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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.

Original publication

DOI

10.1038/ncb974

Type

Journal article

Journal

Nat Cell Biol

Publication Date

05/2003

Volume

5

Pages

401 - 409

Keywords

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