Descriptor: "MESH: ras Proteins" - Searchworks@Jio Institute Digital Library Search Results

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32 results on '"MESH: ras Proteins"'

1. A RAS-CaMKKβ-AMPKα2 pathway promotes senescence by licensing post-translational activation of C/EBPβ through a novel 3'UTR mechanism

Author: Kevin P. Claffey, Peter F. Johnson, Mesfin Gonit, Myriam Gorospe, Atharva Bhat, Jacqueline Salotti, Jiji Chen, Sandip K. Basu, Benoit Viollet, Mouse Cancer Genetics Program [Frederick, MD, USA] (Center for Cancer Research), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)-Center for Cancer Research [Frederick, MD, USA], Lentigen Tech, Inc. [Gaithersburg, MD, USA], Cancer and Inflammation Program [Frederick, MD, USA] (Leidos Biomedical Research Inc.), Frederick National Laboratory for Cancer Research (FNLCR)-NCI-Frederick, Advanced Imaging and Microscopy Resource [Bethesda, MD, USA], National Institutes of Health [Bethesda] (NIH), Laboratory of Genetics [Baltimore, MD, USA] (National Institute on Aging-Intramural Research Program), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology [Farmington, CT, USA], University of Connecticut (UCONN), This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government., and Viollet, Benoit
Subjects: 0301 basic medicine, Cancer Research, AMP-Activated Protein Kinases, MESH: Mice, Knockout, law.invention, ELAV-Like Protein 1, Mice, law, Neoplasms, CEBPB, MESH: Animals, MESH: Neoplasms, MESH: AMP-Activated Protein Kinases, 10. No inequality, 3' Untranslated Regions, Cellular Senescence, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Mice, Knockout, MESH: ELAV-Like Protein 1, MESH: 3' Untranslated Regions, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cell biology, MESH: MCF-7 Cells, MESH: HEK293 Cells, MCF-7 Cells, MESH: ras Proteins, Senescence, MESH: Enzyme Activation, MESH: Cell Line, Tumor, Biology, MESH: CCAAT-Enhancer-Binding Protein-beta, 03 medical and health sciences, Cell Line, Tumor, Genetics, Animals, Humans, Molecular Biology, MESH: Mice, MESH: Humans, Three prime untranslated region, Binding protein, CCAAT-Enhancer-Binding Protein-beta, AMPK, MESH: Cellular Senescence, Enzyme Activation, 030104 developmental biology, HEK293 Cells, Cytoplasm, A549 Cells, Cancer cell, NIH 3T3 Cells, ras Proteins, Suppressor, MESH: A549 Cells, MESH: NIH 3T3 Cells
Abstract: International audience; Oncogene-induced senescence (OIS) is an intrinsic tumor suppression mechanism that requires the p53 and RB pathways and post-translational activation of C/EBPβ through the RAS-ERK cascade. We previously reported that in transformed/proliferating cells, C/EBPβ activation is inhibited by G/U-rich elements (GREs) in its 3'UTR. This mechanism, termed "3'UTR regulation of protein activity" (UPA), maintains C/EBPβ in a low-activity state in tumor cells and thus facilitates senescence bypass. Here we show that C/EBPβ UPA is overridden by AMPK signaling. AMPK activators decrease cytoplasmic levels of the GRE binding protein HuR, which is a key UPA component. Reduced cytoplasmic HuR disrupts 3'UTR-mediated trafficking of Cebpb transcripts to the peripheral cytoplasm-a fundamental feature of UPA-thereby stimulating C/EBPβ activation and growth arrest. In primary cells, oncogenic RAS triggers a Ca++-CaMKKβ-AMPKα2-HuR pathway, independent of AMPKα1, that is essential for C/EBPβ activation and OIS. This axis is disrupted in cancer cells through down-regulation of AMPKα2 and CaMKKβ. Thus, CaMKKβ-AMPKα2 signaling constitutes a key tumor suppressor pathway that activates a novel UPA-cancelling mechanism to unmask the cytostatic and pro-senescence functions of C/EBPβ.
Published: 2017
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2. FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer

Author: Vincent Denis, Christel Larbouret, Laetitia K. Linares, Esther Pérez-Gracia, Delphine Desigaud, Adeline Ayrolles-Torro, Nadia Vie, M. del Rio, Marta Jarlier, Clara Montagut, Diego Tosi, E W-F Lam, Laetitia Marzi, Mar Iglesias, Céline Gongora, Pierre Martineau, Eve Combes, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Medical Oncology [Barcelona, Spain], Hospital del Mar [Barcelona, Spain], Department of Surgery & Cancer [London, UK], Imperial College London-Cancer Imaging Centre [London, UK], This work was supported by INSERM and ICM Val D’Aurelle. LM had a PhD studentship from the French government. EC has a PhD studentship from the Labex MabImprove. AT had a MabImprove post-doctoral fellowship. The research leading to this publication was funded by the French National Research Agency under the programme ‘Investissements d’avenir’ Grant Agreement LabEx MAbImprove: ANR-10-LABX-53 and SIRIC (INCA-DGOS-Inserm 6045)., ANR-10-LABX-53-01/10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development - Better antibodies, better developed and better used(2010), IMIM-Hospital del Mar, Generalitat de Catalunya, Imperial College London, ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), Imperial College Trust, Herrada, Anthony, and Laboratoires d'excellence - Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used - - MAbImprove2010 - ANR-10-LABX-0053 - LABX - VALID
Subjects: 0301 basic medicine, Oncology, MESH: Cell Death, MESH: Signal Transduction, Cancer Research, Colorectal cancer, Cetuximab, medicine.disease_cause, p38 Mitogen-Activated Protein Kinases, MESH: ErbB Receptors, MESH: Antibodies, Monoclonal, Mice, 0302 clinical medicine, MESH: Cetuximab, MESH: Up-Regulation, MAPK p38, MESH: Animals, signalling, Cell Death, Forkhead Box Protein O3, Antibodies, Monoclonal, MESH: Gene Expression Regulation, Neoplastic, 3. Good health, Up-Regulation, ErbB Receptors, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Biomarker (medicine), Female, KRAS, MESH: Caco-2 Cells, Colorectal Neoplasms, MESH: ras Proteins, medicine.drug, Signal Transduction, medicine.medical_specialty, Programmed cell death, MESH: Cell Line, Tumor, Mice, Nude, Context (language use), Antineoplastic Agents, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Forkhead Box Protein O3, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Cell Line, Tumor, MESH: Cell Proliferation, medicine, MESH: Mice, Nude, Animals, Humans, Oncology & Carcinogenesis, FOXO3a, MESH: Mice, neoplasms, Cell Proliferation, MESH: Humans, Cell growth, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, MESH: p38 Mitogen-Activated Protein Kinases, 030104 developmental biology, Apoptosis, ras Proteins, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Antineoplastic Agents, Caco-2 Cells, business, Translational Therapeutics, 1112 Oncology And Carcinogenesis, MESH: Female, MESH: Colorectal Neoplasms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: BACKGROUND: Cetuximab, a monoclonal antibody against EGFR used for the treatment of colorectal cancer (CRC), is ineffective in many patients. The aim of this study was to identify the signalling pathways activated by cetuximab in CRC cells and define new biomarker of response. METHODS: We used in vitro, in vivo models and clinical CRC samples to assess the role of p38 and FOXO3a in cetuximab mechanism of action. RESULTS: We show that cetuximab activates the MAPK p38. Specifically, p38 inhibition reduced cetuximab efficacy on cell growth and cell death. At the molecular level, cetuximab activates the transcription factor FOXO3a and promotes its nuclear translocation via p38-mediated phosphorylation, leading to the upregulation of its target genes p27 and BIM and the subsequent induction of apoptosis and inhibition of cell proliferation. Finally, we found that high FOXO3a and p38 expression levels are associated with better response rate and improved outcome in cetuximab-treated patients with CRC harbouring WT KRAS. CONCLUSIONS: We identify FOXO3a as a key mediator of cetuximab mechanism of action in CRC cells and define p38 as its activator in this context. Moreover, high FOXO3a and p38 expression could predict the response to cetuximab in patients with CRC harbouring WT KRAS.British Journal of Cancer advance online publication, 29 September 2016; doi:10.1038/bjc.2016.313 www.bjcancer.com.
Published: 2016
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3. MET Gene Copy Number in Non-small Cell Lung Cancer: Molecular Analysis in a Targeted Tyrosine Kinase Inhibitor Naïve Cohort

Author: Michèle Beau-Faller, Gilbert Massard, Marie Pierre Gaub, Nicolas Meyer, Pierre Oudet, Michèle Legrain, Elisabeth Quoix, Eric Guérin, Anne-Claire Voegeli, Bertrand Mennecier, Anne-Marie Ruppert, Agnès Neuville, Jean-Marie Wihlm, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MET gene, Lung Neoplasms, medicine.medical_treatment, DNA Mutational Analysis, Gene Dosage, MESH: Adenocarcinoma, Bronchiolo-Alveolar, Bioinformatics, MESH: Gene Dosage, Tyrosine-kinase inhibitor, Targeted therapy, Cohort Studies, MESH: Aged, 80 and over, 0302 clinical medicine, Non-small cell lung cancer, Epidermal growth factor, MESH: Reverse Transcriptase Polymerase Chain Reaction, Carcinoma, Non-Small-Cell Lung, Copy-number variation, MESH: DNA Mutational Analysis, MESH: Cohort Studies, MESH: Aged, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, K-Ras gene, MESH: Carcinoma, Squamous Cell, Middle Aged, Proto-Oncogene Proteins c-met, Prognosis, 3. Good health, ErbB Receptors, Survival Rate, EGFR gene, Oncology, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Adenocarcinoma, Female, MESH: ras Proteins, Adult, Pulmonary and Respiratory Medicine, MESH: Survival Rate, medicine.drug_class, MESH: Receptor, Epidermal Growth Factor, Gene dosage, MESH: Prognosis, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Proto-Oncogene Proteins, MESH: Receptors, Growth Factor, medicine, Humans, Receptors, Growth Factor, RNA, Messenger, Lung cancer, Survival rate, MESH: RNA, Messenger, 030304 developmental biology, Aged, MESH: Humans, business.industry, MESH: Adenocarcinoma, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Adenocarcinoma, Bronchiolo-Alveolar, medicine.disease, MESH: Male, MESH: Lung Neoplasms, respiratory tract diseases, MESH: Proto-Oncogene Proteins, Cancer research, ras Proteins, business, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung
Abstract: Introduction Recent clinical success of epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) have raised hopes that targeting other deregulated growth factor signaling, such as the hepatocyte growth factor/MET pathway, will lead to new therapeutic options for NSCLC. Furthermore, NSCLC present secondary EGFR-TKIs resistance related to exons 20 and 19 EGFR mutations or more recently to MET amplification. The aim of this study was to determine MET copy number related to EGFR copy number and K-Ras mutations in a targeted TKI naive NSCLC cohort. Methods We investigated 106 frozen tumors from surgically resected NSCLC patients. Genes copy number of MET and EGFR were assessed by quantitative relative real-time polymerase chain reaction and K-Ras mutations by sequencing. Results MET is amplified in 22 cases (21%) and deleted in nine cases (8.5%). EGFR is amplified in 31 cases (29%). K-Ras is mutated in 11 cases (10.5%). As observed for EGFR amplification, MET amplification is never associated with K-Ras mutation. MET amplification could be associated with EGFR amplification. MET amplification is not related to clinical and pathologic features. MET amplification and EGFR amplification showed a trend toward poor prognosis in adenocarcinomas. Conclusion In EGFR-TKIs naive NSCLC patients, MET amplification is a frequent event, which could be associated with EGFR amplification, but not with K-Ras mutation. MET amplification may identify a subset of NSCLC for new targeted therapy. It will also be important to evaluate MET copy number to properly interpret future clinical trials.
Published: 2008
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4. Longitudinal Analysis of Gene Expression in Porcine Skeletal Muscle After Post-Injection Local Injury

