ATM is a target for positive regulation by E2F-1.
The E2F-1 transcription factor is a critical downstream target of the tumor suppressor, RB. When activated, E2F-1 induces cell proliferation. In addition, deregulation of E2F-1 constitutes an oncogenic stress that can induce apoptosis. The protein kinase ATM is a pivotal mediator of the response to another type of stress, genotoxic stress. In response to ionizing radiation, ATM activates the tumor suppressor p53, a key player in the control of cell growth and viability. We show here that E2F-1 elevates ATM promoter activity and induces an increase in ATM mRNA and protein levels. This is accompanied by an E2F-induced increase in p53 phosphorylation. Expression of the E7 protein of HPV16, which dissociates RB/E2F complexes, also induces the elevation of ATM levels and p53 phosphorylation, implicating endogenous E2F in these phenomena. These data demonstrate that ATM is transcriptionally regulated by E2F-1 and suggest that ATM serves as a novel, ARF-independent functional link between the RB/E2F pathway and p53.
Berkovich
Eli
E
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Ginsberg
Doron
D
D016475:3T3 Cells / Q000166:cytology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins; D001665:Binding Sites; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; 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; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D002110:Caffeine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases