Regulation of APC/C Cdc20 activity by RASSF1A-APC/C Cdc20 circuitry

C. Chow, N. Wong, M. Pagano, S. W.M. Lun, K. I. Nakayama, K. Nakayama, K. W. Lo

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1975-1987
Number of pages13
JournalOncogene
Volume31
Issue number15
DOIs
Publication statusPublished - 2012 Apr 12

Keywords

  • APC/CCdc20
  • Aurora
  • RASSF1A
  • mitotic checkpoint
  • ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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