Author: Pierre-Louis Toutain, François Hatey, Pierre J. Ferré, Magali SanCristobal, Agnès Bonnet, Gwenola Tosser-Klopp, Laurence Liaubet, Didier Concordet, Emmanuelle Uro-Coste, Hervé P. Lefebvre, Physiologie et Toxicologie Expérimentales, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Génétique Cellulaire (LGC), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-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), Simon, Marie Francoise, Université Toulouse III - Paul Sabatier (UT3), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), 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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), and Régulations cellulaires: lipidoses et atherosclerose.
Subjects: Male, Pathology, Time Factors, MESH: Thymosin, Swine, [SDV]Life Sciences [q-bio], Muscle Proteins, MESH: Collagen Type I, Pharmaceutical Science, Post injection, MESH: Down-Regulation, MESH: Collagen, MESH: Fibronectins, Gene expression, MESH: Up-Regulation, Osteonectin, MESH: Animals, Pharmacology (medical), MESH: Swine, Oligonucleotide Array Sequence Analysis, MESH: Muscle, Skeletal, 0303 health sciences, 030302 biochemistry & molecular biology, MESH: Injections, Intramuscular, Pathophysiology, Up-Regulation, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Matrix Metalloproteinase 2, Molecular Medicine, Collagen, MESH: Osteonectin, Intramuscular injection, MESH: ras Proteins, Biotechnology, medicine.medical_specialty, Down-Regulation, Biology, Injections, Intramuscular, Collagen Type I, MESH: Gene Expression Profiling, MESH: Muscle Proteins, 03 medical and health sciences, medicine, Animals, Muscle, Skeletal, Pathological, 030304 developmental biology, Pharmacology, Gene Expression Profiling, MESH: Time Factors, Organic Chemistry, Skeletal muscle, MESH: Male, Fibronectins, Collagen Type I, alpha 1 Chain, Thymosin, MESH: Matrix Metalloproteinase 2, Gene expression profiling, MESH: Oligonucleotide Array Sequence Analysis, Time course, ras Proteins
Abstract: International audience; PURPOSE: The purpose of this study is to describe the time course of gene expression in a skeletal muscle local injury induced by an intramuscular (IM) injection, and to compare the dynamics of gene expression with pathological events. MATERIALS AND METHODS: Ten piglets received 4 IM injections of propylene glycol in the longissimus dorsi muscles 6 h, 2, 7, and 21 days before euthanasia, where control and injected muscle sites were sampled for RNA isolation and microscopic examination. The hybridization of nylon cDNA microarrays was carried out with radioactive probes obtained from the muscle RNA. RESULTS: 153 genes were found under- or over-expressed at least once among the investigated time-conditions. The eight most discriminant genes were also identified: Two genes (GTP-binding protein RAD and Ankyrin repeat domain protein) were over-expressed at 6 h and six genes between 2 and 21 days (Osteonectin, Fibronectin, Matrix metalloproteinase-2, Collagen alpha 1(I) chain, Collagen alpha 2(I) chain, and Thymosin beta-4). Necrosis, inflammation and regeneration were observed through both the dynamics of gene expression profiles and through the microscopic examinations. CONCLUSION: Our data demonstrate that several pathways are involved in post-injection muscle injury, and that necrosis, inflammation and regeneration are not sequential but occur in parallel.
Published: 2007
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5. Characterization of the enzymatic activity of Clostridium perfringens TpeL

Author: Jean Claude Rousselle, Serge Pauillac, Jacques D'allayer, Pascal Lenormand, Philippe Bouvet, Michel R. Popoff, Bactéries anaérobies et Toxines, Institut Pasteur [Paris], Protéomique (Plate-Forme), This was supported by Institut Pasteur funding, and Institut Pasteur [Paris] (IP)
Subjects: Clostridium perfringens, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, MESH: rac GTP-Binding Proteins, Toxicology, medicine.disease_cause, Substrate Specificity, Rho-GTPases, Tandem Mass Spectrometry, TpeL, Chromatography, High Pressure Liquid, chemistry.chemical_classification, MESH: Clostridium perfringens, 0303 health sciences, Uridine Diphosphate N-Acetylglucosamine, MESH : Substrate Specificity, rac GTP-Binding Proteins, Biochemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, MESH : Tandem Mass Spectrometry, MESH: ras Proteins, Gene isoform, MESH : Clostridium perfringens, Bacterial Toxins, Biology, 03 medical and health sciences, MESH : Chromatography, High Pressure Liquid, MESH : Uridine Diphosphate N-Acetylglucosamine, Rho, MESH: Uridine Diphosphate N-Acetylglucosamine, medicine, MESH: Chromatography, High Pressure Liquid, GTPase, 030304 developmental biology, 030306 microbiology, Toxin, Rho GTPases, MESH: Tandem Mass Spectrometry, MESH : rac GTP-Binding Proteins, Molecular biology, In vitro, Rac, carbohydrates (lipids), Enzyme, Rac glucosylation, chemistry, MESH: Bacterial Toxins, MESH : Bacterial Toxins, ras Proteins, MESH: Substrate Specificity, MESH : ras Proteins, Ras
Abstract: International audience; TpeL is a toxin produced by Clostridium perfringens which belongs to the large clostridial glucosylating toxin family. It was shown that TpeL modifies Ras using UDP-glucose or UDP-N-acetylglucosamine as cosubstrates (Guttenberg et al., 2012; Nagahama et al., 2011). We confirmed that TpeL preferentially glucosaminates the three isoforms of Ras (cH-Ras, N-Ras, and K-Ras) from UDP-N-acetylglucosamine and to a lower extent Rap1a and R-Ras3, and very weakly Rac1. In contrast to previous report, we observed that Ral was not a substrate of TpeL. In addition, we confirmed by in vitro glucosylation and mass spectrometry that TpeL modifies cH-Ras at Thr35.
Published: 2013
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6. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

Author: Raouf Ben Abdelali, Véronique Lhéritier, Jean-Yves Cahn, Françoise Huguet, Norbert Ifrah, Agnès Buzyn, Noémie de Gunzburg, Elizabeth Macintyre, Vahid Asnafi, Dominique Payet-Bornet, Sébastien Maury, Jonathan Bond, Thibaud Leguay, Amélie Trinquand, Bertrand Nadel, André Delannoy, Kheira Beldjord, Hervé Dombret, Xavier Thomas, Jérôme Lambert, Ludovic Lhermitte, Hossein Mossafa, Etienne Lengliné, Yves Chalandon, Caroline Bonmati, Aline Tanguy-Schmidt, Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Cytogénétique - Pasteur-Cerba, Laboratoire Pasteur-Cerba, Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), 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 ), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ), Hôpital de Jolimont, Haine-Saint-Paul and Cliniques Universitaires St Luc, Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'hématologie clinique [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Toulouse III - Paul Sabatier (UT3), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Recherche en Cancérologie de Lyon (CRCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Ras Proteins/genetics, Oncology, Pathology, MESH : F-Box Proteins, DNA Mutational Analysis, Cell Cycle Proteins, MESH : Gene Deletion, MESH: Receptor, Notch1, 0302 clinical medicine, MESH : Cell Cycle Proteins, Receptor, Notch1, MESH: DNA Mutational Analysis, Young adult, ddc:616, 0303 health sciences, Hazard ratio, PTEN Phosphohydrolase/genetics, hemic and immune systems, 3. Good health, MESH : Phenotype, MESH: Young Adult, 030220 oncology & carcinogenesis, Predictive value of tests, Cohort, F-Box Proteins/genetics, MESH : Proto-Oncogene Proteins, MESH: Membrane Proteins, MESH: ras Proteins, medicine.medical_specialty, MESH : Young Adult, MESH : DNA Mutational Analysis, MESH: Phenotype, MESH: PTEN Phosphohydrolase, Disease-Free Survival, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Cell Cycle Proteins, Humans, PTEN, Ubiquitin-Protein Ligases/genetics, MESH : Predictive Value of Tests, MESH: Kaplan-Meier Estimate, Cell Cycle Proteins/genetics, Receptor, Notch1/genetics, [ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Humans, Proportional hazards model, F-Box Proteins, MESH : Humans, MESH: Adult, MESH : Proportional Hazards Models, MESH: Ubiquitin-Protein Ligases, MESH : Membrane Proteins, MESH: Disease-Free Survival, Mutation, ras Proteins, Adult Acute Lymphoblastic Leukemia, MESH : Genetic Predisposition to Disease, MESH : Ubiquitin-Protein Ligases, MESH : GTP Phosphohydrolases, MESH: Female, Gene Deletion, Cancer Research, F-Box-WD Repeat-Containing Protein 7, Time Factors, MESH : Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Kaplan-Meier Estimate, MESH : PTEN Phosphohydrolase, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, GTP Phosphohydrolases, MESH: Proportional Hazards Models, MESH: Risk Factors, Risk Factors, hemic and lymphatic diseases, MESH : Female, biology, MESH : Receptor, Notch1, MESH: Genetic Predisposition to Disease, MESH : Adult, MESH : Risk Factors, MESH: Predictive Value of Tests, MESH: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Phenotype, MESH : Disease-Free Survival, Female, MESH : Mutation, MESH : Time Factors, Adult, MESH: Mutation, MESH: GTP Phosphohydrolases, Ubiquitin-Protein Ligases, MESH : Male, MESH: F-Box Proteins, MESH: Multivariate Analysis, MESH : Kaplan-Meier Estimate, Young Adult, Predictive Value of Tests, Proto-Oncogene Proteins, Internal medicine, medicine, Genetic Predisposition to Disease, Membrane Proteins/genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/classification/genetics/mortality/therapy, Proportional Hazards Models, 030304 developmental biology, business.industry, MESH: Time Factors, PTEN Phosphohydrolase, Membrane Proteins, MESH : Multivariate Analysis, GTP Phosphohydrolases/genetics, MESH: Male, MESH: Proto-Oncogene Proteins, Proto-Oncogene Proteins/genetics, MESH: Gene Deletion, Multivariate Analysis, biology.protein, MESH : ras Proteins, business
Abstract: Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Published: 2013
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7. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump.: Sorafenib inhibits ABCG2 and overcome irinotecan resistance

Author: Mazard, Thibault, Causse, Annick, Simony, Joelle, Leconet, Wilhem, Vezzio-Vie, Nadia, Torro, Adeline, Jarlier, Marta, Evrard, Alexandre, Del Rio, Maguy, Assenat, Eric, Martineau, Pierre, Ychou, Marc, Robert, Bruno, Gongora, Celine, Unité d'Oncologie Médicale [St-Eloi], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Biochimie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), and Funding for this work has been supported by INSERM and CRCL ICM-Val D'Aurelle
Subjects: MESH: Neoplasm Proteins, MESH: Xenograft Model Antitumor Assays, MESH: HCT116 Cells, ABCG2, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Receptor, Epidermal Growth Factor, MESH: Drug Synergism, MESH: Phenylurea Compounds, heterocyclic compounds, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, neoplasms, MESH: Mice, irinotecan, MESH: Humans, MESH: Gene Expression Regulation, Neoplastic, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, digestive system diseases, MESH: Drug Resistance, Neoplasm, MESH: Proto-Oncogene Proteins, MESH: ATP-Binding Cassette Transporters, MESH: Camptothecin, sorafenib, MESH: Niacinamide, MESH: ras Proteins, MESH: Colorectal Neoplasms
Abstract: International audience; Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of patients with irinotecan-refractory CRCs, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy. We used both in vitro (the HCT116, SW48, SW620, and HT29 colon adenocarcinoma cell lines and four SN-38-resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38-resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan or its active metabolite, SN-38. We have shown that sorafenib improved the antitumoral activity of irinotecan in vitro, in both parental and SN-38-resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity. Moreover, we found that sorafenib improved the efficacy of irinotecan by inhibiting the irinotecan-mediated p38 and ERK activation. In conclusion, our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in CRC, particularly in KRAS-mutated tumors.
Published: 2013
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8. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump.: Sorafenib inhibits ABCG2 and overcome irinotecan resistance

