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

研究成果: ジャーナルへの寄稿記事

17 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)1975-1987
ページ数13
ジャーナルOncogene
31
発行部数15
DOI
出版物ステータス出版済み - 4 12 2012

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Mitosis
Cyclin A
Ubiquitination
Prometaphase
Tumor Suppressor Genes
Cell Cycle
Phosphorylation
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

これを引用

Chow, C., Wong, N., Pagano, M., Lun, S. W. M., Nakayama, K. I., Nakayama, K., & Lo, K. W. (2012). Regulation of APC/C Cdc20 activity by RASSF1A-APC/C Cdc20 circuitry. Oncogene, 31(15), 1975-1987. https://doi.org/10.1038/onc.2011.372

Regulation of APC/C Cdc20 activity by RASSF1A-APC/C Cdc20 circuitry. / Chow, C.; Wong, N.; Pagano, M.; Lun, S. W.M.; Nakayama, K. I.; Nakayama, K.; Lo, K. W.

:: Oncogene, 巻 31, 番号 15, 12.04.2012, p. 1975-1987.

研究成果: ジャーナルへの寄稿記事

Chow, C, Wong, N, Pagano, M, Lun, SWM, Nakayama, KI, Nakayama, K & Lo, KW 2012, 'Regulation of APC/C Cdc20 activity by RASSF1A-APC/C Cdc20 circuitry', Oncogene, 巻. 31, 番号 15, pp. 1975-1987. https://doi.org/10.1038/onc.2011.372
Chow C, Wong N, Pagano M, Lun SWM, Nakayama KI, Nakayama K その他. Regulation of APC/C Cdc20 activity by RASSF1A-APC/C Cdc20 circuitry. Oncogene. 2012 4 12;31(15):1975-1987. https://doi.org/10.1038/onc.2011.372
Chow, C. ; Wong, N. ; Pagano, M. ; Lun, S. W.M. ; Nakayama, K. I. ; Nakayama, K. ; Lo, K. W. / Regulation of APC/C Cdc20 activity by RASSF1A-APC/C Cdc20 circuitry. :: Oncogene. 2012 ; 巻 31, 番号 15. pp. 1975-1987.
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