4 results on '"Shaunt Fereshetian"'
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2. Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features
- Author
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Jon M. Madison, Karen Duong, Ellen F. Vieux, Namrata D. Udeshi, Sumaiya Iqbal, Elise Requadt, Shaunt Fereshetian, Michael C. Lewis, Antonio S. Gomes, Kerry A. Pierce, Randall J. Platt, Feng Zhang, Arthur J. Campbell, Dennis Lal, Florence F. Wagner, Clary B. Clish, Steven A. Carr, Morgan Sheng, Edward M. Scolnick, and Jeffrey R. Cottrell
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Molecular Neuroscience ,Proteomics ,Metabolomics ,Science - Abstract
Summary: Genetic variation of the 16p11.2 deletion locus containing the KCTD13 gene and of CUL3 is linked with autism. This genetic connection suggested that substrates of a CUL3-KCTD13 ubiquitin ligase may be involved in disease pathogenesis. Comparison of Kctd13 mutant (Kctd13−/−) and wild-type neuronal ubiquitylomes identified adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in adenosine monophosphate (AMP) synthesis, as a KCTD13 ligase substrate. In Kctd13−/− neurons, there were increased levels of succinyl-adenosine (S-Ado), a metabolite downstream of ADSS. Notably, S-Ado levels are elevated in adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. The increased S-Ado levels in Kctd13−/− neurons were decreased by treatment with an ADSS inhibitor. Lastly, functional analysis of human KCTD13 variants suggests that KCTD13 variation may alter ubiquitination of ADSS. These data suggest that succinyl-AMP metabolites accumulate in Kctd13−/− neurons, and this observation may have implications for our understanding of 16p11.2 deletion syndrome.
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- 2021
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3. Combined Analysis of Metabolomes, Proteomes, and Transcriptomes of Hepatitis C Virus–Infected Cells and Liver to Identify Pathways Associated With Disease Development
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Ralf Bartenschlager, Kazuaki Chayama, Joachim Lupberger, Nabeel Bardeesy, Eloi R. Verrier, Nicolaas Van Renne, Tom Croonenborghs, Philipp Mertins, Armando Andres Roca Suarez, Steven A. Carr, Frank Jühling, Yujin Hoshida, Evelyn Ramberger, Mirjam B. Zeisel, Olivier Gevaert, Nourdine Hamdane, Marine A. Oudot, Gergö Meszaros, Alessia Virzì, Mohsen Nabian, Thomas F. Baumert, Daniel Brumaru, Romeo Ricci, Rileen Sinha, Naoto Fujiwara, Hussein El Saghire, Simonetta Bandiera, Marko Jovanovic, Carole Jamey, Celine Everaert, Shaunt Fereshetian, Nathalie Pochet, Laura Heydmann, Sarah C. Durand, Nassim Dali-Youcef, Atish Mukherji, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Harvard-MIT Division of Health Sciences and Technology [Cambridge], Massachusetts Institute of Technology (MIT), Evergrande Center for Immunologic Diseases [Boston, MA, USA] (Ann Romney Center for Neurologic Diseases), Brigham & Women's Hospital, Harvard Medical School, Université de Strasbourg (UNISTRA), Laboratoire de Biochimie et de Biologie Moléculaire, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Department of Infectious Diseases [Heidelberg, Germany], Heidelberg University Hospital [Heidelberg], Division of Virus-Associated Carcinogenesis [Heidelberg, Germany], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), The Broad Institute [Cambridge, MA, USA], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Proteomics Platform [Berlin, Germany], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz Society [Berlin, Germany], Institute of Public Health [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Hiroshima University, Liver Research Project Center [Hiroshima, Japan], Massachusetts General Hospital [Boston], Harold C. Simmons Comprehensive Cancer Center [Dallas, TX, États-Unis], University of Texas Southwestern Medical Center [Dallas], Cell Circuits Program [Cambridge, MA, USA], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Stanford Center for BioMedical Informatics Research (BMIR), Stanford University, Department of Neurology [Cambridge, MA, USA] (Ann Romney Center for Neurologic Diseases), Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Pôle hépato-digestif [Strasbourg], Nouvel Hôpital Civil, Hospices