Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation.
Cyclin E is a mammalian G1 cyclin that is both required and rate limiting for entry into S phase. The expression of cyclin E is periodic, peaking at the G1-S transition and then decaying as S phase progresses. To understand the mechanisms underlying cyclin E periodicity, we have investigated the regulation of cyclin E degradation. We find that cyclin E is degraded by the ubiquitin-proteasome system, and that this degradation is regulated by both cdk2 binding and cdk2 catalytic activity. Free cyclin E is readily ubiquitinated and degraded by the proteasome. Binding to cdk2 protects cyclin E from ubiquitination, and this protection is reversed by cdk2 activity in a process that involves phosphorylation of cyclin E itself. The data are most consistent with a model in which cdk2 activity initiates cyclin E degradation by promoting the disassembly of cyclin E-cdk2 complexes, followed by the ubiquitination and degradation of free cyclin E.
Clurman
B E
BE
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.
Sheaff
R J
RJ
Thress
K
K
Groudine
M
M
Roberts
J M
JM
D016475:3T3 Cells; D000818:Animals; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014452:Ubiquitins / Q000378:metabolism*
D016213:Cyclins; D046911:Macromolecular Substances; D009097:Multienzyme Complexes; D014452:Ubiquitins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex