Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression
Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression
复制标题
DOI：
10.1074/jbc.m305246200
复制
发表时间：
2003-09-12
影响因子：
4.8
通讯作者：
Gupta, ML
中科院分区：
文献类型：
--
作者：
Chou, MM;Masuda-Robens, JM;Gupta, ML
Rho 家族 GTPase Cdc42 因其在细胞增殖和转化中的作用而得到认可。然而，它促进细胞周期进展的机制仍不清楚。使用诱导型表达系统，我们表明，组成型活性 Cdc42 (Cdc42V12) 本身足以诱导 NIH3T3 细胞中不依赖于贴壁的生长，但不依赖于有丝分裂原的生长。然而，Cdc42V12 显着加速细胞周期蛋白 E-Cdk2 响应有丝分裂原的激活。这些效应具有高度特异性，因为细胞周期蛋白 D-Cdk4 激活的动力学未改变。 Cdc42V12 通过选择性诱导细胞周期蛋白 E 表达来促进 Cdk2 激活，而不影响其他调节蛋白（例如 p27 Cdk 抑制剂或 Cdc25A）。此外，在没有外源丝裂原或粘附的情况下，Cdc42V12能够激活由细胞周期蛋白E启动子驱动的报告基因。细胞周期蛋白 E 诱导对雷帕霉素敏感，但对丝裂原激活蛋白激酶抑制剂不敏感，表明 p70 S6 激酶 (p70S6k) 是相关介质。与这一概念一致，p70S6k 的野生型和组成型活性等位基因足以激活细胞周期蛋白 E 启动子。总之，这些研究为 Cdc42 促进 G(1) 进展的机制提供了新的见解。
The Rho family GTPase Cdc42 is recognized for its role in cellular proliferation and transformation. However, the mechanism by which it promotes cell cycle progression has remained undefined. Using an inducible expression system, we show that constitutively active Cdc42 (Cdc42V12) is sufficient by itself to induce anchorage-independent but not mitogen-independent growth in NIH3T3 cells. However, Cdc42V12 markedly accelerates activation of cyclin E-Cdk2 in response to mitogen. These effects were highly specific, as the kinetics of cyclin D-Cdk4 activation was unaltered. Cdc42V12 promotes Cdk2 activation by selectively inducing cyclin E expression without affecting other regulatory proteins such as the p27 Cdk inhibitor or Cdc25A. Furthermore, Cdc42V12 was able to activate a reporter gene driven by the cyclin E promoter in the absence of exogenous mitogen or adhesion. Cyclin E induction was sensitive to rapamycin but not inhibitors of mitogen-activated protein kinases, implicating p70 S6 kinase (p70S6k) as the relevant mediator. Consistent with this notion, wild type and constitutively active alleles of p70S6k were sufficient to activate the cyclin E promoter. In sum, these studies provide novel insights into the mechanism by which Cdc42 promotes G(1) progression.