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1. Brain tumor with an ATXN1-NUTM1 fusion gene expands the histologic spectrum of NUTM1-rearranged neoplasia

Author

Charlotte Dubucs, Aurore Siegfried, Emmanuelle Uro-Coste, Gaëlle Pierron, I. Catalaa, Marion Gambart, Julien Masliah-Planchon, Badreddine Mohand-Oumoussa, Franck Tirode, Sarah Péricart, Franck Bourdeaut, Franck-Emmanuel Roux, Delphine Larrieu-Ciron, Yvan Nicaise, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), 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), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut Curie, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), TIRODE, Franck, Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
medicine.medical_specialty, Pathology, Neurology, CIC-ATXN1-ATXN1L axis, DNA methylation-based classification, Central nervous system, Brain tumor, Oncogenic gene fusions, CIC-ATXN1-ATXN1L axis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:RC346-429, Pathology and Forensic Medicine, Fusion gene, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ATXN1, medicine, Letter to the Editor, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, NUTM1-rearranged neoplasia, RNA sequencing, NUTM1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Oncogenic gene fusions, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neurology (clinical)
Abstract

International audience

Published
2019

2. RREB1-MKL2 fusion in biphenotypic 'oropharyngeal' sarcoma: New entity or part of the spectrum of biphenotypic sinonasal sarcomas?

Author

Philippe Rochaix, Aurore Siegfried, David Grand, Frédéric Escudié, Claire Romary, Yvan Nicaise, Christine Chevreau, Emmanuelle Uro-Coste, Sophie Le Guellec, Sébastien Vergez, Jean-Michel Coindre, and Béatrice Herbault Barres

Subjects
Male, 0301 basic medicine, Cancer Research, Oncogene Proteins, Fusion, PAX3, Soft Tissue Neoplasms, Biology, medicine.disease_cause, S100 protein, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, Biomarkers, Tumor, Genetics, medicine, Humans, Oncogene Fusion, Gene, Transcription factor, Sarcoma, Middle Aged, medicine.disease, DNA-Binding Proteins, Oropharyngeal Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Spindle cell sarcoma, Gene Fusion, Carcinogenesis, Paranasal Sinus Neoplasms, Transcription Factors
Abstract

An increasing number of sarcomas displaying a primitive, monomorphic spindle cell phenotype have been shown to harbor recurrent gene fusions, including biphenotypic sinonasal sarcoma (SNS). Occurring in the sinonasal area of middle-aged patients, SNS is a locally aggressive tumor harboring in 90% of cases recurrent gene fusions involving the PAX3 gene, in which the chimeric transcription factor induces an aberrant dual myogenic and neural phenotype. Here, we report an unusual oropharyngeal monomorphic spindle cell sarcoma in a 53-year-old man that revealed a novel RREB1-MKL2 gene fusion by RNA sequencing with the Illumina TruSight RNA Fusion Panel. The gene fusion was validated by RT-PCR. Although the tumor location is unusual (but head and neck seated), most of the other clinical, morphologic, immunophenotypic (focal combined expression of S100 protein, SMA, desmin, and myogenin) and oncogenic data suggest that this biphenotypic "oropharyngeal" sarcoma is closely related to the biphenotypic SNS spectrum. Notably, the RREB1-MKL2 chimeric transcription factor encoded by this fusion gene produced an increase in MKL2 expression, which regulates both neural and myogenic differentiation, mimicking the crucial role of PAX3 reported in SNS oncogenesis. NGS and especially RNA sequencing may be used to identify new candidate fusion oncogenes in soft tissue tumors, which would help in updating the existing classification. In turn, this would lead to better therapeutic management of patients.

