Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression
Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression
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DOI：
10.1038/sj.onc.1202104
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发表时间：
1998-10-01
期刊：
影响因子：
8
通讯作者：
Vousden, KH
中科院分区：
文献类型：
--
作者：
Bates, S;Ryan, KM;Vousden, KH
p21（Waf 1/Cip 1）是p53的一个主要转录靶点，是p53诱导G1期细胞阻滞的主要介质之一。我们发现，除了G1阻滞，p21（Waf 1/Cip 1）也可以有助于延迟G2和表达的p21（Waf 1/Cip 1）引起的细胞周期的配置文件基本上无法区分从p53表达后获得的。细胞停滞在G2期可能反映了在p21（Waf 1/Cip 1）存在下不能诱导细胞周期蛋白B1/cdc 2激酶活性，尽管p21（Waf 1/Cip 1）和细胞周期蛋白B1的无效结合表明抑制机制是间接的。从S期阻滞释放的细胞没有被p21（Waf 1/Cip 1）的存在阻碍其通过S期的能力，尽管有效抑制细胞周期蛋白E、A和B1依赖性激酶活性，这表明p21（Waf 1/Cip 1）在抑制体内复制DNA合成方面是无效的。有趣的是，大量的细胞从p21释放出来，（Waf 1/Cip 1）激活的G2阻滞进行核内复制，在进行有丝分裂之前通过另一个S期，这支持有丝分裂激酶在进入有丝分裂中的功能，也支持在阻止S期之后的DNA再复制中的功能，并提示p21的作用。与在这些细胞中诱导凋亡的p53不同，p21（Waf 1/Cip 1）的延长表达导致在这些p53缺失、pRB缺失的肿瘤细胞中表达衰老样表型。
p21(Waf1/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, p21(Waf1/Cip1) can also contribute to a delay in G2 and expression of p21(Waf1/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 p21(Waf1/Cip1), although the inefficient association of p21(Waf1/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 p21(Waf1/Cip1), despite efficient inhibition of cyclin E, A and B1 dependent kinase activity, suggesting that p2l(Waf1/Cip1) is inefficient at inhibiting replicative DNA synthesis in vivo. Interestingly, significant numbers of cells released from the p21(Waf1/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 p21(Waf1/Cip1) in coupling DNA synthesis and mitosis, Unlike p53, which induces apoptosis in these cells, extended expression of p21(Waf1/Cip1) resulted in the expression of a senescent-like phenotype in these p53 null, pRB null tumor cells.