mTOR links incretin signaling to HIF induction in pancreatic beta cells
mTOR links incretin signaling to HIF induction in pancreatic beta cells
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DOI：
10.1073/pnas.1114228108
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发表时间：
2011-10-11
影响因子：
11.1
通讯作者：
Montminy, Marc
中科院分区：
文献类型：
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作者：
Van de Velde, Sam;Hogan, Meghan F.;Montminy, Marc
在进食条件下，肠促胰岛素激素GLP-1通过触发β细胞中的cAMP途径促进胰岛活力。PKA活性的增加刺激CREB的磷酸化，其进而通过上调IRS 2表达来增强β细胞存活。尽管持续的GLP-1作用对于其对胰岛功能的有益作用似乎很重要，但CREB激活的瞬时性质表明在该过程中涉及额外的核因子。在CREB调节基因的急性诱导之后，cAMP触发了通过HIF转录因子进行的基因表达的第二延迟阶段。cAMP的增加通过激活mTOR途径促进HIF 1 α在β细胞中的积累。由于暴露于雷帕霉素破坏了GLP-1对β细胞活力的作用，这些结果表明与肿瘤生长相关的途径也介导了肠促胰岛素激素对胰岛功能的有益作用。
Under feeding conditions, the incretin hormone GLP-1 promotes pancreatic islet viability by triggering the cAMP pathway in beta cells. Increases in PKA activity stimulate the phosphorylation of CREB, which in turn enhances beta cell survival by upregulating IRS2 expression. Although sustained GLP-1 action appears important for its salutary effects on islet function, the transient nature of CREB activation has pointed to the involvement of additional nuclear factors in this process. Following the acute induction of CREB-regulated genes, cAMP triggers a second delayed phase of gene expression that proceeds via the HIF transcription factor. Increases in cAMP promote the accumulation of HIF1 alpha in beta cells by activating the mTOR pathway. As exposure to rapamycin disrupts GLP-1 effects on beta cell viability, these results demonstrate how a pathway associated with tumor growth also mediates salutary effects of an incretin hormone on pancreatic islet function.