Author: Mazard, Thibault, Causse, Annick, Simony, Joelle, Leconet, Wilhem, Vezzio-Vie, Nadia, Torro, Adeline, Jarlier, Marta, Evrard, Alexandre, del Rio, Maguy, Assenat, Eric, Martineau, Pierre, Ychou, Marc, Robert, Bruno, Gongora, Celine, Unité d'Oncologie Médicale [St-Eloi], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Biochimie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Funding for this work has been supported by INSERM and CRCL ICM-Val D'Aurelle, and Le Ster, Yves
Subjects: MESH: Neoplasm Proteins, MESH: Xenograft Model Antitumor Assays, MESH: HCT116 Cells, ABCG2, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Receptor, Epidermal Growth Factor, MESH: Drug Synergism, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Phenylurea Compounds, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, heterocyclic compounds, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, neoplasms, MESH: Mice, irinotecan, MESH: Humans, MESH: Gene Expression Regulation, Neoplastic, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, digestive system diseases, MESH: Drug Resistance, Neoplasm, MESH: Proto-Oncogene Proteins, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: ATP-Binding Cassette Transporters, MESH: Camptothecin, sorafenib, MESH: Niacinamide, MESH: ras Proteins, MESH: Colorectal Neoplasms
Abstract: International audience; Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of patients with irinotecan-refractory CRCs, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy. We used both in vitro (the HCT116, SW48, SW620, and HT29 colon adenocarcinoma cell lines and four SN-38-resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38-resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan or its active metabolite, SN-38. We have shown that sorafenib improved the antitumoral activity of irinotecan in vitro, in both parental and SN-38-resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity. Moreover, we found that sorafenib improved the efficacy of irinotecan by inhibiting the irinotecan-mediated p38 and ERK activation. In conclusion, our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in CRC, particularly in KRAS-mutated tumors.
Published: 2013
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9. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth

Author: Ditte S. Andersen, Valentina Palmerini, Krittalak Chakrabandhu, Julien Colombani, Janine Toggweiler, Michael Röthlisberger, Konrad Basler, Emilie Boone, Marina Mapelli, Pierre Léopold, Anne-Odile Hueber, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), University of Zurich, and Colombani, Julien
Subjects: Male, [SDV]Life Sciences [q-bio], Apoptosis, MESH: Amino Acid Sequence, Receptors, Tumor Necrosis Factor, 0302 clinical medicine, Neoplasms, Cell polarity, Drosophila Proteins, MESH: Animals, MESH: Neoplasms, Receptor, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, Epithelial polarity, 0303 health sciences, Multidisciplinary, Cell Polarity, Anatomy, 10124 Institute of Molecular Life Sciences, Transmembrane protein, Cell biology, Cell Transformation, Neoplastic, Drosophila melanogaster, 030220 oncology & carcinogenesis, MESH: Cell Adhesion Molecules, MESH: Cell Division, Female, MESH: Membrane Proteins, MESH: Cell Polarity, Matrix Metalloproteinase 1, MESH: ras Proteins, Cell Division, SCRIB, Programmed cell death, Polarity (physics), MESH: Drosophila Proteins, MAP Kinase Signaling System, Molecular Sequence Data, Biology, MESH: Drosophila melanogaster, 03 medical and health sciences, Animals, Humans, Neoplasm Invasiveness, Amino Acid Sequence, 030304 developmental biology, 1000 Multidisciplinary, MESH: Humans, MESH: Molecular Sequence Data, MESH: MAP Kinase Signaling System, MESH: Apoptosis, JNK Mitogen-Activated Protein Kinases, Membrane Proteins, MESH: JNK Mitogen-Activated Protein Kinases, MESH: Neoplasm Invasiveness, MESH: Receptors, Tumor Necrosis Factor, MESH: Male, MESH: Matrix Metalloproteinase 1, Disease Models, Animal, MESH: Cell Transformation, Neoplastic, ras Proteins, 570 Life sciences, biology, MESH: Disease Models, Animal, MESH: Female, Cell Adhesion Molecules, Genetic screen
Abstract: International audience; Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth, we identified grindelwald (grnd), a gene encoding a transmembrane protein with homology to members of the tumour necrosis factor receptor (TNFR) superfamily. Here we show that Grnd mediates the pro-apoptotic functions of Eiger (Egr), the unique Drosophila TNF, and that overexpression of an active form of Grnd lacking the extracellular domain is sufficient to activate JNK signalling in vivo. Grnd also promotes the invasiveness of Ras(V12)/scrib(-/-) tumours through Egr-dependent Matrix metalloprotease-1 (Mmp1) expression. Grnd localizes to the subapical membrane domain with the cell polarity determinant Crumbs (Crb) and couples Crb-induced loss of polarity with JNK activation and neoplastic growth through physical interaction with Veli (also known as Lin-7). Therefore, Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth.
Published: 2013
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10. Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience

Author: Pierre Laurent-Puig, Jean-François Emile, Marie-Claude Gorisse, Pascaline Aucouturier, Jean-Philippe Merlio, Florence de Fraipont, Jean-Louis Merlin, Isabelle Durand-Zaleski, Frédérique Nowak, Karen Leroy, Thierry Frebourg, Alain Morel, Hélène Blons, Delphine Le Corre, Gilles Chatellier, Jean-François Côté, Jean-Christophe Sabourin, L'Houcine Ouafik, Etienne Rouleau, Jean-Christophe Boyer, Nathanaël Charrier, Jean-Christophe Pages, Gérard Milano, Patricia de Cremoux, Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Oncogénétique, CRLCC René Huguenin, Service de Santé Publique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], 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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours (UT)-EA3856, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Bordeaux [Bordeaux], Oppelia, Institut Jean Godinot [Reims], UNICANCER, Hôpital Saint Louis, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de pharmacogénomique, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Alexis Vautrin (CAV), CHU Rouen, Normandie Université (NU), Institut national du cancer [Boulogne] (INCA), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Département de la recherche clinique et du développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-EA3856, Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Cliniques de Montréal, Université de Montréal, Université de Montréal [Montréal], Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Godinot, CRLCC Jean Godinot, CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CRLCC Antoine Lacassagne, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service d'anatomie pathologique, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques de l'Hopital Europeen Georges Pompidou, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Montréal, CHRU Tours, Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biochimie et Physiologie Moléculaire des Plantes ( BPMP ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Centre international d'études supérieures en sciences agronomiques ( Montpellier SupAgro ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ) -Institut national de la recherche agronomique [Montpellier] ( INRA Montpellier ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre de Recherches en Oncologie biologique et Oncopharmacologie ( CRO2 ), Aix Marseille Université ( AMU ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Automatique de Nancy ( CRAN ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Alexis Vautrin ( CAV ), Institut national du cancer [Boulogne] ( INCA ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique ( MEPPOT - U1147 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Merlin, Jean-Louis
Subjects: Oncology, Colorectal cancer, Epidemiology, Molecular oncology, MESH: Antibodies, Monoclonal, 0302 clinical medicine, MESH : Fixatives, MESH: Fixatives, Neoplasm Metastasis, lcsh:Science, MESH: Tissue Embedding, 0303 health sciences, MESH: Genetic Testing, Antibodies, Monoclonal, 3. Good health, MESH: Reproducibility of Results, ErbB Receptors, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, MESH : Neoplasm Metastasis, MESH : Proto-Oncogene Proteins, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, MESH : Colorectal Neoplasms, MESH : Sensitivity and Specificity, MESH: ras Proteins, medicine.medical_specialty, MESH: Receptor, Epidermal Growth Factor, Gastroenterology and Hepatology, Sensitivity and Specificity, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Fixatives, MESH : Genetic Testing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], External quality assessment, Gastrointestinal Tumors, Cancer Detection and Diagnosis, Humans, Genetic Testing, Genotyping, Biology, MESH: Humans, Tissue Embedding, MESH : Reproducibility of Results, MESH : Humans, lcsh:R, medicine.disease, MESH: Neoplasm Metastasis, MESH: Sensitivity and Specificity, MESH : Biopsy, ras Proteins, lcsh:Q, MESH : Sequence Analysis, DNA, MESH: Sequence Analysis, DNA, Biopsy, Cancer Treatment, lcsh:Medicine, Bioinformatics, medicine.disease_cause, MESH : Tissue Embedding, MESH: Biopsy, MESH : Receptor, Epidermal Growth Factor, Gastrointestinal Cancers, Sanger sequencing, Multidisciplinary, Drug development, MESH : Antibodies, Monoclonal, symbols, KRAS, France, Colorectal Neoplasms, Research Article, MESH: Cell Line, Tumor, Clinical Research Design, Rectal Cancer, symbols.namesake, Antibody Therapy, Diagnostic Medicine, Molecular genetics, Internal medicine, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, MESH : France, 030304 developmental biology, Population Biology, MESH : Cell Line, Tumor, business.industry, Reproducibility of Results, Cancers and Neoplasms, Sequence Analysis, DNA, MESH: France, MESH: Proto-Oncogene Proteins, Gastric Cancer, MESH : ras Proteins, business, MESH: Colorectal Neoplasms
Abstract: International audience; PURPOSE: Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa) has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM) was granted to analyze reproducibility and costs. METHODS: 96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists. RESULTS: This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from €5.5 to €19.0. CONCLUSION: The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment.
Published: 2013
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11. The mutational spectrum of HRAS, KRAS, NRAS and FGFR3 genes in bladder cancer

Author: Slah Ouerhani, Amel Benammar Elgaaied, Laboratoire d'hématologie moléculaire et cellulaire (LR11IPT07), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, and Université de Tunis El Manar (UTM)
Subjects: Neuroblastoma RAS viral oncogene homolog, Cancer Research, MESH: Receptor, Fibroblast Growth Factor, Type 3, DNA Mutational Analysis, Mutation, Missense, Biology, medicine.disease_cause, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Proto-Oncogene Proteins p21(ras), 0302 clinical medicine, Gene Frequency, Proto-Oncogene Proteins, Genetics, medicine, MESH: Gene Frequency, Humans, Receptor, Fibroblast Growth Factor, Type 3, HRAS, MESH: DNA Mutational Analysis, Genetic Association Studies, 030304 developmental biology, MESH: Genetic Association Studies, 0303 health sciences, MESH: Mutation, Missense, Bladder cancer, MESH: Humans, Oncogene, General Medicine, Fibroblast growth factor receptor 3, medicine.disease, Molecular biology, 3. Good health, MESH: Urinary Bladder Neoplasms, MESH: Proto-Oncogene Proteins, Oncology, Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, ras Proteins, KRAS, Carcinogenesis, MESH: ras Proteins
Abstract: International audience; Bladder cancer is one of the most common cancers worldwide. A number of genetic and epigenetic alterations have been identified in bladder tumorigenesis, including activating mutations in fibroblast growth factor receptor 3 (FGFR3) and RAS family genes. In this study, we have analysed the mutational spectrum of FGFR3 and RAS genes (HRAS, NRAS and KRAS). We have also studied the relationship between mutations. A total of 234 patients with different stages and grades were included in the present study (58 superficial low-grade, 53 superficial high-grade and 123 muscle-invasive tumours). Mutations in exons 1 and 2 of HRAS, KRAS and NRAS genes were screened by PCR and direct sequencing. The hot spot mutations in exons 7, 10 and 15 of the FGFR3 oncogene were studied by multiplex PCR and the SNaP-shot protocol. Overall, 8.97% (21/234) of samples were mutant for one of the RAS genes. Among these mutations 47.61% were detected in KRAS, 33.33% in HRAS and only 19.04% most frequent RAS mutations were KRAS p.G12C and p.G12D. The correlation between RAS mutations and tumour subgroups does not report a statistical significant association (p=0.876). The FGFR3 mutations were detected in 31.19% (73/234) of bladder tumours and were associated with low stages and grades. The study of relationship between RAS and FGFR3 genes revealed that FGFR3 mutations were mutually exclusive with RAS ones (p=10(-4)). In conclusion we retain that activated RAS and FGFR3 do not appear to be drivers in bladder cancer but the mutually exclusive relationship between RAS and FGFR3 mutations indicates a possible clonal advantage of modified signaling via a common pathway.
Published: 2012
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12. Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature

