Activation of double-stranded RNA-dependent protein kinase inhibits proliferation of pancreatic β-cells
Activation of double-stranded RNA-dependent protein kinase inhibits proliferation of pancreatic β-cells
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DOI：
10.1016/j.bbrc.2013.12.051
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发表时间：
2014-01-17
影响因子：
3.1
通讯作者：
Guo, Jun
中科院分区：
文献类型：
--
作者：
Chen, Shan-Shan;Jiang, Teng;Guo, Jun
双链RNA依赖性蛋白激酶（PKR）参与了2型糖尿病（T2 DM）外周组织胰岛素抵抗的发生。同时，PKR也是细胞增殖的重要调节因子。迄今为止，没有研究集中在PKR对胰腺β细胞增殖的影响。本研究采用胰岛素瘤细胞系和小鼠胰岛β细胞，探讨：（1）糖脂毒性和促炎细胞因子对PKR活化的影响;（2）PKR对胰岛β细胞增殖的影响及其机制;（3）PKR对IGF-I促增殖作用的影响及其途径。我们的研究结果首次证明PKR可被糖脂毒性和促炎细胞因子激活，激活的PKR可通过将细胞周期阻滞在G1期而显著抑制细胞增殖。PKR的抗增殖作用与细胞周期蛋白D1和D2的减少以及p27和p53的增加有关，蛋白酶体依赖性降解参与了细胞周期蛋白D1和D2的减少。PKR的激活可通过激活JNK和破坏IRS 1/PI 3 K/Akt信号通路而阻断IGF-I的促增殖作用。这些结果表明PKR对胰腺β细胞的抗增殖作用可能有助于T2 DM的发病机制。(C)2013 Elsevier Inc. All rights reserved.
Double-stranded RNA-dependent protein kinase (PKR) is revealed to participate in the development of insulin resistance in peripheral tissues in type 2 diabetes (T2DM). Meanwhile, PKR is also characterized as a critical regulator of cell proliferation. To date, no study has focused on the impact of PKR on the proliferation of pancreatic beta-cells. Here, we adopted insulinoma cell lines and mice islet beta-cells to investigate: (1) the effects of glucolipotoxicity and pro-inflammatory cytokines on PKR activation; (2) the effects of PKR on proliferation of pancreatic beta-cells and its underlying mechanisms; (3) the actions of PKR on pro-proliferative effects of IGF-I and its underlying pathway. Our results provided the first evidence that PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in pancreatic beta-cells, and activated PKR significantly inhibited cell proliferation by arresting cell cycle at G1 phase. Reductions in cyclin D1 and D2 as well as increases in p27 and p53 were associated with the anti-proliferative effects of PKR, and proteasome-dependent degradation took part in the reduction of cyclin D1 and D2. Besides, PKR activation abrogated the pro-proliferative effects of IGF-I by activating JNK and disrupting IRS1/PI3K/Akt signaling pathway. These findings indicate that the anti-proliferative actions of PKR on pancreatic beta-cells may contribute to the pathogenesis of T2DM. (C) 2013 Elsevier Inc. All rights reserved.