Topoisomerase IIalpha mediates E2F-1-induced chemosensitivity and is a target for p53-mediated transcriptional repression.

Nip J, Hiebert SW
Cell Biochem Biophys. 2000 33 (2): 199-207

PMID: 11325040 · DOI:10.1385/CBB:33:2:199

Mutations of the retinoblastoma tumor suppressor, pRb, or its cyclin-cyclin-dependent kinase (CDK) regulatory kinases or CDK inhibitors, allows unrestrained E2F activity, leading to unregulated cell cycle progression. However, overexpression of E2F-1 also sensitizes cells to apoptosis, suggesting that targeting this pathway may be of therapeutic benefit. Enforced expression of E2F-1 in interleukin-3-dependent myeloid cells led to preferential sensitivity to the topoisomerase II inhibitor, etoposide, which was independent of p53 accumulation. Pretreatment of the E2F-1-expressing cells with ICRF-193, a second topoisomerase II inhibitor that does not cause DNA damage, protected these cells against etoposide-induced apoptosis. However, ICRF-193 cooperated with other DNA-damaging agents to induce apoptosis. Enforced expression of E2F-1 led to accumulation of p53 protein. An E2F-1 mutant that is defective in inducing cell cycle progression also induced p53, suggesting that p53 was responding directly to E2F, and not to secondary events caused by inappropriate cell cycle progression (i.e., DNA damage). Thus, topoisomerase II inhibition and DNA damage cooperate to selectively induce apoptosis in cells that have mutations in the pRb pathway.

MeSH Terms (23)

Antigens, Neoplasm Apoptosis Carrier Proteins Cell Cycle Cell Cycle Proteins Cell Line Cell Survival DNA-Binding Proteins DNA Topoisomerases, Type II E2F1 Transcription Factor E2F Transcription Factors Enzyme Inhibitors Humans Interleukin-3 Isoenzymes Piperazines Retinoblastoma-Binding Protein 1 Sirolimus Topoisomerase II Inhibitors Transcription, Genetic Transcription Factor DP1 Transcription Factors Tumor Suppressor Protein p53

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