Chen J, Jackson P K, Kirschner M W, Dutta A
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Nature. 1995 Mar 23;374(6520):386-8. doi: 10.1038/374386a0.
The protein p21 (WAF1, CIP1 or sdi1), induced by the tumour-suppressor protein p53, interacts with and inhibits two different targets essential for cell-cycle progression. One of these is the cyclin-Cdk family of kinases and the other is the essential DNA replication factor, proliferating-cell nuclear antigen (PCNA). We report here that separate domains of p21 are responsible for interacting with and inhibiting the two targets. An amino-terminal domain inhibits cyclin-Cdk kinases and a carboxy-terminal domain inhibits PCNA. Using these separated domains, we have determined that p21 inhibits different biological systems through different targets. The PCNA-binding domain is sufficient for inhibition of DNA replication based on simian virus 40, whereas the Cdk2-binding domain is sufficient for inhibition of DNA replication based on Xenopus egg extract and for growth suppression in transformed human cells.
由肿瘤抑制蛋白p53诱导产生的蛋白质p21（WAF1、CIP1或sdi1），可与细胞周期进程所必需的两个不同靶点相互作用并对其产生抑制作用。其中一个靶点是细胞周期蛋白依赖性激酶（cyclin-Cdk）家族，另一个是重要的DNA复制因子，即增殖细胞核抗原（PCNA）。我们在此报告，p21的不同结构域分别负责与这两个靶点相互作用并对其进行抑制。氨基末端结构域抑制细胞周期蛋白依赖性激酶，羧基末端结构域抑制PCNA。利用这些分离的结构域，我们确定p21通过不同的靶点抑制不同的生物学系统。基于猿猴病毒40，PCNA结合结构域足以抑制DNA复制，而基于非洲爪蟾卵提取物，Cdk2结合结构域足以抑制DNA复制，并足以抑制转化的人类细胞的生长。
