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A novel function for HSF1-induced mitotic exit failure and genomic instability through direct interaction between HSF1 and Cdc20.

Abstract
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.
AuthorsY J Lee, H J Lee, J S Lee, D Jeoung, C M Kang, S Bae, S J Lee, S H Kwon, D Kang, Y S Lee
JournalOncogene (Oncogene) Vol. 27 Issue 21 Pg. 2999-3009 (May 8 2008) ISSN: 1476-5594 [Electronic] England
PMID18059335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cdc20 Proteins
  • Cdc20 protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Hsf1 protein, mouse
  • Transcription Factors
Topics
  • Aneuploidy
  • Animals
  • Cdc20 Proteins
  • Cell Cycle Proteins (metabolism)
  • Cell Line, Tumor
  • Cells, Cultured
  • DNA-Binding Proteins (metabolism, physiology)
  • Genes, APC
  • Humans
  • Mice
  • Mitosis (physiology)
  • Transcription Factors (metabolism, physiology)

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