A novel function for HSF1-induced mitotic exit failure and genomic instability through direct interaction between
1Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Oncogene
|December 7, 2007
Summary
Heat-shock factor 1 (HSF1) interacts with Cdc20, inhibiting the anaphase-promoting complex (APC/C). This interaction disrupts cell division, leading to aneuploidy and genomic instability, particularly in cancer cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Heat-shock factor 1 (HSF1) is primarily known for regulating heat-shock proteins.
- Other pathways, including aneuploidy and cyclin B1 stability, have been implicated in HSF1 functions.
- The precise mechanisms by which HSF1 influences cell cycle regulation and genomic stability are not fully understood.
Purpose of the Study:
- To investigate the novel role of HSF1 in regulating cell division and genomic stability.
- To elucidate the interaction between HSF1 and components of the cell cycle machinery, specifically Cdc20 and the anaphase-promoting complex (APC/C).
- To determine the functional consequences of HSF1 overexpression in cellular processes related to mitosis and genome integrity.
Main Methods:
- Protein interaction studies using specific amino acid sequences of HSF1 (212-380) and Cdc20 (106-171).
- Analysis of anaphase-promoting complex (APC/C) activity, including Cdc27 phosphorylation and ubiquitination.
- Cellular assays to assess mitotic exit, protein degradation (cyclin B1, securin), multinucleation, micronuclei formation, and genomic alterations.
- Gene manipulation techniques including overexpression and depletion of HSF1.
Main Results:
- HSF1 directly interacts with Cdc20, inhibiting Cdc20-Cdc27 interaction and APC/C ubiquitination activity.
- Overexpression of HSF1 halts mitotic exit, prevents degradation of cyclin B1 and securin, leading to aneuploidy and multinucleated cells.
- HSF1 overexpression increases micronuclei and genomic alterations; HSF1 depletion reduces aneuploidy.
- A regulatory domain-deficient HSF1 mutant did not exhibit these effects.
Conclusions:
- HSF1 inhibits APC/C activity through direct interaction with Cdc20, revealing a novel function beyond heat shock response.
- HSF1 overexpression contributes to aneuploidy and genomic instability, mechanisms frequently observed in cancer cells.
- Targeting HSF1 may offer a therapeutic strategy for cancers characterized by genomic instability.
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