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
Year2012
Month4
Day1
Volume Number31
Issue Number15
PublisherNature Publishing Group: Open Access Hybrid Model Option B
Pages1975 - 1987
ISSN0950-9232
eISSN1476-5594
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 2020-12-09 at 00:43