Degradation of the mammalian cyclin-dependent kinase (CDK) inhibitor p27 is required for the cellular transition from quiescence to the proliferative state. The ubiquitination and subsequent degradation of p27 depend on its phosphorylation by cyclin–CDK complexes. However, the ubiquitin–protein ligase necessary for p27 ubiquitination has not been identified. Here we show that the F-box protein SKP2 specifically recognizes p27 in a phosphorylation-dependent manner that is characteristic of an F-box-protein–substrate interaction. Furthermore, both in vivo and in vitro, SKP2 is a rate-limiting component of the machinery that ubiquitinates and degrades phosphorylated p27. Thus, p27 degradation is subject to dual control by the accumulation of both SKP2 and cyclins following mitogenic stimulation.
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We thank G. Draetta, M. Garabedian, E. Harlow, A. Koff, E. Lees, D. Morgan, A. Pause, Y. Xiong and H. Zhang for reagents; M. Chao, J. Lukas and L. Yamasaki for critically reading the manuscript; and E. Latres and other members of M.P.’s laboratory for their contribution to this work. M.P. thanks L. Yamasaki and T.B. Balduur for their continuous support. A.H. is supported in part by grants from the Israel Ministry of Science and The Council for Tobacco Research, USA, and by a Human Frontier Science Program Organization (HFSPO) grant (RG0229); M.P. is supported by an HFSPO grant (RG0229) and by NIH RO1 grants CA76584 and GM57587.
Correspondence and requests for materials should be addressed to M.P.
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Carrano, A., Eytan, E., Hershko, A. et al. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1, 193–199 (1999). https://doi.org/10.1038/12013
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