Chk2 activates E2F-1 in response to DNA damage

Nat Cell Biol. 2003 May;5(5):401-9. doi: 10.1038/ncb974.

Abstract

The E2F-1 transcription factor is regulated during cell cycle progression and induced by cellular stress, such as DNA damage. We report that checkpoint kinase 2 (Chk2) regulates E2F-1 activity in response to the DNA-damaging agent etoposide. A Chk2 consensus phosphorylation site in E2F-1 is phosphorylated in response to DNA damage, resulting in protein stabilization, increased half-life, transcriptional activation and localization of phosphorylated E2F-1 to discrete nuclear structures. Expression of a dominant-negative Chk2 mutant blocks induction of E2F-1 and prevents E2F-1-dependent apoptosis. Moreover, E2F-1 is resistant to induction by etoposide in tumour cells expressing mutant chk2. Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. These results suggest a role for E2F-1 in checkpoint control and provide a plausible explanation for the tumour suppressor activity of E2F-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Cycle Proteins*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Checkpoint Kinase 2
  • DNA Damage / genetics*
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Etoposide / pharmacology
  • Eukaryotic Cells / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Mutation / genetics
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Phosphorylation / drug effects
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Serine / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Nucleic Acid Synthesis Inhibitors
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Serine
  • Etoposide
  • Protein Kinases
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases