Abstract
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.
MeSH terms
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Amino Acid Sequence
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Antineoplastic Agents / toxicity*
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Breast Neoplasms
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CDC2-CDC28 Kinases*
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Carrier Proteins*
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Cell Cycle / drug effects
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Cell Cycle Proteins*
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Cell Line
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Cell Line, Transformed
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Cell Survival / drug effects
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclins / antagonists & inhibitors*
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DNA-Binding Proteins*
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E2F Transcription Factors
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Enzyme Inhibitors / toxicity*
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Female
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Humans
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Molecular Sequence Data
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Oligopeptides / chemistry
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Oligopeptides / toxicity
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Osteosarcoma
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Peptides / chemistry
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Peptides / toxicity*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors / antagonists & inhibitors*
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Carrier Proteins
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Cell Cycle Proteins
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Cyclins
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DNA-Binding Proteins
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E2F Transcription Factors
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Enzyme Inhibitors
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Oligopeptides
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Peptides
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases