Regulation of P21 during diabetes-associated stress of the endoplasmic reticulum
| Autor: | Hippokratis Kiaris, Athanasios G Papavassiliou, Ioulia Chatzistamou, Chrysovalantou Mihailidou |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Blood Glucose
Cyclin-Dependent Kinase Inhibitor p21 Sucrose Cancer Research Endocrinology Diabetes and Metabolism Stimulation Diet High-Fat Cell Line Diabetes Mellitus Experimental Pathogenesis Endocrinology Cricetinae Insulin-Secreting Cells Diabetes mellitus medicine Animals Glucose homeostasis HSP70 Heat-Shock Proteins Mice Knockout Transcription Factor CHOP business.industry Endoplasmic reticulum Membrane Proteins Endoplasmic Reticulum Stress medicine.disease Mice Inbred C57BL Diabetes Mellitus Type 2 Oncology Apoptosis Unfolded protein response Cancer research Female business Oligopeptides |
| Zdroj: | Endocrine-Related Cancer. 22:217-228 |
| ISSN: | 1479-6821 1351-0088 |
| DOI: | 10.1530/erc-15-0018 |
| Popis: | Endoplasmic reticulum (ER) stress plays a major role in the pathogenesis of diabetes by inducing β-cell apoptosis in the islets of Langerhans. In this study, we show that the transcription factor CHOP, which is instrumental for the induction of ER-stress-associated apoptosis and the pancreatic dysfunction in diabetes, regulates the expression of P21 (WAF1), a cell cycle regulator with anti-apoptotic activity that promotes cell survival. Deficiency of P21 sensitizes pancreatic β-cells to glucotoxicity, while in mice genetic ablation of P21 accelerates experimental diet-induced diabetes, results indicative of a protective role for P21 in the development of the disease. Conversely, pharmacological stimulation of P21 expression by nutlin-3a, an inhibitor of P53–MDM2 interaction, restores pancreatic function and facilitates glucose homeostasis. These findings indicate that P21 acts as an inhibitor of ER-stress-associated tissue damage and that stimulation of P21 activity can be beneficial for the management of diabetes and probably of other conditions in which ER-stress-associated death is undesirable. |
| Databáze: | OpenAIRE |
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