Topoisomerase IIalpha mediates E2F-1-induced chemosensitivity and is a target for p53-mediated transcriptional repression.
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.
Nip
J
J
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Hiebert
S W
SW
D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D054659:Diketopiperazines; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D056465:Retinoblastoma-Binding Protein 1; D020123:Sirolimus / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000951:Antigens, Neoplasm; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D007527:Isoenzymes; D010879:Piperazines; D056465:Retinoblastoma-Binding Protein 1; D059005:Topoisomerase II Inhibitors; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D004250:DNA Topoisomerases, Type II; D020123:Sirolimus