Author: Mylène Tajan, Marianne Mus, Thomas Edouard, Karine Tréguer, Jean-Pierre Salles, Alexandra Montagner, Armelle Yart, Patrick Raynal, Toshiyuki Araki, M. Tauber, Philippe Valet, Audrey De Rocca Serra-Nédélec, Marie Dance, Benjamin G. Neel, Tréguer, Karine, Tajana, Mylène, Yart, Armelle, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), 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 d'Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Campbell Family Cancer Research Institute, University of Toronto-Ontario Cancer Institute, Laboratoire de biologie moléculaire eucaryote (LBME), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Mécanismes des cardiopathies et résistance hormonale dans le Noonan et syndrome apparentés (M2CHRNRS), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Ontario Cancer Institute, Melanie H. Cobb, Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and ProdInra, Archive Ouverte
Subjects: MAPK/ERK pathway, TYROSINE-PHOSPHATASE SHP2, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MESH: Insulin-Like Growth Factor I, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein tyrosine phosphatase, growth hormone insensitivity, MESH: Animals, Newborn, MESH: Janus Kinase 2, [SHS]Humanities and Social Sciences, Mice, Phosphatidylinositol 3-Kinases, Insulin-like growth factor, 0302 clinical medicine, HEIGHT, STAT5 Transcription Factor, MESH: Animals, Insulin-Like Growth Factor I, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, MESH: Biometry, MESH: Extracellular Signal-Regulated MAP Kinases, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, Noonan Syndrome, ACTIVATED PROTEIN-KINASE, MOUSE MODEL, DEFECTS, Biological Sciences, [SDV] Life Sciences [q-bio], MESH: Noonan Syndrome, Signal transduction, medicine.symptom, signaling, MESH: Protein Tyrosine Phosphatase, Non-Receptor Type 11, MESH: ras Proteins, medicine.medical_specialty, MESH: Enzyme Activation, Biometry, MESH: Mutation, MESH: Rats, 030209 endocrinology & metabolism, SIGNALING PATHWAYS, PTPN11 SHP2, MUTATIONS, DELETION, MALFORMATIONS, Biology, Short stature, MESH: Mitogen-Activated Protein Kinase Kinases, MESH: Phosphoproteins, 03 medical and health sciences, Internal medicine, medicine, Animals, MESH: Mice, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Mitogen-Activated Protein Kinase Kinases, Binding Sites, MESH: Phosphorylation, MESH: Proto-Oncogene Proteins c-akt, Growth factor, MESH: STAT5 Transcription Factor, Janus Kinase 2, Phosphoproteins, medicine.disease, Rats, Enzyme Activation, PTPN11, Endocrinology, Animals, Newborn, MESH: Binding Sites, MESH: Phosphatidylinositol 3-Kinases, Growth Hormone, MESH: Growth Hormone, Mutation, ras Proteins, Noonan syndrome, Proto-Oncogene Proteins c-akt
Abstract: Noonan syndrome (NS), a genetic disease caused in half of cases by activating mutations of the tyrosine phosphatase SHP2 ( PTPN11 ), is characterized by congenital cardiopathies, facial dysmorphic features, and short stature. How mutated SHP2 induces growth retardation remains poorly understood. We report here that early postnatal growth delay is associated with low levels of insulin-like growth factor 1 (IGF-1) in a mouse model of NS expressing the D61G mutant of SHP2. Conversely, inhibition of SHP2 expression in growth hormone (GH)-responsive cell lines results in increased IGF-1 release upon GH stimulation. SHP2-deficient cells display decreased ERK1/2 phosphorylation and rat sarcoma (RAS) activation in response to GH, whereas expression of NS-associated SHP2 mutants results in ERK1/2 hyperactivation in vitro and in vivo. RAS/ERK1/2 inhibition in SHP2-deficient cells correlates with impaired dephosphorylation of the adaptor Grb2-associated binder-1 (GAB1) on its RAS GTPase-activating protein (RASGAP) binding sites and is rescued by interfering with RASGAP recruitment or function. We demonstrate that inhibition of ERK1/2 activation results in an increase of IGF-1 levels in vitro and in vivo, which is associated with significant growth improvement in NS mice. In conclusion, NS-causing SHP2 mutants inhibit GH-induced IGF-1 release through RAS/ERK1/2 hyperactivation, a mechanism that could contribute to growth retardation. This finding suggests that, in addition to its previously shown beneficial effect on NS-linked cardiac and craniofacial defects, RAS/ERK1/2 modulation could also alleviate the short stature phenotype in NS caused by PTPN11 mutations.
Published: 2012
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13. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process.: Additive effect of ZOL and mTOR on osteosarcoma development

Author: Moriceau, Gatien, Ory, Benjamin, Mitrofan, Laura, Riganti, Chiara, Blanchard, Frédéric, Brion, Régis, Charrier, Céline, Battaglia, Séverine, Pilet, Paul, Denis, Marc, Shultz, Leonard, Mönkkönen, Jukka, Rédini, Françoise, Heymann, Dominique, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Massachusetts General Hospital Cancer Center, Harvard Medical School [Boston] (HMS), Department of Pharmaceutics, University of Kuopio, Department of Genetics, Biology and Biochemistry, University of Turin, Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Jackson Laboratory [Bar Harbor] (JAX), and This work was supported by a grant from Pharma Novartis (Rueil-Malmaison, France) and by a NIH Cancer Core grant CA34196.
Subjects: musculoskeletal diseases, MESH: Protein Prenylation, MESH: Cell Line, Tumor, MESH: Humans, MESH: Osteosarcoma, MESH: Rats, MESH: Diphosphonates, MESH: Bone Neoplasms, MESH: Male, MESH: Drug Resistance, Neoplasm, MESH: Drug Synergism, MESH: Bone Density Conservation Agents, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Mice, Inbred C57BL, MESH: Cell Growth Processes, MESH: Animals, MESH: Sirolimus, MESH: Mice, Inbred C3H, MESH: Mice, MESH: ras Proteins, MESH: TOR Serine-Threonine Kinases, MESH: Imidazoles
Abstract: International audience; Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated in vivo the effects of RAD001 (Everolimus), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone or in combination with zoledronate (ZOL), an anti-osteoporotic drug used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose- and time-dependent manner with no modification of cell-cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared with single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly with an increase of nonisoprenylated cytosolic Ras in sensitive and resistant osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways.
Published: 2010
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14. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process.: Additive effect of ZOL and mTOR on osteosarcoma development

Author: Moriceau, Gatien, Ory, Benjamin, Mitrofan, Laura, Riganti, Chiara, Blanchard, Frédéric, Brion, Régis, Charrier, Céline, Battaglia, Séverine, Pilet, Paul, Denis, Marc, Shultz, Leonard, Mönkkönen, Jukka, Rédini, Françoise, Heymann, Dominique, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Massachusetts General Hospital Cancer Center, Harvard Medical School [Boston] (HMS), Department of Pharmaceutics, University of Kuopio, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Jackson Laboratory [Bar Harbor] (JAX), This work was supported by a grant from Pharma Novartis (Rueil-Malmaison, France) and by a NIH Cancer Core grant CA34196., and Heymann, D
Subjects: musculoskeletal diseases, MESH: Protein Prenylation, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Cell Line, Tumor, MESH: Humans, MESH: Osteosarcoma, MESH: Rats, MESH: Diphosphonates, MESH: Bone Neoplasms, MESH: Male, MESH: Drug Resistance, Neoplasm, MESH: Drug Synergism, MESH: Bone Density Conservation Agents, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Mice, Inbred C57BL, MESH: Cell Growth Processes, MESH: Animals, MESH: Sirolimus, MESH: Mice, Inbred C3H, MESH: Mice, MESH: ras Proteins, MESH: TOR Serine-Threonine Kinases, MESH: Imidazoles
Abstract: International audience; Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated in vivo the effects of RAD001 (Everolimus), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone or in combination with zoledronate (ZOL), an anti-osteoporotic drug used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose- and time-dependent manner with no modification of cell-cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared with single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly with an increase of nonisoprenylated cytosolic Ras in sensitive and resistant osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways.
Published: 2010
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15. Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice

Author: Ivo J. Huijbers, Benoît Van den Eynde, Lionel Chasson, Saïdi M. Soudja, Anne-Marie Schmitt-Verhulst, Amandine Mas, Maria Wehbe, Céline Powis de Tenbossche, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Ludwig Institute for Cancer Research Ltd., and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Inflammation, Cancer Research, Melanoma, Experimental, Epitopes, T-Lymphocyte, MESH: Antigens, Neoplasm, Adaptive Immunity, CD8-Positive T-Lymphocytes, Immunotherapy, Adoptive, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Genes, Tumor Suppressor, MESH: Animals, MESH: Lymphocytes, Tumor-Infiltrating, Mice, Knockout, Melanoma, Acquired immune system, MESH: CD8-Positive T-Lymphocytes, Tumor antigen, 3. Good health, MESH: Melanoma, Experimental, Oncology, Mice, Inbred DBA, 030220 oncology & carcinogenesis, MESH: Cyclin-Dependent Kinase Inhibitor p16, MESH: Immunotherapy, Adoptive, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, MESH: ras Proteins, Tumor suppressor gene, MESH: Mice, Transgenic, Inflammation, Mice, Transgenic, Biology, MESH: Epitopes, T-Lymphocyte, 03 medical and health sciences, Immune system, Lymphocytes, Tumor-Infiltrating, Antigens, Neoplasm, medicine, Animals, MESH: Mice, Cyclin-Dependent Kinase Inhibitor p16, Oncogene, MESH: Mice, Inbred DBA, MESH: Genes, Tumor Suppressor, medicine.disease, MESH: Male, MESH: Genes, ras, Genes, ras, Tumor progression, MESH: Gene Deletion, Immunology, ras Proteins, MESH: Female, Gene Deletion, MESH: Adaptive Immunity, 030215 immunology
Abstract: We studied the effect of the immune system on two differentially aggressive melanomas developing in mice on conditional deletion of the INK4A/ARF tumor suppressor gene, with concomitant expression of oncogene H-RasG12V and a natural cancer-germline tumor antigen (TA). “Slow progressor” melanomas contained no activated T lymphocytes (TL). In contrast, “aggressive” melanomas were infiltrated by activated TLs lacking effector molecules and expressing high levels of PD-1, indicating an exhausted phenotype. Aggressive melanomas were also infiltrated by immature myeloid cells (IMC). Infiltration was associated with local inflammation and systemic Th2/Th17-oriented chronic inflammation that seemed to impair further activation of TLs, as tumor-specific T cells adoptively transferred into mice bearing aggressive melanomas were poorly activated and failed to infiltrate the melanoma. This immunosuppression also led to the incapacity of these mice to reject inoculated TA-positive tumors, in contrast to slow-progressing melanoma-bearing mice, which were responsive. To test the role of adaptive immunity in tumor progression, we induced melanomas in immunodeficient RagKO compound mice. These mice developed aggressive but not slow-progressing melanomas at a higher frequency and with a shorter latency than immunocompetent mice. Immunodeficient mice also developed abnormal inflammation and infiltration of IMCs in a manner similar to immunocompetent mice, indicating that this phenotype was not dependent on adaptive immunity. Therefore, tumor-intrinsic factors distinguishing the two melanoma types control the initiation of inflammation, which was independent of adaptive immunity. The latter delayed development of aggressive melanomas but was overridden by inflammation. Cancer Res; 70(9); 3515–25. ©2010 AACR.
Published: 2010
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16. Mutation analysis of BRAF exon 15 and KRAS codons 12 and 13 in Moroccan patients with colorectal cancer

