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.
Chen
Wei
W
Neuro-Oncology Branch, National Cancer Institute, National Institutes of Neurological Disorder and Stroke, NIH, Bethesda, Maryland 20892, USA.
Lee
Jeongwu
J
Cho
Steve Y
SY
Fine
Howard A
HA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D019925:Cyclin A; C400427:FAIM2 protein, human; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D011993:Recombinant Fusion Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex