Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation.
Previous work has established a role for p53 in triggering apoptosis in response to DNA damage; p53 also induces apoptosis in response to deregulation of the Rb cell cycle pathway. The latter event is consistent with a role for the Rb-regulated E2F1 protein as a specific inducer of apoptosis and p53 accumulation. We now show that DNA damage leads to a specific induction of E2F1 accumulation, dependent on ATM kinase activity and that the specificity of E2F1 induction reflects a specificity in the phosphorylation of E2F1 by ATM as well as the related kinase ATR. We identify a site for ATM/ATR phosphorylation in the amino terminus of E2F1 and we show that this site is required for ATM-mediated stabilization of E2F1. Finally, we also show that E2F1 is required for DNA damaged induced apoptosis in mouse thymocytes. We conclude that the cellular response to DNA damage makes use of signals from the Rb/E2F cell cycle pathway.
Lin
W C
WC
Department of Genetics, Howard Hughes Medical Institute, Durham, North Carolina 27710, USA.
Lin
F T
FT
Nevins
J R
JR
D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002945:Cisplatin / Q000633:toxicity; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000633:toxicity; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005047:Etoposide / Q000633:toxicity; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D005047:Etoposide; D004317:Doxorubicin; C576897:Atr protein, mouse; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin