Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27KIP1
Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27KIP1
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DOI：
10.1074/jbc.272.52.32966
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发表时间：
1997-12-26
影响因子：
4.8
通讯作者：
Baldassare, JJ
中科院分区：
文献类型：
--
作者：
Weber, JD;Hu, WM;Baldassare, JJ
血小板衍生生长因子（PDGF）诱导的Ras活化是中国仓鼠胚胎成纤维细胞（IIC 9细胞）G（1）进展所必需的。Ras刺激细胞外信号相关激酶（ERK）活化和响应于PDGF刺激的RhoA活化。抑制这些Ras刺激的途径中的任一个导致生长停滞。我们以前已经表明，刺激ERK激活是必不可少的诱导和持续G（1）的细胞周期蛋白D1的表达。在这项研究中，我们研究了Ras诱导的RhoA活性在G（1）进展中的作用，未受刺激的IIC9细胞表达高水平的G（1）细胞周期蛋白依赖性激酶抑制剂p27（KIP 1）。用PDGF刺激导致p27（KIP 1）蛋白表达的显著降低。这种下降归因于p27（KIP 1）蛋白降解的增加。显性负性形式的Ras或RhoA的过表达完全阻断PDGF诱导的p27（KIP 1）降解，但仅显性负性Ras抑制cyclin D1蛋白表达。C3转移酶也抑制PDGF诱导的p27（KIP 1）降解，从而进一步暗示RhoA参与p27（KIP 1）的调节。显性负性ERK的过表达导致PDGF诱导的cyclin D1表达的抑制，但对PDGF诱导的p27（KIP 1）降解没有影响。这些数据表明，Ras协调细胞周期蛋白D1和p27（KIP1）的表达的独立调节分别激活ERK和RhoA，这些途径收敛，以确定激活状态的复合物的细胞周期蛋白D1和细胞周期蛋白依赖性激酶在有丝分裂原。
Platelet-derived growth factor (PDGF)-induced Ras activation is required for G(1) progression in Chinese hamster embryo fibroblasts (IIC9 cells). Ras stimulates both extracellular signal-related kinase (ERK) activation and RhoA activation in response to PDGF stimulation. Inhibition of either of these Ras-stimulated pathways results in growth arrest. We have shown previously that has-stimulated ERK activation is essential for the induction and continued G(1) expression of cyclin D1. In this study we examine the role of Ras-induced RhoA activity in G(1) progression, Unstimulated IIC9 cells expressed high levels of the G(1) cyclin-dependent kinase inhibitor p27(KIP1). Stimulation with PDGF resulted in a dramatic decrease in p27(KIP1) protein expression. This decrease was attributed to increased p27(KIP1) protein degradation, Overexpression of dominant-negative forms of Ras or RhoA completely blocked PDGF-induced p27(KIP1) degradation, but only dominant-negative Ras inhibited cyclin D1 protein expression. C3 transferase also inhibited PDGF-induced p27(KIP1) degradation, thus further implicating RhoA in p27(KIP1) regulation, Overexpression of dominant-negative ERK resulted in inhibition of PDGF-induced cyclin D1 expression but had no effect on PDGF-induced p27(KIP1) degradation. These data suggest that Ras coordinates the independent regulation of cyclin D1 and p27(KIP1) expression by the respective activation of ERK and RhoA and that these pathways converge to determine the activation state of complexes of cyclin D1 and cyclin-dependent kinase in response to mitogen.