Selective Killing of Transformed Cells by Cyclin/Cyclin-Dependent Kinase 2 Antagonists

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 8; pp. 4325 - 4329
• Main Authors: Chen, Ying-Nan P., Sharma, Sushil K., Ramsey, Timothy M., Jiang, Li, Martin, Mary S., Baker, Kayla, Adams, Peter D., Bair, Kenneth W., Kaelin, William G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 13.04.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Amino Acid Sequence; Antineoplastic Agents - toxicity; Apoptosis; B lymphocytes; Biochemistry; Biological Sciences; Breast Neoplasms; Carrier Proteins; CDC2-CDC28 Kinases; Cell culture techniques; Cell Cycle - drug effects; Cell Cycle Proteins; Cell Line; Cell Line, Transformed; Cell lines; Cell Survival - drug effects; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclins; Cyclins - antagonists & inhibitors; Diploidy; DNA-Binding Proteins; E2F Transcription Factors; Enzyme Inhibitors - toxicity; Enzymes; Female; Fibroblasts; HCT116 cells; Humans; Molecular Sequence Data; Oligopeptides - chemistry; Oligopeptides - toxicity; Osteosarcoma; Peptides; Peptides - chemistry; Peptides - toxicity; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Retinoblastoma-Binding Protein 1; Transcription Factor DP1; Transcription Factors - antagonists & inhibitors; Transformed cell line; Tumor Cells, Cultured; Viability
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.8.4325

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.