Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells
Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells
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DOI：
10.1172/jci37978
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发表时间：
2009-10-01
影响因子：
15.9
通讯作者：
Shankland, Stuart J.
中科院分区：
文献类型：
--
作者：
Brinkkoetter, Paul T.;Olivier, Paul;Shankland, Stuart J.
细胞周期蛋白I是一种非典型细胞周期蛋白，因为它在有丝分裂后细胞中最丰富。我们之前表明细胞周期蛋白I不调节增殖，而是控制足细胞的存活，足细胞是终末分化的上皮细胞，对于肾小球的结构和功能完整性至关重要。在这里，我们研究了细胞周期蛋白I保障细胞凋亡的机制，发现细胞周期蛋白I绑定和激活细胞周期蛋白依赖性激酶5（Cdk 5）在分离的小鼠足细胞和神经元。Cdk 5的活性降低，肾小球和脑细胞周期蛋白I缺陷小鼠裂解物，并在体外抑制Cdk 5增加细胞损伤的敏感性细胞凋亡。此外，促生存蛋白Bcl-2和Bcl-XL的水平降低足细胞和神经元cychn I缺陷小鼠，Bcl-2或Bcl-XL表达的恢复防止损伤诱导的细胞凋亡。此外，我们发现磷酸化MEK 1/2和ERK 1/2的水平在细胞周期蛋白I缺陷足细胞中降低，并且抑制MEK 1/2恢复Bcl 2和Bcl-XL蛋白水平。令人感兴趣的是，这种途径在实验性肾小球肾炎小鼠中也有缺陷。两者合计，这些数据表明，细胞周期蛋白I-Cdk 5复合物形成一个关键的抗凋亡因子在终末分化细胞的功能，通过MAPK信号转导调节水平的促生存蛋白Bcl-2和Bcl-XL。
Cyclin I is an atypical cyclin because it is most abundant in postmitotic cells. We previously showed that cyclin I does not regulate proliferation, but rather controls survival of podocytes, terminally differentiated epithelial cells that are essential for the structural and functional integrity of kidney glomeruli. Here, we investigated the mechanism by which cyclin I safeguards against apoptosis and found that cyclin I bound and activated cyclin-dependent kinase 5 (Cdk5) in isolated mouse podocytes and neurons. Cdk5 activity was reduced in glomeruli and brain lysates from cyclin I-deficient mice, and inhibition of Cdk5 increased in vitro the susceptibility to apoptosis in response to cellular damage. In addition, levels of the prosurvival proteins Bcl-2 and Bcl-XL were reduced in podocytes and neurons from cychn I-deficient mice, and restoration of Bcl-2 or Bcl-XL expression prevented injury-induced apoptosis. Furthermore, we found that levels of phosphorylated MEK1/2 and ERK1/2 were decreased in cyclin I-deficient podocytes and that inhibition of MEK1/2 restored Bcl2 and Bcl-XL protein levels. Of interest, this pathway was also defective in mice with experimental glomerulonephritis. Taken together, these data suggest that a cyclin I-Cdk5 complex forms a critical antiapoptotic factor in terminally differentiated cells that functions via MAPK signaling to modulate levels of the prosurvival proteins Bcl-2 and Bcl-XL.