Regulation of APC/C-Cdc20 activity by RASSF1A-APC/C-Cdc20 circuitry
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AbstractRASSF1A is a key tumor-suppressor gene that is often inactivated in a wide variety of solid tumors. Studies have illustrated that RASSF1A plays vital roles in the regulation of cell-cycle progression and functions as a guardian of mitosis. Nevertheless, the precise mechanism of RASSF1A-dependent regulation of mitosis remains largely unclear. APC/C-Cdc20 is the master switch and regulator of mitosis. The activity of APC/C-Cdc20 is tightly controlled by phosphorylation and specific inhibitors to ensure the sequential ubiquitination of downstream targets. Here, we report on the novel finding of a regulated circuitry that controls the timely expression and hence activity of APC/C-Cdc20 during mitosis. Our study showed that RASSF1A and APC/C-Cdc20 form a molecular relay that regulates the APC/C-Cdc20 activity at early mitosis. We found that RASSF1A inhibits APC/C-Cdc20 function through its D-box motifs. Paradoxically, RASSF1A was also demonstrated to be ubiquitinated by APC/C-Cdc20 in vitro and degraded at prometaphase despite of active spindle checkpoint presence. The first two unique D-boxes at the N-terminal of RASSF1A served as specific degron recognized by APC/C-Cdc20. Importantly, we found that Aurora A and Aurora B directly phosphorylate RASSF1A, a critical step by which RASSF1A switches from being an inhibitor to a substrate of APC/C-Cdc20 during the course of mitotic progression. As a result of RASSF1A degradation, APC/C-Cdc20 can then partially activate the ubiquitination of Cyclin A in the presence of spindle checkpoint. This circuitry is essential for the timely degradation of Cyclin A. To conclude, our results propose a new model for RASSF1A-APC/C-Cdc20 interaction in ensuring the sequential progression of mitosis. Oncogene (2012) 31, 1975-1987; doi:10.1038/onc.2011.372; published online 29 August 2011
All Author(s) ListChow C, Wong N, Pagano M, Lun SWM, Nakayama KI, Nakayama K, Lo KW
Journal nameOncogene
Volume Number31
Issue Number15
PublisherNature Publishing Group: Open Access Hybrid Model Option B
Pages1975 - 1987
LanguagesEnglish-United Kingdom
KeywordsAPC/C-Cdc20; Aurora; mitotic checkpoint; RASSF1A; ubiquitination
Web of Science Subject CategoriesBiochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY; Cell Biology; CELL BIOLOGY; Genetics & Heredity; GENETICS & HEREDITY; Oncology; ONCOLOGY

Last updated on 2021-15-09 at 00:08