title: A molecular link between E2F-1 and the MAPK cascade.
abstract: Transcription factor E2F-1 mediates apoptosis and suppresses tumorigenesis. The mechanisms by which E2F-1 functions in these processes are largely unclear. We report here that E2F-1 acts as a transcriptional regulator of MKP-2 (MAPK phosphatase-2), a dual specificity protein phosphatase (DUSP4) with stringent substrate specificity for MAPKs. We show that E2F-1 is required for the cellular apoptotic response to oxidative damage. MKP-2 is greatly increased following oxidative stress, and E2F-1 is necessary for that induction. We found that E2F-1 is physically associated with the MKP-2 promoter and can transactivate the promoter of the MKP-2 gene. Specifically, E2F-1 binds to a perfect palindromic motif in the MKP-2 promoter. Finally, we show that this E2F-1/MKP-2 pathway mediates apoptosis under oxidative stress and that MKP-2 suppresses tumor formation in nude mice. Our findings demonstrate that E2F-1 is a transcriptional activator of MKP-2 and that MKP-2 is an essential cell death mediator in the E2F-1 pathway. Characterization of MKP-2 as a cell death mediator may lead to the development of new strategies for cancer treatment.
authors: Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
authors: Jianli
authors: J
authors: Wang
authors: Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
authors: Wen Hong
authors: WH
authors: Shen
authors: Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
authors: Yan J
authors: YJ
authors: Jin
authors: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032.
authors: Paul W
authors: PW
authors: Brandt-Rauf
authors: Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032. Electronic address: yy151@columbia.edu.
authors: Yuxin
authors: Y
authors: Yin
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D054637:Dual-Specificity Phosphatases; D050687:E2F1 Transcription Factor / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D054639:Mitogen-Activated Protein Kinase Phosphatases; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D050687:E2F1 Transcription Factor; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054648:Protein Phosphatase 2; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases; C522186:Dusp4 protein, mouse; D017027:Protein Tyrosine Phosphatases