Protein Kinase a Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors
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Gpr161 Anchoring of PKA Consolidates GPCR and Camp Signaling
Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling Verena A. Bachmanna,1, Johanna E. Mayrhofera,1, Ronit Ilouzb, Philipp Tschaiknerc, Philipp Raffeinera, Ruth Röcka, Mathieu Courcellesd,e, Federico Apeltf, Tsan-Wen Lub,g, George S. Baillieh, Pierre Thibaultd,i, Pia Aanstadc, Ulrich Stelzlf,j, Susan S. Taylorb,g,2, and Eduard Stefana,2 aInstitute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, 6020 Innsbruck, Austria; bDepartment of Chemistry and Biochemistry, University of California, San Diego, CA 92093; cInstitute of Molecular Biology, University of Innsbruck, 6020 Innsbruck, Austria; dInstitute for Research in Immunology and Cancer, Université de Montréal, Montreal, QC, Canada H3C 3J7; eDépartement de Biochimie, Université de Montréal, Montreal, QC, Canada H3C 3J7; fOtto-Warburg Laboratory, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; gDepartment of Pharmacology, University of California, San Diego, CA 92093; hInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom; iDepartment of Chemistry, Université de Montréal, Montreal, QC, Canada H3C 3J7; and jInstitute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, 8010 Graz, Austria Contributed by Susan S. Taylor, May 24, 2016 (sent for review February 18, 2016; reviewed by John J. G. Tesmer and Mark von Zastrow) Scaffolding proteins organize the information flow from activated G accounts for nanomolar binding affinities to PKA R subunit dimers protein-coupled receptors (GPCRs) to intracellular effector cascades (12, 13). Moreover, additional components of the cAMP signaling both spatially and temporally. By this means, signaling scaffolds, such machinery, such as GPCRs, adenylyl cyclases, and phosphodiester- as A-kinase anchoring proteins (AKAPs), compartmentalize kinase ases, physically interact with AKAPs (1, 5, 11, 14). -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened. -
Role of Phosphodiesterases in the Pathophysiology of Neurodevelopmental Disorders
Molecular Psychiatry https://doi.org/10.1038/s41380-020-00997-9 REVIEW ARTICLE Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders 1 2 Sébastien Delhaye ● Barbara Bardoni Received: 4 July 2020 / Revised: 3 December 2020 / Accepted: 9 December 2020 © The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature 2021. This article is published with open access Abstract Phosphodiesterases (PDEs) are enzymes involved in the homeostasis of both cAMP and cGMP. They are members of a family of proteins that includes 11 subfamilies with different substrate specificities. Their main function is to catalyze the hydrolysis of cAMP, cGMP, or both. cAMP and cGMP are two key second messengers that modulate a wide array of intracellular processes and neurobehavioral functions, including memory and cognition. Even if these enzymes are present in all tissues, we focused on those PDEs that are expressed in the brain. We took into consideration genetic variants in patients affected by neurodevelopmental disorders, phenotypes of animal models, and pharmacological effects of PDE inhibitors, a class of drugs in rapid evolution and increasing application to brain disorders. Collectively, these data indicate the potential 1234567890();,: 1234567890();,: of PDE modulators to treat neurodevelopmental diseases characterized by learning and memory impairment, alteration of behaviors associated with depression, and deficits in social interaction. Indeed, clinical trials are in progress to treat patients with Alzheimer’s disease, schizophrenia, depression, and autism spectrum disorders. Among the most recent results, the application of some PDE inhibitors (PDE2A, PDE3, PDE4/4D, and PDE10A) to treat neurodevelopmental diseases, including autism spectrum disorders and intellectual disability, is a significant advance, since no specific therapies are available for these disorders that have a large prevalence. -
Prevalence of Mutations in TSHR, GNAS, PRKAR1A and RAS Genes
