TY - JOUR
T1 - Proteasome-mediated destruction of the cyclin A/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo
AU - Chen, Wei
AU - Lee, Jeongwu
AU - Cho, Steve Y.
AU - Fine, Howard A.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/6/1
Y1 - 2004/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=2542623585&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2542623585&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-03-3906
DO - 10.1158/0008-5472.CAN-03-3906
M3 - Article
C2 - 15173007
AN - SCOPUS:2542623585
VL - 64
SP - 3949
EP - 3957
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -