Abstract
E2F1, a member of the E2F family of transcription factors, plays a pivotal role in controlling both physiological cell-cycle progression and apoptotic cell death in response to DNA damage and oncogene activation. In response to genotoxic stresses, E2F1 is stabilized by signals that include ATM-dependent phosphorylation. We recently demonstrated that DNA damage induces also E2F1 acetylation, which is required for its recruitment onto apoptotic gene promoters. Here we show that E2F1 is stabilized in response to doxorubicin and cisplatin treatments even in the absence of either ATM-dependent phosphorylation or p53 and cAbl, two major transducers of DNA damage signaling. We found that acetylation of E2F1 is, instead, required to stabilize the protein in response to doxorubicin. Finally, we report that the formation of E2F1-p300/CREB-binding protein-associated factor (P/CAF) complexes is preferentially induced in doxorubicin-treated cells, and that P/CAF acetyltransferase (HAT), but not p300 HAT activity, is required for a significant E2F1 stabilization and accumulation. Our results unveil a differential role of P/CAF and p300 in acetylation-induced stabilization of E2F1, thus supporting a specific role for P/CAF HAT activity in E2F1-dependent apoptosis in response to DNA damage.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Acetyltransferases / metabolism
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Acetyltransferases / physiology*
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Animals
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Apoptosis
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / metabolism
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Cell Cycle Proteins / physiology*
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Cell Line
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Cisplatin / pharmacology
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Cycloheximide / pharmacology
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DNA Damage*
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / metabolism
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Doxorubicin / pharmacology
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E2F Transcription Factors
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E2F1 Transcription Factor
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Histone Acetyltransferases
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Humans
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Immunoblotting
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Mice
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Phosphorylation
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Plasmids / metabolism
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Precipitin Tests
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Promoter Regions, Genetic
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism
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Protein Synthesis Inhibitors / pharmacology
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Signal Transduction
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Time Factors
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Transcription Factors / chemistry*
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Transcription Factors / metabolism
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Transfection
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Tumor Suppressor Proteins
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p300-CBP Transcription Factors
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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E2f1 protein, mouse
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Protein Synthesis Inhibitors
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Transcription Factors
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Tumor Suppressor Proteins
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Doxorubicin
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Cycloheximide
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Acetyltransferases
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Histone Acetyltransferases
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p300-CBP Transcription Factors
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p300-CBP-associated factor
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Cisplatin