European Journal of Endocrinology (2008) 159 623–631 ISSN 0804-4643 CLINICAL STUDY Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain F Palos-Paz1, O Perez-Guerra1, J Cameselle-Teijeiro3,CRueda-Chimeno5, F Barreiro-Morandeira4, J Lado-Abeal1,2 and the Galician Group for the Study of Toxic Multinodular Goitre: D Araujo Vilar1,2, R Argueso7, O Barca1, MBotana7, J M Cabezas-Agrı´cola2, P Catalina6, L Dominguez Gerpe1, T Fernandez9, A Mato8, A Nun˜o11,MPenin10 and B Victoria1 1Unidade de Enfermedades Tiroideas e Metabo´licas (UETeM), 2Endocrinology Section, Department of Medicine, 3Pathology Department and 4Surgery Department, Complexo Hospitalario Universitary de Santiago (CHUS), University of Santiago de Compostela, Santiago de Compostela, 15705, Spain, 5General Surgery Section and 6Endocrinology Section, Complexo Hospitalario de Pontevedra, Pontevedra, Spain, 7Endocrinology Section, Complexo Hospitalario Xeral-Calde, Lugo, Spain, 8Endocrinology Section, Complexo Hospitalario de Ourense, Ourense, Spain, 9Endocrinology Section, Complexo Hospitalario Universitario Juan-Canalejo, A Corun˜a, Spain, 10Endocrinology Section, Hospital Arquitecto Marcide, Ferrol, Spain and 11General Surgery Section, Hospital do Meixoeiro, Complexo Hospitalario Universitario de Vigo, Vigo, Spain (Correspondence should be addressed to J Lado-Abeal who is now at UETeM, Department of Medicine, School of Medicine, University of Santiago de Compostela, C/San Francisco sn 15705, Santiago de Compostela, Spain; Email: [email protected]) Abstract Objective: Toxic thyroid adenoma (TA) is a common cause of hyperthyroidism. Mutations in the TSH receptor (TSHR) gene, and less frequently in the adenylate cyclase-stimulating G alpha protein (GNAS) gene, are well established causes of TA in Europe. -
Genomic Alterations Associated with Recurrence and TNBC Subtype in High
Author Manuscript Published OnlineFirst on August 31, 2018; DOI: 10.1158/1541-7786.MCR-18-0619 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Genomic Alterations Associated with Recurrence and TNBC Subtype in High- risk Early Breast Cancers Timothy R. Wilson1*, Akshata R. Udyavar2*, Ching-Wei Chang3, Jill M. Spoerke1, Junko Aimi1, Heidi M. Savage1, Anneleen Daemen2, Joyce A. O’Shaughnessy4,5,6, Richard Bourgon2 and Mark R. Lackner1 Departments of 1Oncology Biomarker Development, 2Bioinformatics and Computational Biology, 3Biostatistics, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.4US Oncology, 5Baylor University Medical Center, 6Texas Oncology, Dallas, TX, USA. *These authors contributed equally to this work. Correspondence and request for materials should be addressed to T.R.W. (email: [email protected]) or M.R.L. (email: [email protected]). Running Title: Genomic Profiling of High-risk Early Breast Cancers Keywords: early breast cancer, next generation sequencing, risk of recurrence, triple negative breast cancer, tumor mutational burden Conflicts of interest: TRW, ARY, CWC, JMS, JA, HMS, AD, RB and MRL are employed by Genentech and have stocks in Roche. JOS has received speaking fees from Blue Earth Diagnostics and Novartis, consulting fees from AstraZeneca, Celgene, Eli Lilly, LaRoche, Lilly USA, Merck, Novartis and Pfizer, Honoraria from Seattle Genetics and Downloaded from mcr.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 31, 2018; DOI: 10.1158/1541-7786.MCR-18-0619 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. -
Effect of Cigarette Smoke on DNA Methylation and Lung Function
de Vries et al. Respiratory Research (2018) 19:212 https://doi.org/10.1186/s12931-018-0904-y RESEARCH Open Access From blood to lung tissue: effect of cigarette smoke on DNA methylation and lung function Maaike de Vries1,2* , Diana A van der Plaat1,2, Ivana Nedeljkovic3, Rikst Nynke Verkaik-Schakel4, Wierd Kooistra2,5, Najaf Amin3, Cornelia M van Duijn3, Corry-Anke Brandsma2,5, Cleo C van Diemen6, Judith M Vonk1,2 and H Marike Boezen1,2 Abstract Background: Genetic and environmental factors play a role in the development of COPD. The epigenome, and more specifically DNA methylation, is recognized as important link between these factors. We postulate that DNA methylation is one of the routes by which cigarette smoke influences the development of COPD. In this study, we aim to identify CpG-sites that are associated with cigarette smoke exposure and lung function levels in whole blood and validate these CpG-sites in lung tissue. Methods: The association between pack years and DNA methylation was studied genome-wide in 658 current smokers with >5 pack years using robust linear regression analysis. Using mediation analysis, we subsequently selected the CpG-sites that were also associated with lung function levels. Significant CpG-sites were validated in lung tissue with pyrosequencing and expression quantitative trait methylation (eQTM) analysis was performed to investigate the association between DNA methylation and gene expression. Results: 15 CpG-sites were significantly associated with pack years and 10 of these were additionally associated with lung function levels. We validated 5 CpG-sites in lung tissue and found several associations between DNA methylation and gene expression. -
