Latham K M, Eastman S W, Wong A, Hinds P W
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Mol Cell Biol. 1996 Aug;16(8):4445-55. doi: 10.1128/MCB.16.8.4445.
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.
被鼠源p53温度敏感突变体转化的大鼠成纤维细胞在32.5摄氏度时会在G1期经历可逆的生长停滞，此温度下p53呈现野生型构象。尽管存在高水平的细胞周期蛋白E和周期蛋白依赖性激酶激活激酶活性，但停滞的细胞中含有无活性的细胞周期蛋白依赖性激酶2（cdk2）。这部分归因于p2l细胞周期蛋白依赖性激酶抑制剂的p53依赖性表达。转移至39摄氏度后，野生型p53丢失，cdk2激活和pRb磷酸化与p2l的丢失同时发生。这种p53介导的生长停滞可通过cdk4和cdk6的过表达而被消除，但cdk2或细胞周期蛋白的过表达则不能，这导致转染细胞在存在野生型p53和p2l的情况下持续增殖。cdk4和cdk6的激酶失活对应物也能使这些细胞免于生长停滞，这表明cdk4和cdk6在这种对p53介导的生长停滞的抗性中起非催化作用。因此，这些细胞周期激酶的异常表达可能导致对细胞周期进程抑制剂的致癌性干扰。
