Proteasome-mediated destruction of the cyclin A/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo

Wei Chen, Jeongwu Lee, Steve Y. Cho, Howard A. Fine

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclin-dependent kinases (cdks) represent potentially promising molecular targets for cancer therapeutic strategies. To evaluate the antitumor activity of selective cyclin/cdk inhibition, we constructed a chimeric protein composed of a F-box protein (TrCP) fused to a peptide comprising the cyclin/cdk2 binding motif in p21-like cdk inhibitors (TrCP-LFG). We now demonstrate that endogenous cyclin A and its binding substrate, cdk2, can be tethered to β-TrCP, ubiquitinated, and effectively degraded. Degradation of cdk2 and cyclin A together, but not cdk2 alone, results in massive tumor cell apoptosis in vitro and in vivo in a proteasome-dependent manner with no toxicity to normal tissue. These data demonstrate that cyclin A and/or the cyclin A/cdk2 complex is a promising anticancer target with a high therapeutic index.

Original languageEnglish (US)
Pages (from-to)3949-3957
Number of pages9
JournalCancer Research
Volume64
Issue number11
DOIs
StatePublished - Jun 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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