Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8477250 | Molecular and Cellular Endocrinology | 2014 | 11 Pages |
Abstract
Glucocorticoid excess is associated with glucose intolerance and diabetes. In addition to inducing insulin resistance, glucocorticoids impair β-cell function and cause β-cell apoptosis. In this study we show that dexamethasone activates mitogen-activated protein kinases (MAPKs) signaling in MIN6 β-cells, as evident by enhanced phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK). In contrast, the integrated stress response pathway was inhibited by dexamethasone. A p38 MAPK inhibitor attenuated dexamethasone-induced apoptosis in β-cells and isolated islets and decreased glucocorticoid receptor phosphorylation at S220. In contrast, a JNK inhibitor augmented DNA fragmentation and dexamethasone-induced formation of cleaved caspase 3. We also show that inhibition of protein phosphatase 5 (PP5) augments apoptosis in dexamethasone-exposed islets and β-cells, with a concomitant activation of p38 MAPK. In conclusion, our data provide evidence that in islets and β-cells, p38 MAPK and JNK phosphorylation work in concert with PP5 to regulate the cytotoxic effects exerted by glucocorticoids.
Keywords
SB203580PP5T2DMDEXASP600125eIF2αUPRRU486ASK-1Jnkc-Jun N-terminal kinaseMAPKp38 MAPKROSPancreatic isletApoptosisDexamethasoneType 2 diabetes mellituseukaryotic translation initiation factor 2αUnfolded protein responseprotein phosphatase 5mitogen-activated protein kinaseapoptosis signal-regulating kinase 1GlucocorticoidGlucocorticoidsReactive oxygen speciesglucocorticoid receptor
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Authors
Liselotte Fransson, Victoria Rosengren, Titu Kumar Saha, Nina Grankvist, Tohidul Islam, Richard E. Honkanen, Ã
ke Sjöholm, Henrik Ortsäter,