The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC–Cdc20 complex
- 25 January 2004
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature
- Vol. 6 (2), 129-137
- https://doi.org/10.1038/ncb1091
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.Keywords
This publication has 29 references indexed in Scilit:
- The Anaphase-Promoting ComplexMolecular Cell, 2002
- RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumoursOncogene, 2001
- Chromosome segregation and cancer: cutting through the mysteryNature Reviews Cancer, 2001
- The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomasOncogene, 2001
- The candidate tumor suppressor gene, RASSF1A , from human chromosome 3p21.3 is involved in kidney tumorigenesisProceedings of the National Academy of Sciences of the United States of America, 2001
- Epigenetic Inactivation of RASSF1A in Lung and Breast Cancers and Malignant Phenotype SuppressionJNCI Journal of the National Cancer Institute, 2001
- Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3Nature Genetics, 2000
- Whose end is destruction: cell division and the anaphase-promoting complexGenes & Development, 1999
- CDC20 and CDH1 : A Family of Substrate-Specific Activators of APC-Dependent ProteolysisScience, 1997
- How Proteolysis Drives the Cell CycleScience, 1996