Civils de Strasbourg-Institut Hospitalo-Universitaire de strasbourg, This work was supported by the European Union (ERC-AdG-2014 HEPCIR to Thomas F. Baumert and Yujin Hoshida and EU H2020 HEPCAR 667273 to Thomas F. Baumert and Joachim Lupberger), the Agence nationale de recherche sur le sida et les hépatites virales (ECTZ4236 to Joachim Lupberger and ECTZ4446 to Armando Andres Roca Suarez), the French Cancer Agency (ARC IHU201301187 to Thomas F. Baumert), the US Department of Defense (W81XWH-16-1-0363 to Thomas F. Baumert and Yujin Hoshida), the National Institutes of Health (National Institute of Allergy and Infectious Diseases R03AI131066 to Nathalie Pochet and Thomas F. Baumert, National Cancer Institute 1R21CA209940 to Nathalie Pochet, Thomas F. Baumert, and Olivier Gevaert, National Institute of Allergy and Infectious Diseases 5U19AI123862-02 to Thomas F. Baumert, National Cancer Institute/Informatics Technology for Cancer Research (ITCR) U01 CA214846 to Nathalie Pochet and Olivier Gevaert), the Fondation de l’Université de Strasbourg (HEPKIN) (TBA-DON-0002) and the INSERM Plan Cancer 2019-2023 to Thomas F. Baumert. This work has benefitted from support by the Initiative of Excellence IDEX-Unistra (ANR-10-IDEX-0002-02 to Joachim Lupberger) and has been published under the framework of the LABEX ANR-10-LAB-28 (HEPSYS). INSERM Plan Cancer, IDEX, and LABEX are initiatives from the French program 'Investments for the Future.' The work of Ralf Bartenschlager was supported by the Deutsche Forschungsgemeinschaft (TRR179, TP9). Kazuaki Chayama was supported by the Research Program on Hepatitis from the Japanese Agency for Medical Research and Development (AMED) Japan (JP18fk0210020h0002). The work of Romeo Ricci and Gergö Meszaros was supported by a European Research Council (ERC) starting grant (ERC-2011-StG, 281271-STRESS METABOL), by the European Foundation for the Study of Diabetes (EFSD)/Lilly European Diabetes Research Program grant, and by the ANR-10-LABX-0030-INRT grant, a French State fund managed by the ANR under the frame program Investissements d’Avenir ANR-10-IDEX0002-02., daulny, anne, and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Proteomics ,Cirrhosis ,Peroxisome proliferator-activated receptor ,Datasets as Topic ,Hepacivirus ,medicine.disease_cause ,Sciences du Vivant [q-bio]/Cancer ,Transcriptome ,Liver disease ,Mice ,0302 clinical medicine ,Sciences du Vivant [q-bio]/Immunologie ,HCC ,chemistry.chemical_classification ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Fatty liver ,Gastroenterology ,Sciences du Vivant [q-bio]/Biotechnologies ,metabolic disease ,3. Good health ,Liver ,Hepatocellular carcinoma ,030211 gastroenterology & hepatology ,signal transduction ,STAT3 Transcription Factor ,Hepatitis C virus ,Biology ,Sciences du Vivant [q-bio]/Médecine humaine et pathologie ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Peroxisomes ,Animals ,Humans ,Metabolomics ,Transplantation Chimera ,Hepatology ,Gene Expression Profiling ,immune regulation ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Hepatitis C, Chronic ,medicine.disease ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,digestive system diseases ,Disease Models, Animal ,030104 developmental biology ,Glucose ,chemistry ,Cancer research ,Hepatocytes ,Steatohepatitis ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Comment inMulti-omic Analyses Reveal Complex Interactions Between HCV and Hepatocytes Demonstrating That the Red Queen Is Up and Running. [Gastroenterology. 2019]; International audience; BACKGROUND & AIMS:The mechanisms of hepatitis C virus (HCV) infection, liver disease progression, and hepatocarcinogenesis are only partially understood. We performed genomic, proteomic, and metabolomic analyses of HCV-infected cells and chimeric mice to learn more about these processes.METHODS:Huh7.5.1dif (hepatocyte-like cells) were infected with culture-derived HCV and used in RNA sequencing, proteomic, metabolomic, and integrative genomic analyses. uPA/SCID (urokinase-type plasminogen activator/severe combined immunodeficiency) mice were injected with serum from HCV-infected patients; 8 weeks later, liver tissues were collected and analyzed by RNA sequencing and proteomics. Using differential expression, gene set enrichment