In Silico Investigation of Coding Variants Potentially
bioRxiv preprint doi: https://doi.org/10.1101/429258; this version posted September 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. In silico investigation of coding variants potentially affecting the functioning of the glutamatergic N-methyl-D-aspartate receptor in schizophrenia Antonia Tzavou1,2, David Curtis2,3* 1. University of Patras, GR 26500, Patras, Greece. 2. UCL Genetics Institute, UCL, Darwin Building, Gower Street, London WC1E 6BT, UK. 3. Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. *Corresponding author: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/429258; this version posted September 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Background Several lines of evidence support the hypothesis that impaired function of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) might be involved in the aetiology of schizophrenia. NMDAR is activated by phosphorylation by Fyn and there is also some evidence to suggest that abnormalities in Fyn functionality could also be involved in susceptibility to schizophrenia. In a recent weighted burden analysis of exome sequenced schizophrenia cases and controls we noted modest statistical evidence for an enrichment of rare, functional variants in FYN, GRIN1 and GRIN2B in schizophrenia cases. Aims To test the plausibility of the hypothesis that schizophrenia susceptibility might be associated with genetic variants predicted to cause impaired functioning of NMDAR, either directly or indirectly through impairment of the kinases which phosphorylate it. -
Downregulation of Carnitine Acyl-Carnitine Translocase by Mirnas
Page 1 of 288 Diabetes 1 Downregulation of Carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion Mufaddal S. Soni1, Mary E. Rabaglia1, Sushant Bhatnagar1, Jin Shang2, Olga Ilkayeva3, Randall Mynatt4, Yun-Ping Zhou2, Eric E. Schadt6, Nancy A.Thornberry2, Deborah M. Muoio5, Mark P. Keller1 and Alan D. Attie1 From the 1Department of Biochemistry, University of Wisconsin, Madison, Wisconsin; 2Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, New Jersey; 3Sarah W. Stedman Nutrition and Metabolism Center, Duke Institute of Molecular Physiology, 5Departments of Medicine and Pharmacology and Cancer Biology, Durham, North Carolina. 4Pennington Biomedical Research Center, Louisiana State University system, Baton Rouge, Louisiana; 6Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York. Corresponding author Alan D. Attie, 543A Biochemistry Addition, 433 Babcock Drive, Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, (608) 262-1372 (Ph), (608) 263-9608 (fax), [email protected]. Running Title: Fatty acyl-carnitines enhance insulin secretion Abstract word count: 163 Main text Word count: 3960 Number of tables: 0 Number of figures: 5 Diabetes Publish Ahead of Print, published online June 26, 2014 Diabetes Page 2 of 288 2 ABSTRACT We previously demonstrated that micro-RNAs 132 and 212 are differentially upregulated in response to obesity in two mouse strains that differ in their susceptibility to obesity-induced diabetes. Here we show the overexpression of micro-RNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including non-fuel stimuli. We determined that carnitine acyl-carnitine translocase (CACT, Slc25a20) is a direct target of these miRNAs. -
Thermal Manipulation During Embryogenesis Impacts H3k4me3 and H3k27me3 Histone Marks in Chicken Hypothalamus
ORIGINAL RESEARCH published: 26 November 2019 doi: 10.3389/fgene.2019.01207 Thermal Manipulation During Embryogenesis Impacts H3K4me3 and H3K27me3 Histone Marks in Chicken Hypothalamus Sarah-Anne David 1†, Anaïs Vitorino Carvalho 1†, Coralie Gimonnet 1, Aurélien Brionne 1, Christelle Hennequet-Antier 1, Benoît Piégu 2, Sabine Crochet 1, Nathalie Couroussé 1, Thierry Bordeau 1, Yves Bigot 2, Anne Collin 1 and Vincent Coustham 1* 1 BOA, INRA, Université de Tours, Nouzilly, France, 2 PRC, CNRS, IFCE, INRA, Université de Tours, Nouzilly, France Changes in gene activity through epigenetic alterations induced by early environmental Edited by: challenges during embryogenesis are known to impact the phenotype, health, and disease Helene Kiefer, risk of animals. Learning