Be. Clurman et al., TURNOVER OF CYCLIN-E BY THE UBIQUITIN-PROTEASOME PATHWAY IS REGULATEDBY CDK2 BINDING AND CYCLIN PHOSPHORYLATION, Genes & development, 10(16), 1996, pp. 1979-1990
Cyclin E is a mammalian G(1) cyclin that is both required and rate lim
iting for entry into S phase. The expression of cyclin E is periodic,
peaking at the G(1)-S transition and then decaying as S phase progress
es. To understand the mechanisms underlying cyclin E periodicity, we h
ave 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 acti
vity. Free cyclin E is readily ubiquitinated and degraded by the prote
asome. Binding to cdk2 protects cyclin E from ubiquitination, and this
protection is reversed by cdk2 activity in a process that involves ph
osphorylation of cyclin E itself. The data are most consistent with a
model in which cdk2 activity initiates cyclin E degradation by promoti
ng the disassembly of cyclin E-cdk2 complexes, followed by the ubiquit
ination and degradation of free cyclin E.