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 language | English (US) |
---|---|
Pages (from-to) | 3949-3957 |
Number of pages | 9 |
Journal | Cancer Research |
Volume | 64 |
Issue number | 11 |
DOIs | |
State | Published - Jun 1 2004 |
Externally published | Yes |
ASJC Scopus subject areas
- Oncology
- Cancer Research