Glucose-dependent insulinotropic polypeptide promotes β-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase
Glucose-dependent insulinotropic polypeptide promotes β-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase
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DOI：
10.1210/en.2002-0068
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发表时间：
2003-10-01
期刊：
影响因子：
4.8
通讯作者：
McIntosh, CHS
中科院分区：
文献类型：
--
作者：
Ehses, JA;Casilla, VR;McIntosh, CHS
胰岛素依赖性胰岛素样多肽(GIP)是哺乳动物餐后胰岛素分泌的主要调节因子。我们实验室最近的研究和其他研究表明，GIP是包括MAPK(ERK1/2)模块在内的蛋白激酶激活的有力刺激。基于这些研究，我们假设GIP可以调节细胞的命运，并试图研究GIP刺激细胞存活的潜在机制。GIP增强了葡萄糖诱导的β-(INS-1)细胞的生长，达到与GH和GLP-1相当的水平，同时在面对血清和葡萄糖剥夺或Wortmannin或链脲佐菌素治疗的情况下促进细胞存活。在没有GIP的情况下，50%的细胞在停用血清和葡萄糖48h后死亡，而有GIP存在时，91+/-10%的细胞仍然存活[n=3，P<；0.05；EC50为1.24+/-0.48 nM GIP(n=4)]。GIP对细胞存活的影响和对caspase-3的抑制作用可被forskolin模拟，但药理实验排除了MAPK 1/2、磷脂酰肌醇3-激酶、蛋白激酶A、EPAC和Rap 1的作用。GIP的存活作用被抑制剂SB202190阻断，表明p38 MAPK可能有作用。此外，根据RNA干扰研究，caspase-3的活性也受到p38MAPK的调节，而MEK1/2的调节作用较小。我们认为GIP能够通过抑制长期的p38MAPK磷酸化来逆转caspase-3的激活，以应对葡萄糖缺乏(+/-wortmannin)。有趣的是，这些发现与GIP对MKK3/6->；p38MAPK->；ATF-2的短期磷酸化形成对比。因此，这些数据表明，GIP能够通过cAMP信号动态控制p38MAPK的磷酸化来调节INS-1细胞的存活，并进一步支持GIP对MAPK信号的调控是其调控细胞命运的关键。
The incretin glucose-dependent insulinotropic polypeptide ( GIP) is a major regulator of postprandial insulin secretion in mammals. Recent studies in our laboratory, and others have suggested that GIP is a potent stimulus for protein kinase activation, including the MAPK (ERK1/2) module. Based on these studies, we hypothesized that GIP could regulate cell fate and sought to examine the underlying mechanisms involved in GIP stimulation of cell survival. GIP potentiated glucose-induced beta-(INS-1)-cell growth to levels comparable with GH and GLP-1 while promoting cell survival in the face of serum and glucose-deprivation or treatment with wortmannin or streptozotocin. In the absence of GIP, 50% of cells died after 48 h of serum and glucose withdrawal, whereas 91 +/- 10% of cells remained viable in the presence of GIP [n = 3, P < 0.05; EC50 of 1.24 +/- 0.48 nM GIP (n = 4)]. Effects of GIP on cell survival and inhibition of caspase-3 were mimicked by forskolin, but pharmacological experiments excluded roles for MAPK kinase (Mek)1/2, phosphatidylinositol 3-kinase, protein kinase A, Epac, and Rap 1. Survival effects of GIP were ablated by the inhibitor SB202190, indicating a role for p38 MAPK. Furthermore, caspase-3 activity was also regulated by p38 MAPK, with a lesser role for Mek1/2, based on RNA interference studies. We propose that GIP is able to reverse caspase-3 activation via inhibition of long-term p38 MAPK phosphorylation in response to glucose deprivation (+/- wortmannin). Intriguingly, these findings contrasted with short-term phosphorylation of MKK3/6 -> p38 MAPK -> ATF-2 by GIP. Thus, these data suggest that GIP is able to regulate INS-1 cell survival by dynamic control of p38 MAPK phosphorylation via cAMP signaling and lend further support to the notion that GIP regulation of MAPK signaling is critical for its regulation of cell fate.