Author: Bahia Bennani, Chakib Nejjari, Sophie Gilles, Isabelle Nanni, Pierre-Marie Martin, D. Benajeh, Mohammed El Abkari, Afaf Amarti Riffi, Frédéric Fina, L'Houcine Ouafik, Sidi Adil Ibrahimi, Faculté de Médecine et de Pharmacie de Fès, Sidi Mohammed Ben Abdellah University, Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], and Université Sidi Mohamed Ben Abdellah (USMBA)
Subjects: Male, 0301 basic medicine, Cancer Research, MESH: Sequence Analysis, DNA, Colorectal cancer, DNA Mutational Analysis, Clinical Biochemistry, Cell, MESH: Base Sequence, medicine.disease_cause, Exon, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: DNA Mutational Analysis, Aged, 80 and over, Genetics, MESH: Aged, Mutation, MESH: Middle Aged, MESH: Codon, MESH: Genetic Predisposition to Disease, Exons, Middle Aged, 3. Good health, Morocco, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, KRAS, Colorectal Neoplasms, MESH: ras Proteins, Adult, Proto-Oncogene Proteins B-raf, MESH: Mutation, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, Biology, Pathology and Forensic Medicine, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins, medicine, Humans, Genetic Predisposition to Disease, Codon, Aged, MESH: Adolescent, MESH: Proto-Oncogene Proteins B-raf, MESH: Humans, Base Sequence, MESH: Adenocarcinoma, Cancer, MESH: Adult, Sequence Analysis, DNA, medicine.disease, digestive system diseases, MESH: Male, MESH: Proto-Oncogene Proteins, 030104 developmental biology, MESH: Morocco, ras Proteins, Cancer research, Mutation testing, MESH: Exons, MESH: Female, MESH: Colorectal Neoplasms
Abstract: Background The RAS/RAF/MEK/MAP kinase cascade transduces signals from the cell surface to the nucleus in order to control cellular responses including proliferation, differentiation and survival. We investigated the occurrence of BRAF exon 15 and KRAS codon 12 and 13 mutations in Moroccan patients with colorectal cancer. Methods Sixty-two samples from patients with sporadic colorectal adenocarcinomas were studied for BRAF exon 15 and KRAS codon 12 and 13 mutations. DNA from paraffin-embedded tissue specimens was analyzed by a combination of polymerase chain reaction–high resolution melting and direct sequencing. Results Of the analyzed specimens, 29% exhibited KRAS codon 12 or 13 mutations and only 1.6% carried a BRAF codon 600 mutation. KRAS mutations were more often observed in women (35.5%) than in men (22.6%). Patients in the age range between 41 and 60 years were more likely to be carriers of this mutation. No KRAS mutations were detected in patients aged >60 years. Conclusion Despite the limited study sample, our data suggest that KRAS mutations arise more frequently than BRAF mutations in Moroccan patients with colorectal carcinomas. The KRAS mutation status must be assessed in a large cohort of Moroccan patients to confirm these findings and to determine whether this mutation in combination with extrinsic, environmental or microenvironmental factors might be involved in the high frequency of colorectal cancer in middle-aged Moroccans.
Published: 2010

17. Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia

Author: Gilberto Fisone, Emanuela Santini, Véronique Sgambato-Faure, Sandra Dovero, Erwan Bezard, Qin Li, Marc Savasta, Departement Neurosciences, Karolinska Institutet [Stockholm], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institute of Lab Animal Sciences, China Academy of Medical Sciences, Laboratoire Mouvement Adaptation Cognition (MAC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), INSERM U836, équipe 10, Dynamique des réseaux neuronaux du mouvement, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Agence nationale de la Recherche Swedish Research Council 20715 - 13482 Swedish Brain Foundation, and Savasta, Marc
Subjects: MAPK/ERK pathway, Levodopa, 0302 clinical medicine, Cyclic AMP, MESH: Animals, Extracellular Signal-Regulated MAP Kinases, MESH: Extracellular Signal-Regulated MAP Kinases, Neurological Disorders/Movement Disorders, MESH: Cyclic AMP, MESH: Levodopa, 0303 health sciences, Multidisciplinary, Kinase, 3. Good health, Ribosomal protein s6, Phosphorylation, Medicine, Female, medicine.symptom, Neuroscience/Neurobiology of Disease and Regeneration, MESH: ras Proteins, Research Article, medicine.drug, Dopamine and cAMP-Regulated Phosphoprotein 32, medicine.medical_specialty, MAP Kinase Signaling System, Science, AMPA receptor, MESH: Cyclic AMP-Dependent Protein Kinases, Biology, MESH: Dopamine and cAMP-Regulated Phosphoprotein 32, MESH: Macaca mulatta, 03 medical and health sciences, Parkinsonian Disorders, Dopamine, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neuroscience/Neuronal Signaling Mechanisms, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein kinase A, 030304 developmental biology, Dyskinesias, MESH: Parkinsonian Disorders, MESH: MAP Kinase Signaling System, MESH: Dyskinesias, Cyclic AMP-Dependent Protein Kinases, Macaca mulatta, nervous system diseases, Endocrinology, Dyskinesia, ras Proteins, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP - protein kinase A and of the Ras-extracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. METHODOLOGY/RESULTS: We here studied, in the gold-standard non-human primate model of Parkinson's disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. CONCLUSION: Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure. While cAMP signalling enhancement is associated with dyskinesia, abnormal ERK signalling is associated with priming.
Published: 2010
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18. Bias and evolution of the mutationally accessible phenotypic space in a developmental system

Author: Marie-Anne Félix, Charles F. Baer, Christian Braendle, Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), 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: 0106 biological sciences, MESH: Signal Transduction, Cancer Research, Mutant, Evolutionary Biology/Developmental Evolution, 01 natural sciences, Developmental Biology/Pattern Formation, MESH: Genotype, Negative selection, MESH: Animals, MESH: Genetic Variation, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Genetics, 0303 health sciences, biology, MESH: Bias (Epidemiology), Phenotype, Biological Evolution, Caenorhabditis, Evolutionary Biology/Pattern Formation, Mutation (genetic algorithm), Female, Developmental Biology/Developmental Evolution, MESH: ras Proteins, Signal Transduction, Research Article, MESH: Mutation, Genotype, lcsh:QH426-470, MESH: Phenotype, 010603 evolutionary biology, Vulva, 03 medical and health sciences, Bias, Genetic variation, MESH: Evolution, Animals, Cell Lineage, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Evolutionary Biology/Evolutionary and Comparative Genetics, Human evolutionary genetics, Genetic Variation, MESH: Cell Lineage, biology.organism_classification, lcsh:Genetics, MESH: Caenorhabditis, Evolutionary biology, Mutation, Evolutionary developmental biology, ras Proteins, MESH: Vulva, MESH: Female
Abstract: Genetic and developmental architecture may bias the mutationally available phenotypic spectrum. Although such asymmetries in the introduction of variation may influence possible evolutionary trajectories, we lack quantitative characterization of biases in mutationally inducible phenotypic variation, their genotype-dependence, and their underlying molecular and developmental causes. Here we quantify the mutationally accessible phenotypic spectrum of the vulval developmental system using mutation accumulation (MA) lines derived from four wild isolates of the nematodes Caenorhabditis elegans and C. briggsae. The results confirm that on average, spontaneous mutations degrade developmental precision, with MA lines showing a low, yet consistently increased, proportion of developmental defects and variants. This result indicates strong purifying selection acting to maintain an invariant vulval phenotype. Both developmental system and genotype significantly bias the spectrum of mutationally inducible phenotypic variants. First, irrespective of genotype, there is a developmental bias, such that certain phenotypic variants are commonly induced by MA, while others are very rarely or never induced. Second, we found that both the degree and spectrum of mutationally accessible phenotypic variation are genotype-dependent. Overall, C. briggsae MA lines exhibited a two-fold higher decline in precision than the C. elegans MA lines. Moreover, the propensity to generate specific developmental variants depended on the genetic background. We show that such genotype-specific developmental biases are likely due to cryptic quantitative variation in activities of underlying molecular cascades. This analysis allowed us to identify the mutationally most sensitive elements of the vulval developmental system, which may indicate axes of potential evolutionary variation. Consistent with this scenario, we found that evolutionary trends in the vulval system concern the phenotypic characters that are most easily affected by mutation. This study provides an empirical assessment of developmental bias and the evolution of mutationally accessible phenotypes and supports the notion that such bias may influence the directions of evolutionary change., Author Summary Random mutation does not generate random phenotypic variation because genetic and developmental architecture may constrain and bias the mutationally inducible phenotypic spectrum. Understanding such biases in the introduction of phenotypic variation is thus essential to reveal which phenotypes can ultimately be explored and selected through evolution. Here we used lines which had accumulated spontaneous random mutation over 250 generations starting from four distinct wild isolates of the nematode species C. briggsae and C. elegans, to study how a developmental system—vulval cell fate patterning—responds to mutational perturbations. We show that developmental defects and variants increase upon mutation accumulation in lines derived from all four isolates. However, some mutationally induced phenotypic variants occur more frequently than others, and the degree and spectrum of developmental variation further differed between isolates. These results illustrate how the phenotypic spectrum induced by random mutation can be biased due to both developmental system features and variation in the genetic background. Moreover, the mutationally most sensitive phenotypic characters are the ones that show most evolutionary variation among closely related species. These observations show how random mutation translates into a biased, limited range of phenotypes—a phenomenon likely impacting possible trajectories of phenotypic evolution.
Published: 2010
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19. EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: implications for anti-EGFR treatment of a rare lung malignancy

Author: Véronique Hofman, Jérôme Mouroux, Ghyslaine Martel-Planche, Alexis B. Cortot, Thibault Fabas, Marius Ilie, Paul Hofman, Florence Pedeutour, Antoine Italiano, Daniel Pop, Laboratory of Solid Tumors Genetics, Nice University Hospital, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Unit of Environment Cancer Epidemiology, IARC, Infection bactérienne, inflammation, et carcinogenèse digestive, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Groupe de Recherche Angevin en Economie et Management (GRANEM), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de l'Horticulture et du Paysage, Service de Chirurgie thoracique, Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratory of Clinical and Experimental Pathology, and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)
Subjects: Male, Cancer Research, Pathology, Lung Neoplasms, Gene Dosage, medicine.disease_cause, MESH: Gene Dosage, MESH: Aged, 80 and over, 0302 clinical medicine, Carcinosarcoma, Epidermal growth factor receptor, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Aged, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, biology, Middle Aged, Prognosis, 3. Good health, ErbB Receptors, Oncology, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, KRAS, MESH: ras Proteins, medicine.medical_specialty, MESH: Mutation, MESH: Receptor, Epidermal Growth Factor, MESH: Prognosis, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Carcinosarcoma, Proto-Oncogene Proteins, medicine, Humans, Lung cancer, EGFR Protein Overexpression, 030304 developmental biology, Aged, Polysomy, MESH: Humans, Lung Sarcomatoid Carcinoma, Cancer, medicine.disease, MESH: Male, MESH: Lung Neoplasms, respiratory tract diseases, MESH: Proto-Oncogene Proteins, Mutation, Cancer research, biology.protein, ras Proteins, MESH: Female
Abstract: International audience; Sarcomatoid carcinomas (SC) of the lung are uncommon malignant tumors composed of carcinomatous and sarcomatous cell components and characterized by a more aggressive outcome than other histological subtypes of nonsmall cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR)-targeted therapies have emerged as a promising therapeutic approach in patients with advanced typical NSCLC such as adenocarcinoma, the potential clinical activity of these drugs in lung SC is still unknown. To investigate this point, we have analyzed the status of 4 EGFR pathways biomarkers in a series of lung SC. EGFR protein expression, EGFR gene copy number, EGFR mutational status and KRAS mutational status were assessed in a series of 22 consecutive cases of primary lung SC. EGFR protein overexpression was observed in all the cases. High level of polysomy (>or=4 copies of the gene in >40% of cells) was detected in 5 cases (23%). No EGFR mutation was detected. KRAS mutations were found in 8 patients (38%; Gly12Cys in 6 cases and Gly12Val in 2 cases). The consistent EGFR protein overexpression and the high rate of KRAS mutation may contribute to the poorer outcome of lung SC in comparison with typical NSCLC. The rare incidence of increased EGFR gene copy number, the lack of EGFR mutation and the high rate of KRAS mutation observed in our series also suggest that most patients with lung SC are not likely to benefit from anti-EGFR therapies.
Published: 2009
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20. RelB NF-kappaB represses estrogen receptor alpha expression via induction of the zinc finger protein Blimp1.: RelB represses ERα transcription by inducing Blimp

