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Oxidative Stress Stimulates Testicular Orphan Receptor 4 through Forkhead Transcription Factor Forkhead Box O3a

George H. Whipple Laboratory for Cancer Research (G.L., Y.-F.L., S.L., Y.C., S.X., N.-C.L., B.-Y.B., C.C.), Departments of Pathology and Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14642; Department of Urology (G.L., Z.C.), Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; and School of Pharmacy (B.-Y.B.), China Medical University, Taihung 40402, Taiwan

Address all correspondence and requests for reprints to: Chawnshang Chang, George H. Whipple Laboratory for Cancer Research, University of Rochester, Pathology, Box 626, 601 Elmwood Avenue, Rochester, New York 14642. E-mail: chang{at}urmc.rochester.edu.

Early studies reveal that testicular orphan nuclear receptor 4 (TR4) modulates signaling pathways that control various cell functions. However, how TR4 activity is regulated without the involvement of specific ligand(s) remains unclear. Here we identify a daf-16 family protein-binding element (DBE; 5'-TGTTTAC-3') in the TR4 promoter that can be recognized by the forkhead transcriptional factor FOXO3a, a key stress-responsive factor, through which TR4 gene expression is activated. The interaction between DBE and FOXO3a was confirmed using EMSA and chromatin immunoprecipitation assays. Activation of FOXO3a by oxidative stress and phosphatidylinositol 3-kinase inhibitor induced TR4 expression; in contrast, suppression of FOXO3a by small interfering RNA can reduce oxidative stress-induced TR4 expression. The biological consequence of the FOXO3a-induced TR4 by oxidative stress is to protect against stress-induced cell death in which cells with reduced FOXO3a are less resistant to oxidative stress, and addition of functional TR4 can increase stress resistance. These results suggest that this new identified oxidative stress-FOXO3a-TR4 pathway is a fundamentally important mechanism regulating stress resistance and cell survival.