Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists.
Recent studies identified a short peptide motif that serves as a docking site for cyclin/cyclin-dependent kinase (cdk) 2 complexes. Peptides containing this motif block the phosphorylation of substrates by cyclin A/cdk2 or cyclin E/cdk2. Here we report that cell membrane-permeable forms of such peptides preferentially induced transformed cells to undergo apoptosis relative to nontransformed cells. Deregulation of E2F family transcription factors is a common event during transformation and was sufficient to sensitize cells to the cyclin/cdk2 inhibitory peptides. These results suggest that deregulation of E2F and inhibition of cdk2 are synthetically lethal and provide a rationale for the development of cdk2 antagonists as antineoplastic agents.
Chen
Y N
YN
Novartis Institute for Biomedical Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, NJ 07901, USA.
Sharma
S K
SK
Ramsey
T M
TM
Jiang
L
L
Martin
M S
MS
Baker
K
K
Adams
P D
PD
Bair
K W
KW
Kaelin
W G
WG
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000633:toxicity*; D001943:Breast Neoplasms; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000633:toxicity; D012516:Osteosarcoma; D010455:Peptides / Q000737:chemistry / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010455:Peptides; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases