期刊
FASEB JOURNAL
卷 24, 期 9, 页码 3239-3254出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-144592
关键词
oxidative stress; antioxidants; bile pigments; cytokines; heme oxygenase; HIF-1
资金
- NIEHS NIH HHS [R01 ES004066, R01 ES012187-08, R01 ES012187, R01 ES004066-26] Funding Source: Medline
hBVR is a Ser/Thr/Tyr kinase/scaffold protein/transcription factor/intracellular transporter of regulators. hBVR is an upstream activator of the insulin/IGF-1/MAPK/PI3K signaling pathway, and of NF-kappa B. As a reductase, it converts biliverdin to the antioxidant, bilirubin. hBVR gene has 8 exons; exon 1 is not translated. We report the characterization of hBVR promoter and its negative and positive regulation, respectively, by TNF-alpha and hypoxia. The 5' end of exon 1 was defined by primer extension analyses; deletion of an inhibitor sequence 350-425 bp upstream of this exon enhanced the promoter activity. One of two NF-kappa B binding sites in the 836-bp promoter was functional; the P65 subunit of NF-kappa B and TNF-alpha acted as inhibitors. On the basis of EMSA and ChIP assays, TNF-alpha treatment increases binding of NF-kappa B to its regulatory element. Overexpression of I kappa B increased hBVR mRNA. Biliverdin, but not bilirubin, was as effective as TNF-alpha in inhibiting hBVR promoter activity. Only one of 4 hypoxia responsive elements (HREs) bound to HIF-1 alpha and ARNT expressed in HEK293A cells. An abasic site was introduced at the 3' G of the HRE. This element bound HIF-1 in the gel shift and in in-cell luciferase assays. hBVR was detected in the nucleus at 1, 2, and 4 h after hypoxia (1% O-2), at which times its kinase and reductase activities were increased. Because hypoxia positively influences hBVR promoter and phosphorylation and TNF-alpha activated NF-kappa B inhibits the promoter, while biliverdin inhibits both NF-kappa B activity and hBVR promoter, we propose a regulatory mechanism for NF-kappa B by hypoxia and TNF-alpha centered on hBVR/biliverdin.-Gibbs, P. E. M., Miralem, T., Maines, M. D. Characterization of the human biliverdin reductase gene structure and regulatory elements: promoter activity is enhanced by hypoxia and suppressed by TNF-alpha-activated NF-kappa B. FASEB J. 24, 3239-3254 (2010). www.fasebj.org
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据