Down-regulation of nuclear protein ICBP90 by p53/p21Cip1/WAF1-dependent DNA-damage checkpoint signals contributes to cell cycle arrest at G1/S transition
Down-regulation of nuclear protein ICBP90 by p53/p21Cip1/WAF1-dependent DNA-damage checkpoint signals contributes to cell cycle arrest at G1/S transition
复制标题
DOI：
10.1111/j.1356-9597.2004.00710.x
复制
发表时间：
2004-02-01
期刊：
影响因子：
2.1
通讯作者：
Saya, H
中科院分区：
文献类型：
--
作者：
Arima, Y;Hirota, T;Saya, H
检查点监测DNA损伤并调节细胞周期进程，确保基因组完整性并防止转化细胞的繁殖。DNA损伤激活p53依赖性检查点通路，诱导p21（Cip1/WAF1）的表达，通过抑制cdk活性和DNA复制，导致细胞周期阻滞在G1/S过渡。ICBP90被鉴定为一种结合topoii α基因启动子的核蛋白，并被推测参与DNA复制。在正常细胞中，ICBP90的表达受细胞周期调节，但在各种癌细胞系中，ICBP90的表达在整个细胞周期中都保持稳定的高表达。我们在这里证明了ICBP90的表达被p53/p21（Cip1/WAF1）依赖的DNA损伤检查点信号下调。ICBP90的减少似乎是由转录抑制和蛋白质降解共同引起的。腺病毒表达p21（Cip1/WAF1）直接导致p53(-/-) HCT116细胞中ICBP90降低，而DNA无损伤。此外，通过RNA干扰减少ICPB90可显著阻断HeLa细胞DNA损伤后G1/S转变。ICBP90的下调是细胞周期阻滞在G1/S过渡的重要机制，这是由p53/p21（Cip1/WAF1）依赖性dna损伤检查点的激活诱导的。ICBP90的失调可能会破坏检查点激活过程中G1/S转变的控制，并导致基因组不稳定。
Checkpoints, which monitor DNA damage and regulate cell cycle progression, ensure genomic integrity and prevent the propagation of transformed cells. DNA damage activates the p53-dependent checkpoint pathway that induces expression of p21(Cip1/WAF1), resulting in cell cycle arrest at G1/S transition by inhibition of cdk activity and DNA replication. ICBP90 was identified as a nuclear protein that binds to the TopoIIalpha gene promoter and is speculated to be involved in DNA replication. ICBP90 expression is cell cycle regulated in normal cells but stably high throughout cell cycle in various cancer cell lines. We here demonstrate that ICBP90 expression is down-regulated by the p53/p21(Cip1/WAF1)-dependent DNA damage checkpoint signals. The reduction of ICBP90 appeared to be caused by both transcriptional suppression and protein degradation. Adenoviral expression of p21(Cip1/WAF1) directly led to ICBP90 reduction in p53(-/-) HCT116 cells without DNA damage. Furthermore, ICPB90 depletion by RNA interference significantly blocked G1/S transition after DNA damage in HeLa cells. The down-regulation of ICBP90 is an important mechanism for cell cycle arrest at G1/S transition, which is induced by the activation of a p53/p21(Cip1/WAF1)-dependent DNA-damage checkpoint. Deregulation of ICBP90 may impair the control of G1/S transition during checkpoint activation and lead to genomic instability.