E2F-1 cooperates with topoisomerase II inhibition and DNA damage to selectively augment p53-independent apoptosis.

Nip J, Strom DK, Fee BE, Zambetti G, Cleveland JL, Hiebert SW
Mol Cell Biol. 1997 17 (3): 1049-56

PMID: 9032231 · PMCID: PMC231829 · DOI:10.1128/mcb.17.3.1049

Mutations in the retinoblastoma (pRb) tumor suppressor pathway including its cyclin-cdk regulatory kinases, or cdk inhibitors, are a hallmark of most cancers and allow unrestrained E2F-1 transcription factor activity, which leads to unregulated G1-to-S-phase cell cycle progression. Moderate levels of E2F-1 overexpression are tolerated in interleukin 3 (IL-3)-dependent 32D.3 myeloid progenitor cells, yet this induces apoptosis when these cells are deprived of IL-3. However, when E2F activity is augmented by coexpression of its heterodimeric partner, DP-1, the effects of survival factors are abrogated. To determine whether enforced E2F-1 expression selectively sensitizes cells to cytotoxic agents, we examined the effects of chemotherapeutic agents and radiation used in cancer therapy. E2F-1 overexpression in the myeloid cells preferentially sensitized cells to apoptosis when they were treated with the topoisomerase II inhibitor etoposide. Although E2F-1 alone induces moderate levels of p53 and treatment with drugs markedly increased p53, the deleterious effects of etoposide in E2F-1-overexpressing cells were independent of p53 accumulation. Coexpression of Bcl-2 and E2F-1 in 32D.3 cells protected them from etoposide-mediated apoptosis. However, Bcl-2 also prevented apoptosis of these cells upon exposure to 5-fluorouracil and doxorubicin, which were also cytotoxic for control cells. Pretreating E2F-1-expressing cells with ICRF-193, a second topoisomerase II inhibitor that does not damage DNA, protected the cells from etoposide-induced apoptosis. However, ICRF-193 cooperated with DNA-damaging agents to induce apoptosis. Therefore, topoisomerase II inhibition and DNA damage can cooperate to selectively induce p53-independent apoptosis in cells that have unregulated E2F-1 activity resulting from mutations in the pRb pathway.

MeSH Terms (25)

Antineoplastic Agents Apoptosis Bone Marrow Cells Carrier Proteins Cell Cycle Cell Cycle Proteins Cell Survival DNA-Binding Proteins DNA Damage Doxorubicin E2F1 Transcription Factor E2F Transcription Factors Enzyme Inhibitors Etoposide Fluorouracil Gamma Rays Gene Expression Humans Piperazines Proto-Oncogene Proteins c-bcl-2 Retinoblastoma-Binding Protein 1 Topoisomerase II Inhibitors Transcription Factor DP1 Transcription Factors Tumor Suppressor Protein p53

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