miR-204 Targets PERK and Regulates UPR Signaling and β-Cell Apoptosis
| Autor: | Junqin Chen, Anath Shalev, Guanlan Xu, Gu Jing, Truman Grayson |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty Cell signaling Blotting Western Activating transcription factor Apoptosis Activating Transcription Factor 4 Real-Time Polymerase Chain Reaction eIF-2 Kinase 03 medical and health sciences Endocrinology Insulin-Secreting Cells Internal medicine medicine Humans PERK inhibitors Molecular Biology Transcription factor Original Research EIF-2 kinase biology General Medicine Endoplasmic Reticulum Stress Activating Transcription Factor 6 Cell biology MicroRNAs HEK293 Cells 030104 developmental biology Unfolded Protein Response biology.protein Unfolded protein response Signal transduction Signal Transduction |
| Zdroj: | Molecular Endocrinology. 30:917-924 |
| ISSN: | 1944-9917 0888-8809 |
| Popis: | Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of diabetes and the associated β-cell apoptosis. Although microRNAs (miRNAs) have been widely studied in various diseases including diabetes, the role of miRNAs in ER stress and β-cell apoptosis has only started to be elucidated. We recently showed that diabetes increases β-cell miR-204 and have now discovered that miR-204 directly targets the 3'untranslated region of protein kinase R-like ER kinase (PERK), 1 of the 3 ER transmembrane sensors and a key factor of the unfolded protein response (UPR). In addition, by using primary human islets, mouse islets, and INS-1 β-cells, we found that miR-204 decreased PERK expression as well as its downstream factors, activating transcription factor 4 and CCAAT enhancer-binding protein homologous protein, whereas it had no effect on the other 2 ER transmembrane sensors, activating transcription factor 6 and inositol-requiring enzyme-1α. Interestingly, we discovered that miR-204 also inhibited PERK signaling in the context of ER stress, and this exacerbated ER stress-induced β-cell apoptosis. This effect could be mimicked by PERK inhibitors supporting the notion that the miR-204-mediated inhibition of PERK and UPR signaling was conferring these detrimental effects on cell survival. Taken together, we have identified PERK as a novel target of miR-204 and show that miR-204 inhibits PERK signaling and increases ER stress-induced cell death, revealing for the first time a link between this miRNA and UPR. |
| Databáze: | OpenAIRE |
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