Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation.

  1. B E Clurman,
  2. R J Sheaff,
  3. K Thress,
  4. M Groudine, and
  5. J M Roberts
  1. Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.

Abstract

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.

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