Specific silencing of the REST target genes in insulin-secreting cells uncovers their participation in beta cell survival
| Autor: | Asllan Gjinovci, Dorothée Caille, Gérard Waeber, Paolo Meda, Florent Allagnat, Jacques-Antoine Haefliger, Emilie Gesina, David C. Martin |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
lcsh:Medicine Gene Expression Apoptosis Mice 0302 clinical medicine Endocrinology Insulin-Secreting Cells Insulin Secretion Molecular Cell Biology Homeostasis Insulin lcsh:Science Lipid-Linked Proteins 0303 health sciences Multidisciplinary Cell Death Cell biology Gene Knockdown Techniques Medicine RNA Interference Beta cell Research Article Genetically modified mouse Programmed cell death Cell Survival 030209 endocrinology & metabolism Mice Transgenic Biology Response Elements Molecular Genetics 03 medical and health sciences PTPRN Cell Line Tumor Consensus Sequence Diabetes Mellitus Genetics Gene silencing Animals Transcription factor Pancreas 030304 developmental biology Diabetic Endocrinology Base Sequence Endocrine Physiology lcsh:R Computational Biology Diabetes Mellitus Type 1 Diabetes Mellitus Type 2 Molecular biology IRS2 Rats Mice Inbred C57BL Repressor Proteins Cytoskeletal Proteins Glucose Gene Expression Regulation Hyperglycemia lcsh:Q Endocrine Cells Carrier Proteins |
| Zdroj: | PLoS ONE PLoS One PloS one PLoS ONE, Vol 7, Iss 9, p e45844 (2012) PLoS ONE; Vol 7 Plos One, vol. 7, no. 9, pp. e45844 |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|