A molecular link between E2F-1 and the MAPK cascade.
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.
Wang
Jianli
J
Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Shen
Wen Hong
WH
Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Jin
Yan J
YJ
Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Brandt-Rauf
Paul W
PW
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032.
Yin
Yuxin
Y
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.
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
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