Author: Wang, Xiaobo, Belguise, Karine, O'Neill, Christine F., Sánchez-Morgan, Nuria, Romagnoli, Mathilde, Eddy, Sean, Mineva, Nora, Yu, Ziyang, Min, Chengyin, Trinkaus- Randall, Vickery, Chalbos, Dany, Sonenshein, Gail, Department of Biochemistry, Boston University [Boston] (BU), Departments of Ophthalmology and Biochemistry, Boston University School of Medicine (BUSM), Boston University [Boston] (BU)-Boston University [Boston] (BU), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), These studies were supported by NIH grants P01 ES11624, R01 CA129129, R01 CA36355, R01 EY06000 and training grant T32 HL007501 and a fellowship from the American Institute for Cancer Research with funding from the Derx Foundation., and Le Ster, Yves
Subjects: MESH: DNA Primers, MESH: Genes, bcl-2, MESH: Cell Line, Tumor, MESH: Gene Expression, MESH: Humans, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Base Sequence, MESH: Phenotype, MESH: Transcription Factor RelB, MESH: Proto-Oncogene Proteins c-bcl-2, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Repressor Proteins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Neoplasms, Hormone-Dependent, MESH: ras Proteins, MESH: Cell Movement, MESH: Estrogen Receptor alpha, MESH: Female, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, hormones, hormone substitutes, and hormone antagonists, MESH: Breast Neoplasms
Abstract: International audience; Aberrant constitutive expression of NF-kappaB subunits, reported in more than 90% of breast cancers and multiple other malignancies, plays pivotal roles in tumorigenesis. Higher RelB subunit expression was demonstrated in estrogen receptor alpha (ERalpha)-negative breast cancers versus ERalpha-positive ones, due in part to repression of RelB synthesis by ERalpha signaling. Notably, RelB promoted a more invasive phenotype in ERalpha-negative cancers via induction of the BCL2 gene. We report here that RelB reciprocally inhibits ERalpha synthesis in breast cancer cells, which contributes to a more migratory phenotype. Specifically, RelB is shown for the first time to induce expression of the zinc finger repressor protein Blimp1 (B-lymphocyte-induced maturation protein), the critical mediator of B- and T-cell development, which is transcribed from the PRDM1 gene. Blimp1 protein repressed ERalpha (ESR1) gene transcription. Commensurately higher Blimp1/PRDM1 expression was detected in ERalpha-negative breast cancer cells and primary breast tumors. Induction of PRDM1 gene expression was mediated by interaction of Bcl-2, localized in the mitochondria, with Ras. Thus, the induction of Blimp1 represents a novel mechanism whereby the RelB NF-kappaB subunit mediates repression, specifically of ERalpha, thereby promoting a more migratory phenotype.
Published: 2009
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21. RelB NF-kappaB represses estrogen receptor alpha expression via induction of the zinc finger protein Blimp1

Author: Wang, Xiaobo, Belguise, Karine, O'Neill, Christine F., Sánchez-Morgan, Nuria, Romagnoli, Mathilde, Eddy, Sean, Mineva, Nora, Yu, Ziyang, Min, Chengyin, Trinkaus- Randall, Vickery, Chalbos, Dany, Sonenshein, Gail, Department of Biochemistry, Boston University [Boston] (BU), Departments of Ophthalmology and Biochemistry, Boston University School of Medicine (BUSM), Boston University [Boston] (BU)-Boston University [Boston] (BU), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and These studies were supported by NIH grants P01 ES11624, R01 CA129129, R01 CA36355, R01 EY06000 and training grant T32 HL007501 and a fellowship from the American Institute for Cancer Research with funding from the Derx Foundation.
Subjects: MESH: DNA Primers, MESH: Genes, bcl-2, MESH: Cell Line, Tumor, MESH: Gene Expression, MESH: Humans, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Base Sequence, MESH: Phenotype, MESH: Transcription Factor RelB, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Repressor Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Neoplasms, Hormone-Dependent, MESH: ras Proteins, MESH: Cell Movement, MESH: Estrogen Receptor alpha, MESH: Female, hormones, hormone substitutes, and hormone antagonists, MESH: Breast Neoplasms
Abstract: International audience; Aberrant constitutive expression of NF-kappaB subunits, reported in more than 90% of breast cancers and multiple other malignancies, plays pivotal roles in tumorigenesis. Higher RelB subunit expression was demonstrated in estrogen receptor alpha (ERalpha)-negative breast cancers versus ERalpha-positive ones, due in part to repression of RelB synthesis by ERalpha signaling. Notably, RelB promoted a more invasive phenotype in ERalpha-negative cancers via induction of the BCL2 gene. We report here that RelB reciprocally inhibits ERalpha synthesis in breast cancer cells, which contributes to a more migratory phenotype. Specifically, RelB is shown for the first time to induce expression of the zinc finger repressor protein Blimp1 (B-lymphocyte-induced maturation protein), the critical mediator of B- and T-cell development, which is transcribed from the PRDM1 gene. Blimp1 protein repressed ERalpha (ESR1) gene transcription. Commensurately higher Blimp1/PRDM1 expression was detected in ERalpha-negative breast cancer cells and primary breast tumors. Induction of PRDM1 gene expression was mediated by interaction of Bcl-2, localized in the mitochondria, with Ras. Thus, the induction of Blimp1 represents a novel mechanism whereby the RelB NF-kappaB subunit mediates repression, specifically of ERalpha, thereby promoting a more migratory phenotype.
Published: 2009
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22. TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy

Author: Gaëlle Bougeard, F. Boissière, Jean-Jacques Tuech, J.-C. Sabourin, Frédéric Bibeau, Marc Ychou, David Tougeron, Françoise Charbonnier, Pierre Michel, F. Le Pessot, Aude Lamy, Thierry Frebourg, F. Di Fiore, Alice Oden-Gangloff, F. Blanchard, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire Ecologie Fonctionnelle et Environnement (LEFE), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Neurobiologie des réseaux sensorimoteurs (NRS (U7060)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Sciences du Génie Chimique (LSGC), Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cancer de Montpellier (ICM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Bougeard, Gaëlle, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire Ecologie Fonctionnelle et Environnement (ECOLAB), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), and Hôpital Lapeyronie [Montpellier] (CHU)
Subjects: Male, Cancer Research, endocrine system diseases, Colorectal cancer, medicine.medical_treatment, Cetuximab, medicine.disease_cause, Targeted therapy, Metastasis, MESH: Dose-Response Relationship, Drug, MESH: Antibodies, Monoclonal, MESH: Genotype, 0302 clinical medicine, MESH: Cetuximab, TP53, Neoplasm Metastasis, MESH: Tumor Suppressor Protein p53, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, Colerectal cancer, Antibodies, Monoclonal, DNA, Neoplasm, Exons, Middle Aged, targeted therapy, MESH: Amino Acid Substitution, 3. Good health, Exact test, Oncology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Disease Progression, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Disease Progression, Female, KRAS, Colorectal Neoplasms, MESH: ras Proteins, medicine.drug, MESH: Mutation, Genotype, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, colorectal cancer, Antibodies, Monoclonal, Humanized, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Proto-Oncogene Proteins p21(ras), [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Proto-Oncogene Proteins, medicine, Humans, neoplasms, Molecular Diagnostics, 030304 developmental biology, Aged, molecular marker, Chemotherapy, MESH: Humans, Dose-Response Relationship, Drug, business.industry, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, MESH: Neoplasm Metastasis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, digestive system diseases, MESH: Proto-Oncogene Proteins, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Amino Acid Substitution, MESH: Antibodies, Monoclonal, Humanized, Mutation, Cancer research, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, ras Proteins, MESH: Antineoplastic Agents, Tumor Suppressor Protein p53, business, MESH: Exons, MESH: Female, MESH: Colorectal Neoplasms
Abstract: International audience; Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan-Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT.
Published: 2009
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23. Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping

Author: Thomas Lavaux, Michèle Legrain, Eric Guérin, Michèle Beau-Faller, Gilbert Massard, Marie Pierre Gaub, Elisabeth Quoix, Agnès Neuville, Jean-Marie Wihlm, Anne-Claire Voegeli, Anne-Marie Ruppert, Pierre Oudet, Laboratoire de Biochimie et de Biologie Moléculaire, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Service de pneumologie, CHU Strasbourg-Hopital Civil, Laboratoire de Pathologie, Service de Chirurgie Thoracique, CHU Strasbourg-Nouvel Hôpital Civil, Peney, Maité, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Peptide Nucleic Acids, Cancer Research, Pathology, Lung Neoplasms, K-Ras mutations, medicine.disease_cause, Polymerase Chain Reaction, law.invention, MESH: Nucleic Acid Hybridization, 0302 clinical medicine, law, Carcinoma, Non-Small-Cell Lung, Mutation frequency, Polymerase chain reaction, MESH: Aged, 0303 health sciences, Mutation, MESH: Middle Aged, Nucleic Acid Hybridization, Middle Aged, 3. Good health, ErbB Receptors, Real-time polymerase chain reaction, Oncology, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, MESH: ras Proteins, medicine.medical_specialty, MESH: Mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Receptor, Epidermal Growth Factor, Biology, Sensitivity and Specificity, Proto-Oncogene Proteins p21(ras), MESH: Peptide Nucleic Acids, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Proto-Oncogene Proteins, medicine, Humans, Lung cancer, Molecular Diagnostics, non-small cell lung cancer, 030304 developmental biology, Aged, COLD-PCR, MESH: Humans, Cancer, MESH: Polymerase Chain Reaction, medicine.disease, sensitivity, MESH: Sensitivity and Specificity, MESH: Male, MESH: Lung Neoplasms, MESH: Proto-Oncogene Proteins, MESH: Genes, ras, Genes, ras, Cancer research, ras Proteins, real-time PCR, MESH: Female, PNA, MESH: Carcinoma, Non-Small-Cell Lung
Abstract: International audience; Non-small cell lung cancers (NSCLC), in particular adenocarcinoma, are often mixed with normal cells. Therefore, low sensitivity of direct sequencing used for K-Ras mutation analysis could be inadequate in some cases. Our study focused on the possibility to increase the detection of K-Ras mutations in cases of low tumour cellularity. Besides direct sequencing, we used wild-type hybridisation probes and peptide-nucleic-acid (PNA)-mediated PCR clamping to detect mutations at codons 12 and 13, in 114 routine consecutive NSCLC frozen surgical tumours untreated by targeted drugs. The sensitivity of the analysis without or with PNA was 10 and 1% of tumour DNA, respectively. Direct sequencing revealed K-Ras mutations in 11 out of 114 tumours (10%). Using PNA-mediated PCR clamping, 10 additional cases of K-Ras mutations were detected (21 out of 114, 18%, P
Published: 2009
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24. Physical interaction of calmodulin with the 5-hydroxytryptamine2C receptor C-terminus is essential for G protein-independent, arrestin-dependent receptor signaling

