p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells
p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells
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DOI：
10.1038/sj.onc.1201543
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发表时间：
1998-01-22
期刊：
影响因子：
8
通讯作者：
Ducommun, B
中科院分区：
文献类型：
--
作者：
Cayrol, C;Knibiehler, M;Ducommun, B
p21区别于其他细胞周期蛋白依赖性激酶（CDK）抑制剂的独特特征是其与增殖细胞核抗原（PCNA）结合的能力，PCNA是DNA聚合酶δ和β的辅助因子。虽然现在已经确定p21抑制细胞周期蛋白/CDK复合物可以导致G1期细胞周期停滞，但p21/PCNA相互作用对细胞周期进程的影响尚未确定。在这里，我们显示，使用四环素调节系统，野生型p21在p53缺陷的DLD 1人结肠癌细胞中的表达抑制DNA合成，并导致G1和G2细胞周期停滞。在表达与CDK相互作用受损的p21（CDK-）突变体的细胞中观察到类似的效果，但在表达与PCNA相互作用缺陷的突变体p21（PCNA-）的细胞中没有观察到类似的效果。用p21衍生的PCNA结合肽处理的细胞的分析提供了额外的证据，即p21和p21（CDK-）的生长抑制作用是由于它们结合PCNA的能力。我们的研究结果表明，p21可能通过两种独立的机制抑制细胞周期进程，抑制细胞周期蛋白/CDK复合物，抑制PCNA功能，导致G1和G2期阻滞。
A unique feature of p21 that distinguishes it from the other cyclin-dependent kinase (CDK) inhibitors is its ability to associate with the proliferating cell nuclear antigen (PCNA), an auxiliary factor for DNA polymerases delta and epsilon. While it is now well established that inhibition of cyclin/CDK complexes by p21 can result in G1 cell cycle arrest, the consequences of p21/PCNA interaction on cell cycle progression have not yet been determined. Here, we show, using a tetracycline-regulated system, that expression of wild-type p21 in p53-deficient DLD1 human colon cancer cells inhibits DNA synthesis and causes G1 and G2 cell cycle arrest. Similar effects are observed in cells expressing p21(CDK-) mutant impaired in the interaction with CDKs, but not in cells expressing p21(PCNA-), a mutant deficient for the interaction with PCNA. Analysis of cells treated with a p21-derived PCNA-binding peptide provides additional evidence that the growth inhibitory effects of p21 and p21(CDK-) result from their ability to bind to PCNA. Our results suggest that p21 might inhibit cell cycle progression by two independent mechanisms, inhibition of cyclin/CDK complexes, and inhibition of PCNA function resulting in both G1 and G2 arrest.