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E2f-1 cooperates with topoisomerase ii inhibition and DNA damage to selectively augment p53-independent apoptosis

Academic Article
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Overview

authors

  • Nip, J.
  • Strom, D. K.
  • Fee, B. E.
  • Zambetti, G.
  • Cleveland, John
  • Hiebert, S. W.

publication date

  • March 1997

journal

  • Molecular and Cellular Biology  Journal

abstract

  • 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.

subject areas

  • Antineoplastic Agents
  • Apoptosis
  • Bone Marrow Cells
  • Carrier Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Survival
  • DNA Damage
  • DNA-Binding Proteins
  • Doxorubicin
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • 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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Identity

PubMed Central ID

  • PMC231829

International Standard Serial Number (ISSN)

  • 0270-7306

PubMed ID

  • 9032231
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Additional Document Info

start page

  • 1049

end page

  • 1056

volume

  • 17

issue

  • 3

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