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1 Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven 06520; 2 Connecticut Veterans Affairs HealthCare System, West Haven, Connecticut 06516; 4 Division of Toxicological Sciences and Department of Environmental Health Sciences, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205; 5 Department of Molecular Genetics, Alton Ochsner Medical Foundation, and Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, New Orleans, Louisiana 70121; and 3 Division of Pulmonary and Critical Care Medicine, University of Arizona and Tucson Veterans Affairs Medical Center, Tucson, Arizona 85723
We have previously shown marked induction of the stress-inducible gene heme oxygenase-1 (HO-1) in vivo and in vitro after hyperoxia. In RAW 264.7 cells, HO-1 induction is transcriptionally regulated and dependent on cooperation between the HO-1 gene promoter and the 5' distal enhancer element SX2. In our present study, further deletional and mutational analyses demonstrate that signal transducer and activator of transcription (STAT) DNA binding sites located in the promoter of HO-1 and activator protein (AP)-1 DNA binding sites in the distal enhancer element SX2 are necessary for optimal HO-1 gene activation after hyperoxia. Interestingly, a second 5' distal enhancer element, AB1, located 10 kb upstream from the HO-1 promoter, alone is activated after hyperoxia but cannot confer maximal hyperoxia-induced HO-1 gene transcription. Mutational analysis of the AB1 enhancer shows that AP-1 is essential for AB1-mediated HO-1 gene transcription after hyperoxia. Electromobility shift assays show increased STAT1, STAT3, STAT5, and AP-1 DNA binding activity in RAW 264.7 cells after hyperoxia. Taken together, our data suggest that the 5' distal enhancer elements of the HO-1 gene in concert with the promoter regulate HO-1 gene induction and highlight the complexity of HO-1 gene transcription in response to hyperoxia.
signal transducer and activator of transcription; activator protein-1; gene regulation; oxidative stress; transcription factor; oxygen
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