title: Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release.
abstract: The transcription factor Hes3 is a component of a signaling pathway that supports the growth of neural stem cells with profound consequences in neurodegenerative disease models. Here we explored whether Hes3 also regulates pancreatic islet cells. We showed that Hes3 is expressed in human and rodent pancreatic islets. In mouse islets it co-localizes with alpha and beta cell markers. We employed the mouse insulinoma cell line MIN6 to perform in vitro characterization and functional studies in conditions known to modulate Hes3 based upon our previous work using neural stem cell cultures. In these conditions, cells showed elevated Hes3 expression and nuclear localization, grew efficiently, and showed higher evoked insulin release responses, compared with serum-containing conditions. They also exhibited higher expression of the transcription factor Pdx1 and insulin. Furthermore, they were responsive to pharmacological treatments with the GLP-1 analog Exendin-4, which increased nuclear Hes3 localization. We employed a transfection approach to address specific functions of Hes3. Hes3 RNA interference opposed cell growth and affected gene expression as revealed by DNA microarrays. Western blotting and PCR approaches specifically showed that Hes3 RNA interference opposes the expression of Pdx1 and insulin. Hes3 overexpression (using a Hes3-GFP fusion construct) confirmed a role of Hes3 in regulating Pdx1 expression. Hes3 RNA interference reduced evoked insulin release. Mice lacking Hes3 exhibited increased islet damage by streptozotocin. These data suggest roles of Hes3 in pancreatic islet function.
authors.affiliation: From the Department of Medicine and.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Masjkur
authors.affiliation: From the Department of Medicine and.
authors.forename: Carina
authors.initials: C
authors.lastname: Arps-Forker
authors.affiliation: From the Department of Medicine and.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Poser
authors.affiliation: From the Department of Medicine and.
authors.forename: Polyxeni
authors.initials: P
authors.lastname: Nikolakopoulou
authors.affiliation: From the Department of Medicine and.
authors.forename: Louiza
authors.initials: L
authors.lastname: Toutouna
authors.affiliation: the Applied Bioinformatics Group, BioInnovations Zentrum, University of Dresden, 01307 Dresden, Germany.
authors.forename: Ramu
authors.initials: R
authors.lastname: Chenna
authors.affiliation: the Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine and.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: the Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine and.
authors.forename: Antonios
authors.initials: A
authors.lastname: Chatzigeorgiou
authors.affiliation: the Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine and.
authors.forename: Lan-Sun
authors.initials: LS
authors.lastname: Chen
authors.affiliation: Department of Medicine, OncoRay National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, 01307 Dresden, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Dubrovska
authors.affiliation: the Diabetes Research Group, King's College London, London SE5 9RS, United Kingdom.
authors.forename: Pratik
authors.initials: P
authors.lastname: Choudhary
authors.affiliation: the Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany, and.
authors.forename: Ingo
authors.initials: I
authors.lastname: Uphues
authors.affiliation: the Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
authors.affiliation: From the Department of Medicine and.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: From the Department of Medicine and the Center for Regenerative Therapies Dresden, 01307 Dresden, Germany andreas.theotokis@uniklinikum-dresden.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Androutsellis-Theotokis
mesh_terms: D000328:Adult; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077270:Exenatide; D015870:Gene Expression; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D034622:RNA Interference; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D000077270:Exenatide; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D009419:Nerve Tissue Proteins; D010455:Peptides; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014688:Venoms; C495457:HES3 protein, human; C411886:Hes3 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein
keywords: Beta Cell (B-cell); Cell Culture; Islet; Neural Stem Cell (NSC); Neurodegenerative Disease; Neuroprogenitor Cell; Notch Pathway; Pancreas; Parkinson Disease; Signal Transduction