analyses, and protein interaction mapping, we identified pathways that changed in response to HCV infection. We validated our findings in studies of liver tissues from 216 patients with HCV infection and early-stage cirrhosis and paired biopsy specimens from 99 patients with hepatocellular carcinoma, including 17 patients with histologic features of steatohepatitis. Cirrhotic liver tissues from patients with HCV infection were classified into 2 groups based on relative peroxisome function; outcomes assessed included Child-Pugh class, development of hepatocellular carcinoma, survival, and steatohepatitis. Hepatocellular carcinomas were classified according to steatohepatitis; the outcome was relative peroxisomal function.RESULTS:We quantified 21,950 messenger RNAs (mRNAs) and 8297 proteins in HCV-infected cells. Upon HCV infection of hepatocyte-like cells and chimeric mice, we observed significant changes in levels of mRNAs and proteins involved in metabolism and hepatocarcinogenesis. HCV infection of hepatocyte-like cells significantly increased levels of the mRNAs, but not proteins, that regulate the innate immune response; we believe this was due to the inhibition of translation in these cells. HCV infection of hepatocyte-like cells increased glucose consumption and metabolism and the STAT3 signaling pathway and reduced peroxisome function. Peroxisomes mediate β-oxidation of very long-chain fatty acids; we found intracellular accumulation of very long-chain fatty acids in HCV-infected cells, which is also observed in patients with fatty liver disease. Cells in livers from HCV-infected mice had significant reductions in levels of the mRNAs and proteins associated with peroxisome function, indicating perturbation of peroxisomes. We found that defects in peroxisome function were associated with outcomes and features of HCV-associated cirrhosis, fatty liver disease, and hepatocellular carcinoma in patients.CONCLUSIONS:We performed combined transcriptome, proteome, and metabolome analyses of liver tissues from HCV-infected hepatocyte-like cells and HCV-infected mice. We found that HCV infection increases glucose metabolism and the STAT3 signaling pathway and thereby reduces peroxisome function; alterations in the expression levels of peroxisome genes were associated with outcomes of patients with liver diseases. These findings provide insights into liver disease pathogenesis and might be used to identify new therapeutic targets.
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- 2019
4. Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
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Francesco Graziano, J. Alan Diehl, Yu Imamura, Les Henderson, Rachel Rendak, Peng Xu, Jens Puschhof, Charles Zou, Sarit Schwartz, Steven A. Carr, Jin Zhou, Philipp Mertins, Xinsen Xu, Masayuki Watanabe, Wei-Li Liao, Eiji Oki, Annamaria Ruzzo, Gabrielle S. Wong, Tianxia Li, Daniel V.T. Catenacci, Jie Bin Liu, Adam J. Bass, Kwok-Kin Wong, Anil K. Rustgi, Steven E. Schumacher, Rameen Beroukhim, Emily O'Day, Shaunt Fereshetian, Kenichi Nakamura, Hideo Baba, David Xu, Zhong Wu, Karin Jensen, Fabiola Cecchi, Austin M. Dulak, Christopher Szeto, James M. McFarland, and Todd Hembrough
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0301 basic medicine ,MAPK/ERK pathway ,Esophageal Neoplasms ,endocrine system diseases ,Pyridones ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Pyrimidinones ,Protein tyrosine phosphatase ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Proto-Oncogene Proteins p21(ras) ,Mice ,03 medical and health sciences ,Piperidines ,Stomach Neoplasms ,In vivo ,Cell Line, Tumor ,Gene duplication ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,neoplasms ,Mitogen-Activated Protein Kinase Kinases ,Gene Amplification ,Wild type ,Cancer ,General Medicine ,medicine.disease ,digestive system diseases ,respiratory tract diseases ,3. Good health ,Disease Models, Animal ,Pyrimidines ,030104 developmental biology ,SOS1 ,Cancer research ,KRAS - Abstract
The role of KRAS, when activated through canonical mutations, has been well established in cancer1. Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas2-4. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.
- Published
- 2018
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