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

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.
Mesh Terms:
Animals, Apoptosis, Apoptosis Regulatory Proteins, CDC2-CDC28 Kinases, Carrier Proteins, Cell Division, Cell Line, Tumor, Cyclin A, Cyclin-Dependent Kinase 2, Cysteine Endopeptidases, Female, Glioma, HeLa Cells, Humans, Membrane Proteins, Mice, Mice, Nude, Multienzyme Complexes, Proteasome Endopeptidase Complex, Protein Engineering, Recombinant Fusion Proteins, Transduction, Genetic, Xenograft Model Antitumor Assays, beta-Transducin Repeat-Containing Proteins
Cancer Res.
Date: Jun. 01, 2004
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