Bates S, Ryan K M, Phillips A C, Vousden K H
ABL Basic Research Program, NCI-FCRDC, Frederick, Maryland 21702-1201, USA.
Oncogene. 1998 Oct 1;17(13):1691-703. doi: 10.1038/sj.onc.1202104.
p21Waf1/Cip1 is a major transcriptional target of p53 and has been shown to be one of the principal mediators of the p53 induced G1 cell cycle arrest. We show that in addition to the G1 block, p21Waf1/Cip1 can also contribute to a delay in G2 and expression of p21Waf1/Cip1 gives rise to cell cycle profiles essentially indistinguishable from those obtained following p53 expression. Arrest of cells in G2 likely reflects an inability to induce cyclin B1/cdc2 kinase activity in the presence of p21Waf1/Cip1, although the inefficient association of p21Waf1/Cip1 and cyclin B1 suggests that the mechanism of inhibition is indirect. Cells released from an S-phase block were not retarded in their ability to progress through S-phase by the presence of p21Waf1/Cip1, despite efficient inhibition of cyclin E, A and B1 dependent kinase activity, suggesting that p21Waf1/Cip1 is inefficient at inhibiting replicative DNA synthesis in vivo. Interestingly, significant numbers of cells released from the p21Waf1/Cip1 activated G2 block undergo endoreduplication, passing through another S-phase before undergoing mitosis. This supports a function of the mitotic kinases in both entry into mitosis, and also in preventing re-replication of DNA following S-phase and suggests a role for p21Waf1/Cip1 in coupling DNA synthesis and mitosis. Unlike p53, which induces apoptosis in these cells, extended expression of p21Waf1/Cip1 resulted in the expression of a senescent-like phenotype in these p53 null, pRB null tumor cells.
p21Waf1/Cip1是p53的一个主要转录靶点，并且已被证明是p53诱导的G1期细胞周期阻滞的主要介导因子之一。我们发现，除了G1期阻滞外，p21Waf1/Cip1还会导致G2期延迟，并且p21Waf1/Cip1的表达所产生的细胞周期谱与p53表达后获得的细胞周期谱基本无法区分。细胞在G2期阻滞可能反映了在存在p21Waf1/Cip1的情况下无法诱导细胞周期蛋白B1/细胞周期蛋白依赖性激酶2（cdc2）激酶活性，尽管p21Waf1/Cip1与细胞周期蛋白B1的低效结合表明抑制机制是间接的。尽管p21Waf1/Cip1能有效抑制细胞周期蛋白E、A和B1依赖性激酶活性，但从S期阻滞释放的细胞在通过S期的能力上并未因p21Waf1/Cip1的存在而受到阻碍，这表明p21Waf1/Cip1在体内抑制复制性DNA合成的效率较低。有趣的是，从p21Waf1/Cip1激活的G2期阻滞中释放的大量细胞会进行核内复制，在进入有丝分裂之前先经过另一个S期。这支持了有丝分裂激酶在进入有丝分裂以及防止S期后DNA重新复制中的作用，并暗示了p21Waf1/Cip1在连接DNA合成和有丝分裂中的作用。与在这些细胞中诱导凋亡的p53不同，p21Waf1/Cip1的延长表达在这些p53缺失、视网膜母细胞瘤蛋白（pRB）缺失的肿瘤细胞中导致了类似衰老的表型表达。
