferation and adipocyte differentiation of multipotent stem cells derived from human adipose tissue. Results Our results showed that GSK3 inhibitors inhibited proliferation and clonogenicity of human stem cells, strongly suggesting that GSK3 inhibitors could be potent regulators of the pool of adipocyte precursors in adipose tissue. The impact of GSK3 inhibition on differentiation of hMADS cells was also investigated. Adipogenic and osteogenic differentiations were inhibited upon hMADS treatment with BIO. Whereas a chronic treatment was required to inhibit osteogenesis, a treatment that was strictly restricted to the early step of differentiation was sufficient to inhibit adipogenesis. Conclusion These results demonstrated the feasibility of a pharmacological approach to regulate adipose-derived stem cell function and that GSK3 could represent a potential target for controlling adipocyte precursor pool under conditions where fat tissue formation is impaired.

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