Wang Y, Prives C
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Nature. 1995 Jul 6;376(6535):88-91. doi: 10.1038/376088a0.
Central to the role of p53 in cell regulation are its sequence-specific interactions with genes that control the cell cycle and apoptosis. p53 response elements contain two or more copies of a somewhat promiscuous consensus sequence: 5'-XXXC(A,T)(T,A)GYY-3' (where X is a purine and Y is a pyrimidine) (ref. 3). The sequence-specific DNA-binding region of p53 resides in its central conserved region. Although this region itself is not known to be phosphorylated, the amino and carboxy termini of human p53 contain sites for phosphorylation by several protein kinases. We have examined the role of cyclin-dependent kinase (Cdk) shown previously to phosphorylate human p53 at serine 315 (ref. 5). We report here that p53 is efficiently and selectively phosphorylated by S and G2/M Cdks. Such phosphorylation markedly stimulates sequence-specific DNA binding by p53 and also causes a distinctive conformational change in p53 as revealed by partial protease analysis. Strikingly, Cdk phosphorylation also confers binding-site preference on p53. These data suggest a potential regulatory mechanism of p53 activity.
p53在细胞调控中的核心作用在于它与控制细胞周期和凋亡的基因进行序列特异性相互作用。p53反应元件包含两个或更多拷贝的一个有点混杂的共有序列：5'-XXXC(A,T)(T,A)GYY-3'（其中X是嘌呤，Y是嘧啶）（参考文献3）。p53的序列特异性DNA结合区域位于其中心保守区域。尽管该区域本身未知是否被磷酸化，但人p53的氨基和羧基末端含有多个蛋白激酶磷酸化的位点。我们研究了先前显示可在丝氨酸315处磷酸化人p53的细胞周期蛋白依赖性激酶（Cdk）的作用（参考文献5）。我们在此报告，p53被S期和G2/M期的Cdk高效且选择性地磷酸化。这种磷酸化显著刺激p53的序列特异性DNA结合，并且如部分蛋白酶分析所揭示的，还会导致p53发生独特的构象变化。引人注目的是，Cdk磷酸化还赋予p53结合位点偏好性。这些数据提示了一种p53活性的潜在调控机制。
