A novel promoter element containing multiple overlapping xenobiotic and hypoxia response elements mediates induction of cytochrome P4502S1 by both dioxin and hypoxia.
Cytochrome P4502S1 (CYP2S1) is expressed at high levels in epithelial tissues and is inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) via the aryl hydrocarbon receptor (AHR). Transcriptional initiation of mouse Cyp2s1 was found to occur at three regions, approximately 198, 102, and 22 nucleotides from the translational initiation codon. Approximately 400 nucleotides upstream of its translational initiation codon, mouse Cyp2s1 contains three overlapping xenobiotic-responsive element (XRE) sequences, which make a major contribution toward dioxin inducibility. Each XRE sequence in this trimeric XRE can bind the AHR/aryl hydrocarbon receptor nuclear translocator (ARNT) dimer in a dioxin-dependent fashion in vitro and can mediate dioxin-dependent transcription. Cyp2s1 is also markedly inducible by hypoxia. Induction is dependent on hypoxiainducible factor-1 (HIF-1) and is mediated in large part by three overlapping hypoxia response elements (HREs) embedded within the trimeric XRE segment. Although each HRE within this segment can bind HIF-1alpha/ARNT in vitro, the most 3' HRE contributes the most toward hypoxia inducibility. AHR/ARNT and HIF-1alpha/ARNT dimers bind to the region containing the trimeric XRE segment of the endogenous Cyp2s1 gene in vivo in a dioxin-dependent fashion and hypoxia-dependent fashion, respectively. These observations identify a novel regulatory cassette that mediates changes in Cyp2s1 expression.
Rivera
Steven P
SP
Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
Wang
Feng
F
Saarikoski
Sirkku T
ST
Taylor
Robert T
RT
Chapman
Brett
B
Zhang
Ruixue
R
Hankinson
Oliver
O
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004147:Dioxins / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020218:Response Elements; D015262:Xenobiotics / Q000494:pharmacology*
D004147:Dioxins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; C422564:CYP2S1 protein, human