Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex.
Cell-cycle transitions are driven by waves of ubiquitin-dependent degradation of key cell-cycle regulators. SCF (Skp1/Cullin/F-box protein) complexes and anaphase-promoting complexes (APC) represent two major classes of ubiquitin ligases whose activities are thought to regulate primarily the G1/S and metaphase/anaphase cell-cycle transitions, respectively. The major target of the Skp1/Cul1/Skp2 (SCF(SKP2)) complex is thought to be the Cdk inhibitor p27 during S phase, whereas the principal targets for the APC are thought to be involved in chromatid separation (securin) and exit from mitosis (cyclin B). Although the role of the APC in mitosis is relatively clear, there is mounting evidence that APCs containing Cdh1 (APC(CDH1)) also have a function in the G1 phase of the cell cycle. Here, we show that the F-box protein Skp2 is polyubiquitinated, and hence earmarked for destruction, by APC(CDH1). As a result, accumulation of SCF(SKP2) requires prior inactivation of APC(CDH1). These findings provide an insight into the orchestration of SCF and APC activities during cell-cycle progression, and into the involvement of the APC in G1.
Wei
Wenyi
W
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Ayad
Nagi G
NG
Wan
Yong
Y
Zhang
Guo-Jun
GJ
Kirschner
Marc W
MW
Kaelin
William G
WG
D020816:Amino Acid Motifs; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D002457:Cell Extracts; D005434:Flow Cytometry; D016193:G1 Phase; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D002457:Cell Extracts; D044786:S-Phase Kinase-Associated Proteins; D025801:Ubiquitin; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044843:SKP Cullin F-Box Protein Ligases