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The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC–Cdc20 complex

Nature Cell Biology volume 6, pages 129–137 (2004)Cite this article

Abstract

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.

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Figure 1: RASFF1A localizes to microtubules and induces mitotic arrest at prometaphase.
Figure 2: RASSF1A interacts with Cdc20.
Figure 3: RASSF1A regulates APC–Cdc20 activity.
Figure 4: RASSF1A inhibits APC–Cdc20 independently of the spindle assembly checkpoint or Emi1.
Figure 5: Loss of RASSF1A results in acceleration of mitotic progression and in mitotic abnormalities.

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Acknowledgements

We thank M. White and C. H. Lee for RASSF1A and Cdc20 cDNAs, respectively, and B. S. Suh for comments on the manuscript. This work was supported by grants from the 21st Century Frontier Functional Human Genome Project of KISTEP (Ministry of Science and Technology of Korea) and the Biomedical Research Program of KISTEP to D.-S.L., by a grant from the National Creative Research Program of KISTEP to E.-J.C, and by a grant from the Korea Health 21 R&D Project (02-PJ-PG10-20802-0012) to H.K. D.-S.L. was also supported by a grant from the Korea National Cancer Center Control Program (0320370-1).

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  1. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Guseoung-D, Yuseong-G, Daejeon, 305-701, Korea

    Min Sup Song, Su Jeong Song, Jin Sook Chang, Joo Hyun Lee, Hyun Kyung Hong, Ho Lee & Dae-Sik Lim

  2. School of Life Science and Biotechnology, Korea University, 1,5-Ka Anam-Dong, Sungbuk-G, Seoul, 136-701, Korea

    Min Sup Song, Jin Woo Kim & Eui-Ju Choi

  3. Department of Cell Biology, Harvard Medical School, 2000 Longwood Avenue, Boston, 02115, MA, USA

    Nagi G. Ayad & Marc W. Kirschner

  4. Samsung Medical Center, 50-Ka Ilweon-D, Kangnam-G, Seoul, 135-230, Korea

    Naeyun Choi, Jhingook Kim & Hojoong Kim

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Song, M., Song, S., Ayad, N. et al. The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC–Cdc20 complex. Nat Cell Biol 6, 129–137 (2004). https://doi.org/10.1038/ncb1091

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