Author: Carine Bécamel, Eric Reiter, Marilyne Labasque, Philippe Marin, Joël Bockaert, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre CNRS-INSERM de Pharmacologie Endocrinologie (CCIPE), CCIPE, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, GTPase-activating protein, Arrestins, MESH: Heterotrimeric GTP-Binding Proteins, MESH: Neurons, MESH: Amino Acid Sequence, Mice, MESH: Protein Structure, Tertiary, RECEPTEUR A LA SEROTONINE, Receptor, Serotonin, 5-HT2C, 5-HT5A receptor, Protease-activated receptor, MESH: Animals, Extracellular Signal-Regulated MAP Kinases, MESH: Extracellular Signal-Regulated MAP Kinases, MESH: HSP70 Heat-Shock Proteins, beta-Arrestins, Neurons, 0303 health sciences, MESH: Retina, 030302 biochemistry & molecular biology, Articles, MESH: Calmodulin, Heterotrimeric GTP-Binding Proteins, MESH: Motor Activity, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Cell biology, MESH: Epithelial Cells, MESH: Calcium, MESH: Neuroglia, MESH: Arrestins, Signal transduction, MESH: ras Proteins, MESH: Spectrometry, Fluorescence, Protein Binding, Signal Transduction, MESH: Enzyme Activation, MAP Kinase Signaling System, Molecular Sequence Data, Biology, Cell Line, MESH: Drosophila melanogaster, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 03 medical and health sciences, Calmodulin, Enzyme-linked receptor, Animals, Humans, MESH: Protein Binding, Amino Acid Sequence, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, MESH: Mice, 030304 developmental biology, G protein-coupled receptor, G protein-coupled receptor kinase, MESH: Molecular Sequence Data, MESH: Humans, MESH: Proto-Oncogene Proteins c-akt, MESH: MAP Kinase Signaling System, MESH: Receptor, Serotonin, 5-HT2C, Epithelial Cells, MESH: Immunohistochemistry, Cell Biology, Molecular biology, MESH: Huntington Disease, Protein Structure, Tertiary, MESH: Cell Line, Enzyme Activation, MESH: Choroid Plexus, Choroid Plexus, ras Proteins, Calcium, Estrogen-related receptor gamma, MESH: Disease Models, Animal
Abstract: The serotonin (5-hydroxytryptamine; 5-HT)2C receptor is a G protein-coupled receptor (GPCR) exclusively expressed in CNS that has been implicated in numerous brain disorders, including anxio-depressive states. Like many GPCRs, 5-HT2C receptors physically interact with a variety of intracellular proteins in addition to G proteins. Here, we show that calmodulin (CaM) binds to a prototypic Ca2+-dependent “1-10” CaM-binding motif located in the proximal region of the 5-HT2C receptor C-terminus upon receptor activation by 5-HT. Mutation of this motif inhibited both β-arrestin recruitment by 5-HT2C receptor and receptor-operated extracellular signal-regulated kinase (ERK) 1,2 signaling in human embryonic kidney-293 cells, which was independent of G proteins and dependent on β-arrestins. A similar inhibition was observed in cells expressing a dominant-negative CaM or depleted of CaM by RNA interference. Expression of the CaM mutant also prevented receptor-mediated ERK1,2 phosphorylation in cultured cortical neurons and choroid plexus epithelial cells that endogenously express 5-HT2C receptors. Collectively, these findings demonstrate that physical interaction of CaM with recombinant and native 5-HT2C receptors is critical for G protein-independent, arrestin-dependent receptor signaling. This signaling pathway might be involved in neurogenesis induced by chronic treatment with 5-HT2C receptor agonists and their antidepressant-like activity.
Published: 2008
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25. Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation

Author: Emmanuelle Stebe, Gilles Pagès, Christoph Moroni, Khadija Essafi-Benkhadir, Cercina Onesto, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institute for Medical Microbiology, and University of Basel (Unibas)
Subjects: MAPK/ERK pathway, Untranslated region, Vascular Endothelial Growth Factor A, Angiogenic Switch, RNA Stability, Tristetraprolin, chemistry.chemical_compound, Hemoglobins, Mice, 0302 clinical medicine, Genes, Reporter, Neoplasms, MESH: RNA, Small Interfering, MESH: Microcirculation, MESH: Animals, MESH: Neoplasms, RNA, Small Interfering, Mitogen-Activated Protein Kinase 1, 0303 health sciences, Mitogen-Activated Protein Kinase 3, Kinase, MESH: RNA Stability, Articles, 3. Good health, Vascular endothelial growth factor, Vascular endothelial growth factor A, MESH: Hemoglobins, 030220 oncology & carcinogenesis, MESH: Tristetraprolin, MESH: Mitogen-Activated Protein Kinase 3, MESH: ras Proteins, MESH: Mitogen-Activated Protein Kinase 1, Protein Binding, MESH: Enzyme Activation, MESH: Xenograft Model Antitumor Assays, MAP Kinase Signaling System, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, MESH: Mice, Nude, MESH: Protein Binding, Animals, Humans, RNA, Messenger, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Messenger RNA, MESH: Humans, MESH: MAP Kinase Signaling System, MESH: Vascular Endothelial Growth Factor A, Microcirculation, MESH: Genes, Reporter, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Molecular biology, Xenograft Model Antitumor Assays, Enzyme Activation, chemistry, Cancer research, ras Proteins
Abstract: Vascular endothelial growth factor (VEGF) is one of the most important regulators of physiological and pathological angiogenesis. Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway and overexpression of VEGF are common denominators of tumors from different origins. We have established a new link between these two fundamental observations converging on VEGF mRNA stability. In this complex phenomenon, tristetraprolin (TTP), an adenylate and uridylate-rich element-associated protein that binds to VEGF mRNA 3′-untranslated region, plays a key role by inducing VEGF mRNA degradation, thus maintaining basal VEGF mRNA amounts in normal cells. ERKs activation results in the accumulation of TTP mRNA. However, ERKs reduce the VEGF mRNA-destabilizing effect of TTP, leading to an increase in VEGF expression that favors the angiogenic switch. Moreover, TTP decreases RasVal12-dependent VEGF expression and development of vascularized tumors in nude mice. As a consequence, TTP might represent a novel antiangiogenic and antitumor agent acting through its destabilizing activity on VEGF mRNA. Determination of TTP and ERKs status would provide useful information for the evaluation of the angiogenic potential in human tumors.
Published: 2007
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26. 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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27. Inducible expression of a MAP kinase phosphatase-3-GFP chimera specifically blunts fibroblast growth and ras-dependent tumor formation in nude mice

Author: S, Marchetti, C, Gimond, D, Roux, E, Gothié, J, Pouysségur, Gilles, Pagès, 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: endocrine system, Blotting, Western, Green Fluorescent Proteins, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Protein Tyrosine Phosphatases, Transfection, environment and public health, MESH: Tetracycline, Cell Line, Mice, MESH: Green Fluorescent Proteins, Protein Phosphatase 1, MESH: Anti-Bacterial Agents, MESH: Mice, Nude, Animals, MESH: Blotting, Northern, MESH: Blotting, Western, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, MESH: Mice, MESH: Chimera, Mitogen-Activated Protein Kinase 1, MESH: Phosphorylation, Chimera, MESH: Protein Phosphatase 1, MESH: Transfection, Dual Specificity Phosphatase 1, Neoplasms, Experimental, Fibroblasts, Tetracycline, Blotting, Northern, Anti-Bacterial Agents, MESH: Cell Line, Luminescent Proteins, enzymes and coenzymes (carbohydrates), MESH: Neoplasms, Experimental, MESH: Fibroblasts, ras Proteins, MESH: Cell Division, MESH: Luminescent Proteins, Protein Tyrosine Phosphatases, biological phenomena, cell phenomena, and immunity, MESH: ras Proteins, Cell Division, MESH: Dual Specificity Phosphatase 1, MESH: Mitogen-Activated Protein Kinase 1
Abstract: International audience; The p42/p44 mitogen activated protein kinase (MAPK) pathway participates in a wide range of cellular programs including proliferation, migration, differentiation, and survival. Specific pharmacological inhibitors, like PD98059 and U0126, are often used to inhibit p42/p44 MAPK signaling. However, these inhibitors are not appropriate to study the function of these kinases in whole organisms. We thus developed an inducible system designed to inhibit p42/p44 MAPK activity through the expression of a phosphatase specific for these two kinases, the MAPK phosphatase 3 (MKP-3). A fibroblast cell line was established in which MKP-3 expression is controlled by tetracycline. Tetracycline-induced MKP-3 resulted in partial de-phosphorylation of p42/p44 MAPKs in serum-stimulated cells. However, we could improve MKP-3 stability and thereby the rate of MAPK de-phosphorylation, when the C-terminal end of MKP-3 was fused to the green fluorescent protein (GFP). Importantly, the fusion of GFP to MKP-3 did not alter the specificity of the phosphatase towards its MAPK substrates. We further show that conditional expression of MKP-3-GFP in this fibroblast cell line results in the inhibition of: (a) the phosphorylation of the p42/p44 MAPK substrates Elk1 and HIF-1alpha, (b) vascular endothelial growth factor (VEGF), cyclin D1, and c-fos gene transcription in response to MAPK pathway activation, and (c) cell proliferation. Finally, the MKP-3-GFP inducible cell line was transformed by Ha-ras and injected into nude mice. Treatment of mice with the tetracycline analog doxycycline resulted in a large delay in tumor emergence and growth as compared to the untreated control group, indicating that MKP-3-GFP activity is maintained in vivo. Altogether, these results show that inducible expression of MKP-3-GFP constitutes a valuable tool to study the role of p42/p44 MAPKs in various cellular responses in both cultured cell and animal models, a tool that may also be used to block unwanted cell growth in pathological conditions.
Published: 2004
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28. Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs

Author: Kohno, Michiaki, Pouyssegur, Jacques, Laboratory of Cell Regulation, Nagasaki University, 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, MESH: Humans, Molecular Structure, Cell Cycle, MESH: Drug Screening Assays, Antitumor, MESH: Molecular Structure, Antineoplastic Agents, MESH: Cell Cycle, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Mitogen-Activated Protein Kinases, MESH: Enzyme Inhibitors, Neoplasms, ras Proteins, Animals, Humans, MESH: Antineoplastic Agents, MESH: Animals, MESH: Neoplasms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Mitogen-Activated Protein Kinases, MESH: ras Proteins, Signal Transduction
Abstract: International audience; The ERK signaling pathway, also known as the p42/p44 MAP kinase pathway, is a major determinant in the control of cell growth, cell differentiation and cell survival. This pathway, which operates downstream of Ras, is often up-regulated in human tumors and as such represents an attractive target for anticancer therapy. In this chapter we review the rationale for targeting the components of the ERK pathway, either alone or in association with cytotoxic anticancer agents. We present the most advanced inhibitors of this pathway and discuss their specificity and mechanism of action.
Published: 2003

29. The Ras GDP/GTP cycle is regulated by oxidizing agents at the level of Ras regulators and effectors

Author: Carmela Giglione, Marco Vanoni, Katia Accorsi, Andrea Parmeggiani, Groupe de Biophysique-Equipe 2, École polytechnique (X), Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Accorsi, K, Giglione, C, Vanoni, M, and Parmeggiani, A
Subjects: MESH: Oxidation-Reduction, GTP', GTPase-activating protein, GTPase activating protein, Biophysics, MESH: Guanosine Diphosphate, Saccharomyces cerevisiae, MESH: GTPase-Activating Proteins, Biology, Signal transduction, Biochemistry, Guanosine Diphosphate, Nucleotide exchange factor, Redox, 03 medical and health sciences, Structural Biology, Anti-apoptotic Ras signalling cascade, MESH: Oxidants, Genetics, Guanine Nucleotide Exchange Factors, MESH: Guanine Nucleotide Exchange Factors, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Molecular Biology, 030304 developmental biology, 0303 health sciences, reactive oxygen specie, MESH: Guanosine Triphosphate, Effector, 030302 biochemistry & molecular biology, GTPase-Activating Proteins, MESH: Reactive Oxygen Species, Cell Biology, Raf, Oxidants, MESH: Saccharomyces cerevisiae, Cell biology, Proto-Oncogene Proteins c-raf, Scintillation proximity assay, ras Proteins, MESH: Proto-Oncogene Proteins c-raf, Guanine nucleotide exchange factor, Guanosine Triphosphate, Reactive Oxygen Species, Oxidation-Reduction, MESH: ras Proteins
Abstract: Reactive oxygen species (ROS) have been found to play important roles in regulating cellular functions. Their action in vivo has been related to specific effects on signal transduction pathways, such as Ras pathway, In order to characterize which elements of Res pathway are affected by ROS, we have analyzed the action of different oxidizing agents on the ability of GTPase activating protein GAP and nucleotide exchange factor GEF to enhance the intrinsic activities of Pas, The action of these agents on the binding between H-Ras and its effector c-Raf-1 was also investigated. No effects were observed on the intrinsic activities of H-Ras or Ras2p, On the other hand, reversible inhibitions of GEF and GAP actions on Ras were found, whose extent was dependent on the agent used, As tested with the scintillation proximity assay, these agents also inhibited the binding of c-Raf-1 to H-Ras. Our data reveal new potential targets for the action of ROS on Ras pathway and suggest that they can influence the Ras activation state indirectly via regulators and effectors, (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
Published: 2001
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30. RotundRacGAP functions with ras during spermatognesis and retinal differentiation in Drosophila melanogaster

