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Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1–S transition

Oncogene volume 27, pages 3176–3185 (2008)Cite this article

Abstract

The tumor suppressor RASSF1A is inactivated in many human cancers and is implicated in regulation of microtubule stability, cell cycle progression and apoptosis. However, the precise mechanisms of RASSF1A action and their regulation remain unclear. Here we show that Skp2, an oncogenic subunit of the Skp1–Cul1–F–box ubiquitin ligase complex, interacts with, ubiquitinates, and promotes the degradation of RASSF1A at the G1–S transition of the cell cycle. This Skp2-dependent destruction of RASSF1A requires phosphorylation of the latter on serine-203 by cyclin D–cyclin-dependent kinase 4. Interestingly, mutation of RASSF1A-phosphorylation site Ser203 to alanine results in a delay in cell cycle progression from G1 to S phase. Moreover, enforced expression of Skp2 abolishes the inhibitory effect of RASSF1A on cell proliferation. Finally, the delay in G1–S progression after Skp2 removal is normalized by depletion of RASSF1A. These findings suggest that the Skp2-mediated degradation of RASSF1A plays an important role in cell proliferation and survival.

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Acknowledgements

We are grateful to M Pagano, JW Harper, JB Yoon, HW Lee, F Liu for DNAs and to G Pfeifer for RASSF1A wild-type and null MEFs. This study was supported by a grant from the Korea Research Foundation and the 21st Century Frontier Functional Human Genome Project of KISTEP (Ministry of Science and Technology of Korea), and the National Research Laboratory Program of Korea.

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  1. M S Song and S J Song: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea

    M S Song, S J Song, S J Kim & D-S Lim

  2. Division of Developmental Genetics, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    K Nakayama

  3. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    K I Nakayama

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  1. M S Song
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Correspondence to D-S Lim.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Song, M., Song, S., Kim, S. et al. Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1–S transition. Oncogene 27, 3176–3185 (2008). https://doi.org/10.1038/sj.onc.1210971

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