title: Specific silencing of the REST target genes in insulin-secreting cells uncovers their participation in beta cell survival.
abstract: The absence of the transcriptional repressor RE-1 Silencing Transcription Factor (REST) in insulin-secreting beta cells is a major cue for the specific expression of a large number of genes. These REST target genes were largely ascribed to a function of neurotransmission in a neuronal context, whereas their role in pancreatic beta cells has been poorly explored. To identify their functional significance, we have generated transgenic mice expressing REST in beta cells (RIP-REST mice), and previously discovered that REST target genes are essential to insulin exocytosis. Herein we characterized a novel line of RIP-REST mice featuring diabetes. In diabetic RIP-REST mice, high levels of REST were associated with postnatal beta cell apoptosis, which resulted in gradual beta cell loss and sustained hyperglycemia in adults. Moreover, adenoviral REST transduction in INS-1E cells led to increased cell death under control conditions, and sensitized cells to death induced by cytokines. Screening for REST target genes identified several anti-apoptotic genes bearing the binding motif RE-1 that were downregulated upon REST expression in INS-1E cells, including Gjd2, Mapk8ip1, Irs2, Ptprn, and Cdk5r2. Decreased levels of Cdk5r2 in beta cells of RIP-REST mice further confirmed that it is controlled by REST, in vivo. Using siRNA-mediated knock-down in INS-1E cells, we showed that Cdk5r2 protects beta cells against cytokines and palmitate-induced apoptosis. Together, these data document that a set of REST target genes, including Cdk5r2, is important for beta cell survival.
authors.affiliation: Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Martin
authors.forename: Florent
authors.initials: F
authors.lastname: Allagnat
authors.forename: Emilie
authors.initials: E
authors.lastname: Gesina
authors.forename: Dorothee
authors.initials: D
authors.lastname: Caille
authors.forename: Asllan
authors.initials: A
authors.lastname: Gjinovci
authors.forename: Gerard
authors.initials: G
authors.lastname: Waeber
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.forename: Jacques-Antoine
authors.initials: JA
authors.lastname: Haefliger
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D016384:Consensus Sequence; D003598:Cytoskeletal Proteins; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D058635:Lipid-Linked Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020218:Response Elements; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D005947:Glucose; D007328:Insulin; D058635:Lipid-Linked Proteins; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C578513:Cdk5r2 protein, mouse