Letter abstract
Nature Cell Biology 6, 129 - 137 (2004)
Published online: 25 January 2004 | doi:10.1038/ncb1091
The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC–Cdc20 complex
Min Sup Song1,2, Su Jeong Song1, Nagi G. Ayad3, Jin Sook Chang1, Joo Hyun Lee1, Hyun Kyung Hong1, Ho Lee1, Naeyun Choi4, Jhingook Kim4, Hojoong Kim4, Jin Woo Kim2, Eui-Ju Choi2, Marc W. Kirschner3 & Dae-Sik Lim1
The tumour suppressor gene RASSF1A is frequently silenced in lung cancer and other sporadic tumours as a result of hypermethylation of a CpG island in its promoter1, 2, 3, 4, 5, 6. However, the precise mechanism by which RASSF1A functions in cell cycle regulation and tumour suppression has remained unknown. Here we show that RASSF1A regulates the stability of mitotic cyclins and the timing of mitotic progression. RASSF1A localizes to microtubules during interphase and to centrosomes and the spindle during mitosis. The overexpression of RASSF1A induced stabilization of mitotic cyclins and mitotic arrest at prometaphase. RASSF1A interacts with Cdc20, an activator of the anaphase-promoting complex (APC), resulting in the inhibition of APC activity. Although RASSF1A does not contribute to either the Mad2-dependent spindle assembly checkpoint or the function of Emi1 (ref. 1), depletion of RASSF1A by RNA interference accelerated the mitotic cyclin degradation and mitotic progression as a result of premature APC activation. It also caused a cell division defect characterized by centrosome abnormalities and multipolar spindles. These findings implicate RASSF1A in the regulation of both APC–Cdc20 activity and mitotic progression.
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Guseoung-D, Yuseong-G, Daejeon 305-701, Korea.
- School of Life Science and Biotechnology, Korea University, 1,5-Ka Anam-Dong, Sungbuk-G, Seoul 136-701, Korea.
- Department of Cell Biology, Harvard Medical School, 2000 Longwood Avenue, Boston, MA 02115, USA.
- Samsung Medical Center, 50-Ka Ilweon-D, Kangnam-G, Seoul 135-230, Korea.
Correspondence to: Dae-Sik Lim1 e-mail: daesiklim@kaist.ac.kr
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