A role of p73 in mitotic exit
A role of p73 in mitotic exit
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DOI：
10.1074/jbc.m500635200
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发表时间：
2005-08-26
影响因子：
4.8
通讯作者：
Levrero, M
中科院分区：
文献类型：
--
作者：
Merlo, P;Fulco, M;Levrero, M
p53相关的p73蛋白调节发育过程、细胞生长和DNA损伤反应。p73的功能受翻译后修饰和蛋白质-蛋白质相互作用的调节。在G（2）/M转换时，p73在Thr-86处被p34 cdc 2/cyclin B复合物磷酸化;这与其从凝聚的染色体中被排除以及DNA结合和转录激活能力的丧失有关。在这里，我们发现，p73低磷酸化的物种重新出现在有丝分裂退出，伴随着p73重新定位到末期细胞核和恢复能力，激活转录。通过小干扰RNA（siRNA）功能性敲除p73基因表达改变了有丝分裂进程，产生了减数分裂末期细胞的增加、异常晚期有丝分裂图的积累以及随后的间期异常的出现。这种p73在M-到-G（1）转换的活性是由其反式激活功能介导的，因为转录显性负突变体p73 DD的表达诱导了相同的有丝分裂退出表型。我们还发现，细胞周期蛋白依赖性激酶抑制剂Kip 2/p57基因是p73在有丝分裂退出和重新进入G（1）过程中调控的特异性靶点。通过siRNA敲除p73基因表达和通过p73 DD突变体废除p73依赖性转录都废除了Kip 2/p57在M到G（1）转变时的增加。此外，类似的异常（e。G.有丝分裂晚期的延迟，伴随着异常的间-末期图的积累，以及随后的间期的异常）。这些结果确定了一种新的p73-Kip 2/p57途径，该途径协调有丝分裂退出和向G（1）的过渡。
The p53-related p73 proteins regulate developmental processes, cell growth, and DNA damage response. p73 function is regulated by post-translational modifications and protein-protein interactions. At the G(2)/M transition, p73 is phosphorylated at Thr-86 by the p34cdc2/cyclin B complex; this is associated with its exclusion from condensed chromosomes and loss of DNA binding and transcriptional activation ability. Here we showed that p73 hypo-phosphorylated species reappear during mitotic exit, concomitant with p73 relocalization to telophase nuclei and recovered ability to activate transcription. Functional knock-out of p73 gene expression by small interfering RNAs ( siRNAs) alters mitotic progression, yielding an increase of ana-telophase cells, the accumulation of aberrant late mitotic figures, and the appearance of abnormalities in the subsequent interphase. This p73 activity at the M-to-G(1) transition is mediated by its transactivating function because expression of the transcription dominant negative mutant p73DD induces the same mitotic exit phenotype. We also found that the cyclin-dependent kinase inhibitor Kip2/p57 gene is a specific target of p73 regulation during mitotic exit and re-entry into G(1). Both knock-out of p73 gene expression by siRNAs and abrogation of p73-dependent transcription by the p73DD mutant abrogate Kip2/p57 increase at the M-to-G(1) transition. Moreover, similar abnormalities ( e. g. delay in late mitotic stages with the accumulation of aberrant ana-telophase figures, and abnormalities in the following interphase) are observed in cultures in which the expression of Kip2/p57 is abrogated by siRNAs. These results identify a novel p73-Kip2/p57 pathway that coordinates mitotic exit and transition to G(1).