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

Overview

MeSH Major

  • CDC2-CDC28 Kinases
  • Carrier Proteins
  • Cyclin A
  • Cysteine Endopeptidases
  • Multienzyme Complexes
  • beta-Transducin Repeat-Containing Proteins

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 beta-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.

publication date

  • June 2004

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-03-3906

PubMed ID

  • 15173007

Additional Document Info

start page

  • 3949

end page

  • 57

volume

  • 64

number

  • 11