Published
2018

3. EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity

Author

Anne-Isabelle Bertozzi, Emmanuelle Uro-Coste, Claude-Alain Maurage, Sarah Péricart, Sergio Boetto, Yvan Nicaise, Sophie Le Guellec, Camille Franchet, Alix Delrieu, Matthieu Vinchon, David Grand, Frédéric Escudié, David T.W. Jones, Valérie Rigau, Anne Gomez-Brouchet, Aurore Siegfried, Jean-Christophe Sol, Audrey Rousseau, Franck-Emmanuel Roux, Dominique Figarella-Branger, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), 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), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Pathologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Pathologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Claudius-Regaud [IUCT, Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Département de Neurochirurgie [CHU Toulouse], Département de Neurochirurgie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Toulouse Neuro Imaging Center (ToNIC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Département de Pathologie [Centre Médical Universitaire Montpellier], Centre Médical Universitaire Montpellier - CMUM, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncopédiatrie [CHU Toulouse], Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], Division of Pediatric Neurooncology [Heidelberg, Germany], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-German Cancer Consortium [Heidelberg] (DKTK), Département de Pathologie [CHU Marseille], CHU Marseille, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), D. Jones is supported by funding for the Everest Centre for Paediatric Low- Grade Brain Tumour Research through the Brain Tumour Charity (UK). We are grateful to Karen Silva for her help in handling tumor samples from the different pathological departments. Samples from Marseille were retrieved from the AP-HM tumor bank AC 2017:1786. Samples from Toulouse were retrieved from the CHU de Toulouse tumor bank BB-0033-00014., Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Neurochirurgie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Bernardo, Elizabeth, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA - Département NOHMAD - Equipe 17), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopp Children's Cancer Center at the NCT Heidelberg - KiTZ [Heidelber, Germany]g, Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre hospitalier universitaire d'Angers ( CHU Angers ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille ( U837 INSERM - IRCL ), Institut pour la recherche sur le cancer de Lille [Lille] ( IRCL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Universitaire du Cancer Toulouse - Oncopôle ( IUCT ), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Toulouse Neuro Imaging Center ( ToNIC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Purpan - Centre Hospitalier Universitaire (CHU) de Toulouse-Université Toulouse III - Paul Sabatier, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), German Cancer Research Center ( DKFZ ) -German Cancer Consortium - DKTK [Heidelberg, Germany], Institut de neurophysiopathologie ( INP ), and Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
0301 basic medicine, Adult, Male, DNA Copy Number Variations, Kruppel-Like Transcription Factors, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Ganglioglioma, Fusion gene, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, medicine, Biomarkers, Tumor, Humans, Copy-number variation, Child, In Situ Hybridization, Fluorescence, Research Articles, Sanger sequencing, Brain Neoplasms, General Neuroscience, Methylation, DNA Methylation, medicine.disease, Neoplasms, Neuroepithelial, 3. Good health, Repressor Proteins, 030104 developmental biology, Fusion transcript, Cancer research, symbols, Female, Neurology (clinical), Gene Fusion, RNA-Binding Protein EWS, 030217 neurology & neurosurgery
Abstract

International audience; We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1-PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1-PATZ1 fusion transcript. RT-PCR followed by Sanger sequencing confirmed the EWSR1-PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N terminal transcriptional activation domain of EWSR1 gene and the C terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB-ZF (broad-complex, tramtrack and bric-à-brac -zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1-PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAF[V600E] negative ganglioglioma, the second a BRAF[V600E] negative glioneuronal tumor, not otherwise specified, and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAF[V600E] negative gangliogliomas were screened by FISH using EWSR1 break-apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well-defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1-PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.

Published
2019

4. Cardioprotective Angiotensin-(1-7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

Author

Jean-Michel Senard, Marie-Hélène Seguelas, Du N’Guyen, Caroline Dubroca, Jean-Louis Banères, Céline M'Kadmi, Yvan Nicaise, Céline Galés, Atul Pathak, Cédric Boularan, Colette Denis, Claire Pilette, Ségolène Galandrin, and Jacky Marie

Subjects
0301 basic medicine, Biased ligand, medicine.medical_specialty, Cardiotonic Agents, Peptide, Receptor, Angiotensin, Type 2, Sensitivity and Specificity, Renin-Angiotensin System, 03 medical and health sciences, Phenylephrine, Internal medicine, Renin–angiotensin system, Internal Medicine, medicine, Functional selectivity, Animals, Humans, Aorta, Abdominal, Receptor, Cells, Cultured, beta-Arrestins, G protein-coupled receptor, chemistry.chemical_classification, Angiotensin 1, Angiotensin II, Muscles, Peptide Fragments, 030104 developmental biology, Endocrinology, HEK293 Cells, chemistry, Vasoconstriction, cardiovascular system, Angiotensin I, hormones, hormone substitutes, and hormone antagonists, Signal Transduction
Abstract

Hyperactivity of the renin–angiotensin–aldosterone system through the angiotensin II (Ang II)/Ang II type 1 receptor (AT1-R) axis constitutes a hallmark of hypertension. Recent findings indicate that only a subset of AT1-R signaling pathways is cardiodeleterious, and their selective inhibition by biased ligands promotes therapeutic benefit. To date, only synthetic biased ligands have been described, and whether natural renin–angiotensin–aldosterone system peptides exhibit functional selectivity at AT1-R remains unknown. In this study, we systematically determined efficacy and potency of Ang II, Ang III, Ang IV, and Ang-(1–7) in AT1-R–expressing HEK293T cells on the activation of cardiodeleterious G-proteins and cardioprotective β-arrestin2. Ang III and Ang IV fully activate similar G-proteins than Ang II, the prototypical AT1-R agonist, despite weaker potency of Ang IV. Interestingly, Ang-(1–7) that binds AT1-R fails to promote G-protein activation but behaves as a competitive antagonist for Ang II/Gi and Ang II/Gq pathways. Conversely, all renin–angiotensin–aldosterone system peptides act as agonists on the AT1-R/β-arrestin2 axis but display biased activities relative to Ang II as indicated by their differences in potency and AT1-R/β-arrestin2 intracellular routing. Importantly, we reveal Ang-(1–7) a known Mas receptor-specific ligand, as an AT1-R–biased agonist, selectively promoting β-arrestin activation while blocking the detrimental Ang II/AT1-R/Gq axis. This original pharmacological profile of Ang-(1–7) at AT1-R, similar to that of synthetic AT1-R–biased agonists, could, in part, contribute to its cardiovascular benefits. Accordingly, in vivo, Ang-(1–7) counteracts the phenylephrine-induced aorta contraction, which was blunted in AT1-R knockout mice. Collectively, these data suggest that Ang-(1–7) natural-biased agonism at AT1-R could fine-tune the physiology of the renin–angiotensin–aldosterone system.

