Abstract
The retinoblastoma protein (pRB) negatively regulates the progression from G1 to S phase of the cell cycle, in part, by repressing E2F-dependent transcription1. pRB also possesses E2F-independent functions that contribute to cell-cycle control — for example, during pRB-mediated cell-cycle arrest pRB associates with Skp2, the F-box protein of the Skp1–Cullin–F-box protein (SCF) E3 ubiquitin ligase complex, and promotes the stability of the cyclin-dependent kinase-inhibitor p27Kip1 through an unknown mechanism2,3. Degradation of p27Kip1 is mediated by ubiquitin-dependent targeting of p27Kip1 by SCF –Skp2 (ref. 4). Here, we report a novel interaction between pRB and the anaphase-promoting complex/cyclosome (APC/C) that controls p27Kip1 stability by targeting Skp2 for ubiquitin-mediated degradation. Cdh1, an activator of APC/C, not only interacts with pRB but is also required for a pRB-induced cell-cycle arrest. The results reveal an unexpected physical convergence between the pRB tumour-suppressor protein and E3 ligase complexes, and raise the possibility that pRB may direct APC/C to additional targets during pRB-mediated cell-cycle exit.
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Acknowledgements
We thank: C. Pfleger for numerous APC/C-related plasmids; R. Watson for Myc-tagged pRB, p107, p130 plasmids; S. Lowe for U2OS shRB cell line; J. Rocco for pcDNA6/TR and pcDNA4/TO plasmids; and B. Schulman for the CMV–Myc–Skp2 plasmid. We also like to thank P. Hinds and K. Münger for helpful comments on the manuscript. This study was supported by National Institutes of Health (NIH) grant CA64402 to N.J.D and by the Massachusetts General Hospital Fund for Medical Discovery to U.K.B.
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Binné, U., Classon, M., Dick, F. et al. Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol 9, 225–232 (2007). https://doi.org/10.1038/ncb1532
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DOI: https://doi.org/10.1038/ncb1532
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