A novel function for HSF1-induced mitotic exit failure and genomic instability through direct interaction between HSF1 and Cdc20.
Although heat-shock factor (HSF) 1 is a known transcriptional factor of heat-shock proteins, other pathways like 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 findings 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.
Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Y J
YJ
Lee
H J
HJ
Lee
J S
JS
Lee
D
D
Jeoung
C M
CM
Kang
S
S
Bae
S J
SJ
Lee
S H
SH
Kwon
D
D
Kang
Y S
YS
Lee
D000782:Aneuploidy; D000818:Animals; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D017491:Genes, APC; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D014157:Transcription Factors