Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit.
The retinoblastoma protein (pRB) negatively regulates the progression from G1 to S phase of the cell cycle, in part, by repressing E2F-dependent transcription. 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 p27(Kip1) through an unknown mechanism. Degradation of p27(Kip1) is mediated by ubiquitin-dependent targeting of p27(Kip1) by SCF -Skp2 (ref. 4). Here, we report a novel interaction between pRB and the anaphase-promoting complex/cyclosome (APC/C) that controls p27(Kip1) 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.
Binné
Ulrich K
UK
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, MA 02129, USA.
Classon
Marie K
MK
Dick
Frederick A
FA
Wei
Wenyi
W
Rape
Michael
M
Kaelin
William G
WG
Näär
Anders M
AM
Dyson
Nicholas J
NJ
D000705:Anaphase; D064173:Anaphase-Promoting Complex-Cyclosome; D015820:Cadherins / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
D015820:Cadherins; D016160:Retinoblastoma Protein; D044786:S-Phase Kinase-Associated Proteins; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome