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
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Cycle Proteins*
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Cell Nucleus / genetics
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Cell Nucleus / metabolism*
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Checkpoint Kinase 2
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DNA Damage / genetics*
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DNA-Binding Proteins*
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E2F Transcription Factors
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E2F1 Transcription Factor
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Etoposide / pharmacology
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Eukaryotic Cells / metabolism*
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Mutation / genetics
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Phosphorylation / drug effects
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases*
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Serine / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation / drug effects
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Transcriptional Activation / genetics
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F1 protein, human
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Nucleic Acid Synthesis Inhibitors
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Transcription Factors
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Tumor Suppressor Proteins
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Serine
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Etoposide
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Protein Kinases
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Checkpoint Kinase 2
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CHEK2 protein, human
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Protein Serine-Threonine Kinases