Author: Karine Raymond, Michel Cazemajor, Ruth Griffin-Shea, Isabelle Pignot-Paintrand, Evelyne Bergeret, Annabel Guichard, Marie-Odile Fauvarque, Centre de Recherches sur les Macromolécules Végétales (CERMAV), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Carret, Michèle, Transduction du signal : signalisation calcium, phosphorylation et inflammation, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), inconnu, Inconnu, and Griffin, Ruth
Subjects: Male, GTPase-activating protein, MESH: Drosophila Proteins, Genes, Insect, MESH: GTPase-Activating Proteins, MESH: Genes, Insect, Biology, Retina, MESH: Drosophila melanogaster, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, MESH: Gene Expression Regulation, Developmental, medicine, Animals, Drosophila Proteins, MESH: Animals, Spermatogenesis, Cell Growth and Development, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Spermatid, MESH: Retina, GTPase-Activating Proteins, Gene Expression Regulation, Developmental, Spermatid differentiation, Retinal, Cell Biology, biology.organism_classification, Null allele, Phenotype, MESH: Male, Cell biology, Drosophila melanogaster, medicine.anatomical_structure, chemistry, ras Proteins, MESH: Spermatogenesis, MESH: ras Proteins, 030217 neurology & neurosurgery
Abstract: International audience; Our analysis of rotund (rn) null mutations in Drosophila melanogaster revealed that deletion of the rn locus affects both spermatid and retinal differentiation. In the male reproductive system, the absence of RnRacGAP induced small testes, empty seminal vesicles, short testicular cysts, reduced amounts of interspermatid membrane, the absence of individualization complexes, and incomplete mitochondrial condensation. Flagellar growth continued within the short rn null cysts to produce large bulbous terminations of intertwined mature flagella. Organization of the retina was also severely perturbed as evidenced by grossly misshapen ommatidia containing reduced numbers of photoreceptor and pigment cells. These morphological phenotypes were rescued by genomic rnRacGAP transgenes, demonstrating that RnRacGAP function is critical to spermatid and retinal differentiation. The testicular phenotypes were suppressed by heterozygous hypomorphic mutations in the Dras1 and drk genes, indicating cross talk between RacGAP-regulated signaling and that of the Ras pathway. The observed genetic interactions are consistent with a model in which Rac signaling is activated by Ras and negatively regulated by RnRacGAP during spermatid differentiation. RnRacGAP and Ras cross talk also operated during retinal differentiation; however, while the heterozygous hypomorphic drk mutation continued to act as a suppressor of the rn null mutation, the heterozygous hypomorphic Dras1 mutation induced novel retinal phenotypes.
Published: 2001

31. N-terminal and C-terminal plasma membrane anchoring modulate differently agonist-induced activation of cytosolic phospholipase A2

Author: Klapisz, E., Ziari, M., Wendum, D., Koumanov, K., Brachet-Ducos, C., Olivier, J. L., Béréziat, G., Trugnan, G., Masliah, J., CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Enzyme Activation, Recombinant Fusion Proteins, Molecular Sequence Data, MESH: Cricetinae, MESH: Amino Acid Sequence, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, CHO Cells, In Vitro Techniques, Phospholipases A, Mice, Cytosol, MESH: Cytosol, MESH: CHO Cells, Cricetinae, MESH: Recombinant Fusion Proteins, Animals, Humans, MESH: Animals, Amino Acid Sequence, MESH: Mice, MESH: Phospholipases A2, Conserved Sequence, MESH: Lymphocyte Specific Protein Tyrosine Kinase p56(lck), MESH: Humans, MESH: Molecular Sequence Data, MESH: Conserved Sequence, Arachidonic Acid, Binding Sites, MESH: Molecular Weight, Cell Membrane, MESH: Arachidonic Acid, Enzyme Activation, Molecular Weight, Phospholipases A2, MESH: Binding Sites, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), ras Proteins, MESH: Phospholipases A, MESH: ras Proteins, MESH: Cell Membrane
Abstract: International audience; The 85 kDa cytosolic phospholipase A2 (cPLA2) plays a key role in liberating arachidonic acid from the sn-2 position of membrane phospholipids. When activated by extracellular stimuli, cPLA2 undergoes calcium-dependent translocation from cytosol to membrane sites which are still a matter of debate. In order to evaluate the effect of plasma membrane association on cPLA2 activation, we constructed chimeras of cPLA2 constitutively targeted to the plasma membrane by the N-terminal targeting sequence of the protein tyrosine kinase Lck (Lck-cPLA2) or the C-terminal targeting signal of K-Ras4B (cPLA2-Ras). Constitutive expression of these chimeras in Chinese hamster ovary cells overproducing the alpha2B adrenergic receptor (CHO-2B cells) did not affect the basal release of [3H]arachidonic acid, indicating that constitutive association of cPLA2 with cellular membranes did not ensure the hydrolysis of membrane phospholipids. However, Lck-cPLA2 increased [3H]arachidonic acid release in response to receptor stimulation and to increased intracellular calcium, whereas cPLA2-Ras inhibited it, compared with parental CHO-2B cells and CHO-2B cells producing comparable amounts of recombinant wild-type cPLA2. The lack of stimulation of cPLA2-Ras was not due to a decreased enzymatic activity as measured using an exogenous substrate, or to a decreased phosphorylation of the protein. These results show that the plasma membrane is a suitable site for cPLA2 activation when orientated correctly.
Published: 1999

32. JunD Reduces Tumor Angiogenesis by Protecting Cells from Oxidative Stress

Author: Jacques Pouysségur, Damien Gerald, Denise A. Chan, Fatima Mechta-Grigoriou, Amato J. Giaccia, Moshe Yaniv, Edurne Berra, Daniel Mansuy, Yves Frapart, Expression Génétique et Maladies, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut de signalisation, biologie du développement et cancer ( ISBDC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques ( LCBPT - UMR 8601 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Dept of Radiation Oncology, Stanford University [Stanford], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Department of Radiation Oncology [Stanford], Stanford Medicine, Stanford University-Stanford University, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Vascular Endothelial Growth Factor A, MESH : Oxidative Stress, MESH : Transcription Factors, Proto-Oncogene Proteins c-jun, Angiogenesis, Cell, MESH : Reactive Oxygen Species, medicine.disease_cause, Antioxidants, MESH : Iron, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Neovascularization, 0302 clinical medicine, Neoplasms, MESH: Up-Regulation, MESH: Animals, MESH: Neoplasms, MESH : Up-Regulation, G alpha subunit, chemistry.chemical_classification, Regulation of gene expression, MESH: Iron, 0303 health sciences, MESH: Oxidative Stress, MESH : Procollagen-Proline Dioxygenase, Neovascularization, Pathologic, integumentary system, MESH: Reactive Oxygen Species, MESH: Transcription Factors, MESH: Gene Expression Regulation, Neoplastic, Up-Regulation, Cell biology, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH : Vascular Endothelial Growth Factor A, MESH: Hydrogen Peroxide, MESH : Antioxidants, medicine.symptom, MESH: ras Proteins, MESH : Proto-Oncogene Proteins c-jun, MESH: Procollagen-Proline Dioxygenase, MESH : Hypoxia-Inducible Factor 1, alpha Subunit, MESH : Gene Expression Regulation, Neoplastic, Iron, Procollagen-Proline Dioxygenase, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, General Biochemistry, Genetics and Molecular Biology, Dioxygenases, Hypoxia-Inducible Factor-Proline Dioxygenases, 03 medical and health sciences, MESH : Dioxygenases, MESH: Dioxygenases, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Transcription factor, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Reactive oxygen species, MESH: Humans, MESH: Proto-Oncogene Proteins c-jun, Biochemistry, Genetics and Molecular Biology(all), MESH: Vascular Endothelial Growth Factor A, MESH: Antioxidants, MESH : Humans, MESH : Neovascularization, Pathologic, Hydrogen Peroxide, Hypoxia-Inducible Factor 1, alpha Subunit, Molecular biology, MESH : Neoplasms, Oxidative Stress, chemistry, ras Proteins, MESH : Animals, MESH : Hydrogen Peroxide, MESH : ras Proteins, Reactive Oxygen Species, MESH: Neovascularization, Pathologic, Oxidative stress, Transcription Factors
Abstract: International audience; Reactive oxygen species (ROS) are implicated in the pathophysiology of various diseases, including cancer. In this study, we show that JunD, a member of the AP-1 family of transcription factors, reduces tumor angiogenesis by limiting Ras-mediated production of ROS. Using junD-deficient cells, we demonstrate that JunD regulates genes involved in antioxidant defense, H2O2 production, and angiogenesis. The accumulation of H2O2 in junD-/- cells decreases the availability of FeII and reduces the activity of HIF prolyl hydroxylases (PHDs) that target hypoxia-inducible factors-alpha (HIFalpha) for degradation. Subsequently, HIF-alpha proteins accumulate and enhance the transcription of VEGF-A, a potent proangiogenic factor. Our study uncovers the mechanism by which JunD protects cells from oxidative stress and exerts an antiangiogenic effect. Furthermore, we provide new insights into the regulation of PHD activity, allowing immediate reactive adaptation to changes in O2 or iron levels in the cell.
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32 results on '"MESH: ras Proteins"'

1. A RAS-CaMKKβ-AMPKα2 pathway promotes senescence by licensing post-translational activation of C/EBPβ through a novel 3'UTR mechanism

2. FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer

3. MET Gene Copy Number in Non-small Cell Lung Cancer: Molecular Analysis in a Targeted Tyrosine Kinase Inhibitor Naïve Cohort

4. Longitudinal Analysis of Gene Expression in Porcine Skeletal Muscle After Post-Injection Local Injury

5. Characterization of the enzymatic activity of Clostridium perfringens TpeL

6. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

7. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump.: Sorafenib inhibits ABCG2 and overcome irinotecan resistance

8. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump.: Sorafenib inhibits ABCG2 and overcome irinotecan resistance

9. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth

10. Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience

11. The mutational spectrum of HRAS, KRAS, NRAS and FGFR3 genes in bladder cancer

12. Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature

13. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process.: Additive effect of ZOL and mTOR on osteosarcoma development

14. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process.: Additive effect of ZOL and mTOR on osteosarcoma development

15. Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice

16. Mutation analysis of BRAF exon 15 and KRAS codons 12 and 13 in Moroccan patients with colorectal cancer

17. Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia

18. Bias and evolution of the mutationally accessible phenotypic space in a developmental system

19. EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: implications for anti-EGFR treatment of a rare lung malignancy

20. RelB NF-kappaB represses estrogen receptor alpha expression via induction of the zinc finger protein Blimp1.: RelB represses ERα transcription by inducing Blimp

21. RelB NF-kappaB represses estrogen receptor alpha expression via induction of the zinc finger protein Blimp1

22. TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy

23. Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping

24. Physical interaction of calmodulin with the 5-hydroxytryptamine2C receptor C-terminus is essential for G protein-independent, arrestin-dependent receptor signaling

25. Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation

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

27. Inducible expression of a MAP kinase phosphatase-3-GFP chimera specifically blunts fibroblast growth and ras-dependent tumor formation in nude mice

28. Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs

29. The Ras GDP/GTP cycle is regulated by oxidizing agents at the level of Ras regulators and effectors

30. RotundRacGAP functions with ras during spermatognesis and retinal differentiation in Drosophila melanogaster

31. N-terminal and C-terminal plasma membrane anchoring modulate differently agonist-induced activation of cytosolic phospholipase A2

32. JunD Reduces Tumor Angiogenesis by Protecting Cells from Oxidative Stress

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32 results on '"MESH: ras Proteins"'

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