Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival
| Autor: | Benjamin Glaser, Rotem Karni, Yuval Dor, Ayat Hija, Pushkar Malakar, Gil Leibowitz, Lital Chartarifsky |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty Cell Survival MAP Kinase Signaling System medicine.medical_treatment Biology Article Mice 03 medical and health sciences Antigens CD Cell Line Tumor Insulin-Secreting Cells Internal medicine Insulin receptor substrate medicine Animals Humans Insulin Multidisciplinary Alternative splicing nutritional and metabolic diseases Receptor Insulin IRS2 Cell biology Alternative Splicing Insulin receptor 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 Lipotoxicity biology.protein Beta cell Signal transduction hormones hormone substitutes and hormone antagonists |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep31222 |
| Popis: | Type 2 Diabetes (T2DM) affects more than 300 million people worldwide. One of the hallmarks of T2DM is peripheral insulin resistance, in part due to unproductive insulin signaling through the insulin receptor. The insulin receptor (INSR) exists as two isoforms, INSR-A and INSR-B, which results from skipping or inclusion of exon 11 respectively. What determines the relative abundance of the different insulin receptor splice variants is unknown. Moreover, it is not yet clear what the physiological roles of each of the isoforms are in normal and diseased beta cells. In this study, we show that insulin induces INSR exon 11 inclusion in pancreatic beta cells in both human and mouse. This occurs through activation of the Ras-MAPK/ERK signaling pathway and up-regulation of the splicing factor SRSF1. Induction of exon 11 skipping by a splice-site competitive antisense oligonucleotide inhibited the MAPK-ERK signaling pathway downstream of the insulin receptor, sensitizing the pancreatic β-cell line MIN6 to stress-induced apoptosis and lipotoxicity. These results assign to insulin a regulatory role in INSR alternative splicing through the Ras-MAPK/ERK signaling pathway. We suggest that in beta cells, INSR-B has a protective role, while INSR-A expression sensitizes beta cells to programmed cell death. |
| Databáze: | OpenAIRE |
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