A novel function for HSF1-induced mitotic exit failure and genomic instability through direct interaction between HSF1 and Cdc20
A novel function for HSF1-induced mitotic exit failure and genomic instability through direct interaction between HSF1 and Cdc20
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DOI：
10.1038/sj.onc.1210966
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发表时间：
2008-05-08
期刊：
影响因子：
8
通讯作者：
Lee, Y. S.
中科院分区：
文献类型：
--
作者：
Lee, Y. J.;Lee, H. J.;Lee, Y. S.
虽然热休克因子(HSF)1是已知的热休克蛋白的转录因子，但也有人提出了其他途径，如产生非整倍体和增加细胞周期蛋白B1的蛋白质稳定性。在本研究中，HSF1的调节域(氨基酸序列212-380)被发现与CDC20的氨基酸序列106-171直接相互作用。HSF1和Cdc20的结合抑制了Cdc27和Cdc20之间的相互作用，抑制了Cdc27的磷酸化和后期促进复合体(APC)的泛素化活性。HSF1的过表达抑制了有丝分裂的退出和细胞周期蛋白B1和Securin的降解，从而导致非整倍体和多核细胞的产生，而调控结构域缺失的HSF1则没有。此外，过表达HSF1的细胞表现出更高的微核水平和基因组改变。从高表达HSF1的细胞中去除HSF1可以减少诺康唑介导的细胞非整倍体。这些发现提示HSF1在癌细胞中频繁过表达的一种新功能，通过与CDC20相互作用抑制APC/C活性，并导致非整倍体发育和基因组不稳定。
Although heat-shock factor (HSF) 1 is a known transcriptional factor of heat-shock proteins, other pathwayslike production of aneuploidy and increased protein stability of cyclin B1 have been proposed. In the present study, the regulatory domain of HSF1 (amino-acid sequence 212-380) was found to interact directly with the amino-acid sequence 106-171 of Cdc20. The association between HSF1 and Cdc20 inhibited the interaction between Cdc27 and Cdc20, the phosphorylation of Cdc27 and the ubiquitination activity of anaphase-promoting complex (APC). The overexpression of HSF1 inhibited mitotic exit and the degradations of cyclin B1 and securin, which resulted in production of aneuploidy and multinucleated cells, but regulatory domain-deficient HSF1 did not. Moreover, HSF1-overexpressing cells showed elevated levels of micronuclei and genomic alteration. The depletion of HSF1 from cells highly expressing HSF1 reduced nocodazole-mediated aneuploidy in cells. These findingss suggest a novel function of HSF1 frequently overexpressed in cancer cells, to inhibit APC/C activity by interacting with Cdc20, and to result in aneuploidy development and genomic instability.