Publication in refereed journal
香港中文大学研究人员 ( 现职)
| 伦慧敏博士 (化学病理学系) |
| 罗国炜教授 (病理解剖及细胞学系) |
| 王昭春教授 (病理解剖及细胞学系) |
| 周捷博士 (病理解剖及细胞学系) |
全文
| 数位物件识别号 (DOI) http://dx.doi.org/10.1038/onc.2011.372 |
引用次数
Web of Sciencehttp://aims.cuhk.edu.hk/converis/portal/Publication/10WOS source URL
其它资讯
摘要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. Oncogene (2012) 31, 1975-1987; doi:http://aims.cuhk.edu.hk/converis/portal/Publication/10.http://aims.cuhk.edu.hk/converis/portal/Publication/1038/onc.2011.372; published online 29 August 2011
着者Chow C, Wong N, Pagano M, Lun SWM, Nakayama KI, Nakayama K, Lo KW
期刊名称Oncogene
出版年份2012
月份4
日期1
卷号31
期次15
出版社Nature Publishing Group: Open Access Hybrid Model Option B
页次1975 - 1987
国际标準期刊号0950-9232
电子国际标準期刊号1476-5594
语言英式英语
关键词APC/C-Cdc20; Aurora; mitotic checkpoint; RASSF1A; ubiquitination
Web of Science 学科类别Biochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY; Cell Biology; CELL BIOLOGY; Genetics & Heredity; GENETICS & HEREDITY; Oncology; ONCOLOGY
