Induction of p27(Kip1) degradation and anchorage independence by Ras through the MAP kinase signaling pathway
Induction of p27(Kip1) degradation and anchorage independence by Ras through the MAP kinase signaling pathway
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DOI：
10.1038/sj.onc.1201228
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发表时间：
1997-08-07
期刊：
影响因子：
8
通讯作者：
Uehara, Y
中科院分区：
文献类型：
--
作者：
Kawada, M;Yamagoe, S;Uehara, Y
虽然大多数未转化的细胞生长需要底物附着(锚定依赖性)，但致癌的转化细胞缺乏这一要求(锚定独立性)，并且通常是致瘤的。然而，锚定依赖丧失的机制尚不完全清楚。当大鼠正常成纤维细胞悬浮培养时，细胞周期停滞于G1期，细胞周期蛋白依赖的蛋白抑制因子p27(Kip1)及其mRNA积聚。癌基因RAS的条件性表达诱导了细胞周期的G1-S转变，并在不改变其基因水平的情况下显著缩短了p27(Kip1)蛋白的半衰期。环状AMP升高剂和MEK抑制剂抑制丝裂原活化蛋白(MAP)激酶的激活，可阻止RAS诱导的p27(KIP1)的致癌降解。这些结果表明，底物附着的丧失通过上调p27(Kip1)的mRNA诱导细胞周期停滞，而致癌的RAS通过激活MAP激酶信号通路加速p27(Kip1)的降解，从而使细胞获得锚定独立性。此外，我们还发现p27(Kip1)在体外被MAP激酶磷酸化，并且磷酸化的p27(Kip1)不能与CDK2结合并抑制CDK2。
While most untransformed cells require substrate attachment for growth (anchorage dependence), the oncogenic transformed cells lack this requirement (anchorage independence) and are often tumorigenic. However, the mechanism of loss of anchorage dependence is not fully understood. When rat normal fibroblasts were cultured in suspension without substrate attachment, the cell cycle arrested in G1 phase and the cyclin-dependent kinase inhibitor p27(Kip1) protein and its mRNA accumulated. Conditional expression of oncogenic Ras induced the G1-S transition of the cell cycle and significantly shortened the half-life of p27(Kip1) protein without altering its mRNA level. Inhibition of the activation of mitogen-activated protein (MAP) kinase by cyclic AMP-elevating agents and a MEK inhibitor prevented the oncogenic Ras-induced degradation of p27(KiP1). These results suggest that the loss of substrate attachment induces the cell cycle arrest through the upregulation of p27(Kip1) mRNA, but the oncogenic Ras confers anchorage independence by accelerating p27(Kip1) degradation through the activation of the MAP kinase signaling pathway. Furthermore, we have found that p27(Kip1) is phosphorylated by MAP kinase in vitro and the phosphorylated p27(Kip1) cannot bind to and inhibit cdk2.