CHK2-BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly
Abstract
Inactivation of the tumor-suppressor gene breast cancer susceptibility type 1 (BRCA1) triggers abnormal microtubule assembly during mitosis, causing chromosome missegregation and aneuploidy. Unraveling how BRCA1 is regulated during mitosis and how it contributes to microtubule assembly is pivotal to understand its tumor-suppressor function. We showed that BRCA1 is positively regulated during mitosis by the tumor-suppressor kinase checkpoint kinase 2 (Chk2). This regulation is required for the recruitment of a protein phosphatase, which restrains oncogenic Aurora-A kinase activity bound to BRCA1. Unleashed Aurora-A, in turn, can negatively regulate the mitotic function of BRCA1. Thus we define a network in which the Chk2-BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A to ensure proper function of BRCA1 in mitosis essential for normal regulation of microtubule dynamics and chromosome segregation.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- February 2016
- DOI:
- 10.1073/pnas.1525129113
- Bibcode:
- 2016PNAS..113.1817E