Regulation of APC/CCdc20 activity by RASSF1A–APC/CCdc20 circuitry

Citations Over TimeTop 17% of 2011 papers

Abstract

RASSF1A 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.

Related Papers

• → Destruction Box–Dependent Degradation of Aurora B Is Mediated by the Anaphase-Promoting Complex/Cyclosome and Cdh1(2005)161 cited
• → Phosphorylation at serine 331 is required for Aurora B activation(2011)88 cited
• → Control of Aurora-A stability through interaction with TPX2(2010)87 cited
• → Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of Aurora B(2008)116 cited
• → Human papillomavirus type 16 E7 oncoprotein inhibits the anaphase promoting complex/cyclosome activity by dysregulating EMI1 expression in mitosis(2013)17 cited