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首页> 外文期刊>Molecular and Cellular Biology >Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases.
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Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases.

机译：细胞周期蛋白依赖性激酶的过表达抑制p53介导的生长停滞。

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摘要

Rat fibroblasts transformed by a temperature-sensitive mutant of murine p53 undergo a reversible growth arrest in G1 at 32.5 degrees C, the temperature at which p53 adopts a wild-type conformation. The arrested cells contain inactive cyclin-dependent kinase 2 (cdk2) despite the presence of high levels of cyclin E and cdk-activating kinase activity. This is due in part to p53-dependent expression of the p2l cdk inhibitor. Upon shift to 39 degrees C, wild-type p53 is lost and cdk2 activation and pRb phosphorylation occur concomitantly with loss of p2l. This p53-mediated growth arrest can be abrogated by overexpression of cdk4 and cdk6 but not cdk2 or cyclins, leading to continuous proliferation of transfected cells in the presence of wild-type p53 and p2l. Kinase-inactive counterparts of cdk4 and cdk6 also rescue these cells from growth arrest, implicating a noncatalytic role for cdk4 and cdk6 in this resistance to p53-mediated growth arrest. Aberrant expression of these cell cycle kinases may thus result in an oncogenic interference with inhibitors of cell cycle progression.
机译：由鼠p53的温度敏感突变体转化的大鼠成纤维细胞在32.5摄氏度（p53呈野生型构型的温度）下在G1中发生可逆的生长停滞。尽管存在高水平的细胞周期蛋白E和cdk激活激酶活性，但被捕细胞仍含有失活的细胞周期蛋白依赖性激酶2（cdk2）。这部分归因于p21 cdk抑制剂的p53依赖性表达。转变为39摄氏度时，野生型p53丢失，cdk2激活和pRb磷酸化与p21丢失同时发生。 p53介导的生长停滞可以通过cdk4和cdk6的过表达而被废除，而不能通过cdk2或细胞周期蛋白的过表达被废除，从而导致在野生型p53和p21的存在下转染细胞的持续增殖。 cdk4和cdk6的激酶无活性对应物也将这些细胞从生长停滞中拯救出来，暗示了cdk4和cdk6在对p53介导的生长停滞的抗性中没有催化作用。这些细胞周期激酶的异常表达可能因此导致对细胞周期进程抑制剂的致癌干扰。

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