p53-independent increase in E2F-1 expression enhances the cytotoxic effects of etoposide and of adriamycin

Int J Oncol. 1999 Jan;14(1):5-14.


The transcription factor E2F-1 drives cell cycle progression at the G1- to S-phase boundary; however, overexpression of E2F-1 can induce apoptosis. We show here that E2F-1 protein levels increase in human medulloblastoma, glioma, lung, colon, and bladder cancer cell lines (n=7) following treatment with the DNA damaging agents adriamycin or etoposide. This induction of E2F-1 occurs independently of Rb or p53 status and involves new protein synthesis. Although E2F-1 protein levels increase following DNA damage, several genes transcriptionally targeted by E2F-1 are not similarly induced. Rather, induction of E2F-1 in the tumor cells correlates with their sensitivity to adriamycin or to etoposide. Correspondingly, fibroblasts from E2F-1 knockout mice are more resistant to DNA damage than cells from normal mice. Overexpression of E2F-1 protein in tumor cell lines infected with an adenovirus encoding wild-type E2F-1 leads to enhanced cytotoxicity following exposure to DNA damaging agents, which results from enhanced apoptosis. The results of this study implicate a role for E2F-1 in p53-independent cytotoxicity of chemotherapy and provide a pharmacological tool for increasing levels of the apoptosis-inducing E2F-1 protein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carrier Proteins*
  • Cell Cycle Proteins*
  • Cycloheximide / pharmacology
  • DNA / drug effects*
  • DNA Damage*
  • DNA-Binding Proteins*
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Etoposide / pharmacology*
  • Humans
  • Mice
  • Retinoblastoma Protein / physiology
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors / biosynthesis*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / physiology*


  • Arid4a protein, mouse
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2f1 protein, mouse
  • Retinoblastoma Protein
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Etoposide
  • Doxorubicin
  • DNA
  • Cycloheximide