how environmental cues translate into persisting epigenetic INRA Centre Jouy-en-Josas, France memory may open new doors to improve robustness and resilience of developing animals. Reviewed by: Christoph Grunau, It has previously been shown that the heat tolerance of male broiler chickens was improved Université de Perpignan Via Domitia, by cyclically elevating egg incubation temperature. The embryonic thermal manipulation France enhanced gene expression response in muscle (P. major) when animals were heat Naoko Hattori, National Cancer Center Research challenged at slaughter age, 35 days post-hatch. However, the molecular mechanisms Institute, Japan underlying this phenomenon remain unknown. Here, we investigated the genome-wide *Correspondence: distribution, in hypothalamus and muscle tissues, of two histone post-translational Vincent Coustham [email protected] modifications, H3K4me3 and H3K27me3, known to contribute to environmental memory in eukaryotes. We found 785 H3K4me3 and 148 H3K27me3 differential peaks in the †These authors have contributed equally to this work hypothalamus, encompassing genes involved in neurodevelopmental, metabolic, and gene regulation functions. -
Study of Human PRKAR1A and Its Role in Autophagy
UiT The Arctic University of Norway Faculty of Health Science, Department of Medical Biology Research group: Molecular Cancer Research Group Study of human PRKAR1A and its role in autophagy Apsana Lamsal Master thesis in Biomedicine May 2018 Supervisor Professor Terje Johansen Assistant supervisor Assoc. Professor Eva Sjøttem ACKNOWLEDGEMENTS Foremost, I would like to extend my sincere gratitude to my main supervisor Professor Terje Johansen not only for his continuous support and guidance throughout my master’s degree but also for his patience, motivation, enthusiasm and immense knowledge. My deepest gratitude to my assistant supervisor, Assoc. Professor Eva Sjøttem for her nurturing supervision. I had the opportunity to strengthen my troubleshooting and analytical thinking skills, which are essential for my research career. I could not have imagined having a better advisor and mentor for my thesis. I would like to mention a huge thanks to Dr. Pradip in assisting in my procedures, all the analytics, and encouraging me to think outside the box. I would like to thank all the members of MCRG, Gry Evjen and Hanne Britt, Aud for your technical support and supervision especially during my pregnancy. Without your expertise, I would not have been able to complete my experiments, let alone graduate on time. Experiment days were always shorter and a bit easier having so lovely people in the lab. I thank Kenneth Bowitz Larsen for his invaluable technical excellence in microscopy and imaging. Finally, I am very grateful to my parents for their continuous motivation, my husband, Pushpa Shigdel, who has always been there for me. To my little daughter, Prazna who constantly tolerated my absence. -
Jcem1109.Pdf
JCEM ONLINE Advances in Genetics—Endocrine Research Identification of Gene Expression Profiles Associated With Cortisol Secretion in Adrenocortical Adenomas Hortense Wilmot Roussel,* Delphine Vezzosi,* Marthe Rizk-Rabin, Olivia Barreau, Bruno Ragazzon, Fernande René-Corail, Aurélien de Reynies, Jérôme Bertherat, and Guillaume Assie´ Institut National de la Santé et de la Recherche Médicale Unité 1016 (H.W.R., D.V., M.R.-R., O.B., B.R., Downloaded from https://academic.oup.com/jcem/article/98/6/E1109/2536811 by guest on 28 September 2021 F.R.-C., J.B., G.A.); Institut Cochin, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104 (H.W.R., D.V., M.R.-R, O.B., B.R., F.R.-C., J.B., G.A.); and Department of Endocrinology (H.W.R., O.B., J.B., G.A.), Reference Center for Rare Adrenal Diseases (J.B.), Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France; Faculté de Médecine Paris Descartes (H.W.R., D.V., M.R.-R., O.B., B.R., F.R.-C., J.B., G.A.), Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Department of Endocrinology (D.V.), Hôpital Larrey, 31480 Toulouse, France; and Plateforme de Bioinformatique (A.d.R.), Carte d’Identité des Tumeurs, Ligue Contre le Cancer, 75013 Paris, France Context: The cortisol secretion of adrenocortical adenomas can be either subtle or overt. The mechanisms leading to the autonomous hypersecretion of cortisol are unknown. Objective: The objective of the study was to identify the gene expression profile associated with the autonomous and excessive cortisol secretion of adrenocortical adenomas.