Letter abstract
Nature Cell Biology 9, 225 - 232 (2006)
Published online: 24 December 2006 | doi:10.1038/ncb1532
There is a Corrigendum (March 2007) associated with this Letter.
Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit
Ulrich K. Binné1, Marie K. Classon1, Frederick A. Dick2, Wenyi Wei3, Michael Rape4, William G. Kaelin, Jr.3,5, Anders M. Näär1,6 & Nicholas J. Dyson1
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.
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, MA 02129, USA.
- Department of Biochemistry, Schulich School of Medicine, London, Ontario N6A 4L6, Canada.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
- Howard Hughes Medical Institute and Brigham and Women's Hospital, Boston, Massachusetts, MA 02115, USA.
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
Correspondence to: Nicholas J. Dyson1 e-mail: Dyson@helix.mgh.harvard.edu
Correspondence to: Anders M. Näär1,6 e-mail: Naar@helix.mgh.harvard.edu
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