Published
2016

5. Colony induction and growth inhibition in Desmodesmus quadrispina (Chlorococcales) by allelochemicals released from the filamentous alga Uronema confervicolum (Ulotrichales)

Author

Joséphine Leflaive, Yvan Nicaise, Loïc Ten-Hage, and Gérard Lacroix

Subjects
0106 biological sciences, 0303 health sciences, biology, 010604 marine biology & hydrobiology, fungi, Ulotrichales, Biofilm, Context (language use), Desmodesmus, Chlorococcales, biology.organism_classification, 01 natural sciences, Microbiology, Monoraphidium, 03 medical and health sciences, Algae, Botany, 14. Life underwater, Ecology, Evolution, Behavior and Systematics, Allelopathy, 030304 developmental biology
Abstract

In biofilms, the competition between microorganisms for light, nutrients and space is extreme. Moreover, planktonic algae can be considered as competitors insofar as they decrease the available light for the benthic algae. One of the strategies employed by microorganisms to eliminate competitors is the release of inhibiting compounds, a process known as allelopathy. Here we demonstrate that a benthic/epiphytic alga, Uronema confervicolum, produces allelopathic compounds that induce oxidative stress and growth inhibition in the planktonic Desmodesmus quadrispina. Some of these compounds can also trigger the formation of colony in D. quadrispina. As colonies have higher sedimentation rates than unicells, their induction by U. confervicolum might decrease shading. This study is the first report of colony induction in the context of alga-alga interaction. Our results also suggest the implication of mitogen-activated protein (MAP) kinases in the transduction of the signal leading to the formation of reactive oxygen species in the cells. A comparison with allelochemicals from another planktonic green alga, Monoraphidium aff. dybowski, emphasizes the specificity of colony induction by U. confervicolum, in contrast with oxidative stress which is induced by several compounds. The reciprocal production of inhibiting compounds by D. quadrispina makes this interaction an interesting example of co-evolution between two microorganisms belonging to different compartments of the ecosystem.

Published
2008

6. Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease

Author

Johnatan Ceccom, Claude Alain Maurage, Yvan Nicaise, Olivier Cuvillier, Stuart M. Pitson, Charles Duyckaerts, Valérie Lauwers-Cances, Marie-Bernadette Delisle, Catherine Gentil, Najat Loukh, Christian Touriol, Emmanuelle Uro-Coste, Service d'Anatomie Pathologique, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service d'Epidémiologie, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), 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), Centre for Cancer Biology, SA Pathology, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Service de Pathologie, Université Lille Nord (France)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), This work was supported by a grant from the Clinical Research Hospital Program from the French Ministry of Health (PHRC 2010, n° 18_02) and the Fondation Plan Alzheimer., Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Epidémiologie clinique et santé publique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Ceccom, Johnatan, Loukh, Najat, Lauwers-, Cances Valerie, Touriol, Christian, Nicaise, Yvan, Gentil, Catherine, Uro-Coste, Emmanuelle, Pitson, Stuart, Maurage, Claude Alain, Duyckaerts, Charles, Cuvillier, Olivier, Delisle, Marie-Bernadette, and BMC, Ed.

Subjects
Male, Statistics as Topic, chemistry.chemical_compound, 0302 clinical medicine, Receptor, Neuropathology, Aged, 80 and over, Neurons, 0303 health sciences, sphingoising1-phosphate lyase-neuropatholgy, Neurodegeneration, Brain, Sphingosine kinase-1, Middle Aged, Alzheimer's disease, Cell biology, Sphingosine 1-phosphate lyase, Phosphotransferases (Alcohol Group Acceptor), Biochemistry, Sphingosine kinase 1, sphingosine kinase-1, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer’s disease, Alzheimer ' s disease, Signal Transduction, beta amyloid, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Sphingosine-1-phosphate, Aged, Aldehyde-Lyases, 030304 developmental biology, Sphingolipids, Amyloid beta-Peptides, sphingolipids, Sphingosine, Cell growth, Research, Beta amyloid, Lipid signaling, medicine.disease, Sphingolipid, Gene Expression Regulation, chemistry, biology.protein, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: The accumulation of beta amyloid (Aβ) peptides, a hallmark of Alzheimer's disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Aβ accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Aβ peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling. RESULTS: Herein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P. CONCLUSIONS: Collectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor.

Published
2014

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