共查询到20条相似文献,搜索用时 62 毫秒
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Warnatz HJ Schmidt D Manke T Piccini I Sultan M Borodina T Balzereit D Wruck W Soldatov A Vingron M Lehrach H Yaspo ML 《The Journal of biological chemistry》2011,286(26):23521-23532
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Catalytic inactive heme oxygenase-1 protein regulates its own expression in oxidative stress 总被引:1,自引:0,他引:1
Lin QS Weis S Yang G Zhuang T Abate A Dennery PA 《Free radical biology & medicine》2008,44(5):847-855
Heme oxygenase-1 (HO-1) catalyzes the degradation of heme and forms antioxidant bile pigments as well as the signaling molecule carbon monoxide. HO-1 is inducible in response to a variety of chemical and physical stress conditions to function as a cytoprotective molecule. Therefore, it is important to maintain the basal level of HO-1 expression even when substrate availability is limited. We hypothesized that the HO-1 protein itself could regulate its own expression in a positive feedback manner, and that this positive feedback was important in the HO-1 gene induction in response to oxidative stress. In cultured NIH 3T3 cells, transfection of HO-1 cDNA or intracellular delivery of pure HO-1 protein resulted in activation of a 15-kb HO-1 promoter upstream of luciferase as visualized by bioluminescent technology and increased HO-1 mRNA and protein levels. These effects were independent of HO activity because an enzymatically inactive mutant form of HO-1 similarly activated the HO-1 promoter and incubation with HO inhibitor metalloporphyrin SnPP did not affect the promoter activation. In addition, HO-1-specific siRNA significantly reduced hemin and cadmium chloride-mediated HO-1 induction. Furthermore, deletion analyses demonstrated that the E1 and E2 distal enhancers of the HO-1 promoter are required for this HO-1 autoregulation. These experiments document feed-forward autoregulation of HO-1 in oxidative stress and suggest that HO-1 protein has a role in the induction process. We speculate that this mechanism may be useful for maintaining HO-1 expression when substrate is limited and may also serve to up-regulate other genes to promote cytoprotection and to modulate cell proliferation. 相似文献
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Redox regulation of the transcriptional repressor Bach1 总被引:4,自引:0,他引:4
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Endothelial heme oxygenase-1 induction by hypoxia. Modulation by inducible nitric-oxide synthase and S-nitrosothiols 总被引:11,自引:0,他引:11
Motterlini R Foresti R Bassi R Calabrese V Clark JE Green CJ 《The Journal of biological chemistry》2000,275(18):13613-13620
The stress protein heme oxygenase-1 (HO-1) is induced in endothelial cells exposed to nitric oxide (NO)-releasing agents, and this process is finely modulated by thiols (Foresti, R., Clark, J. E., Green, C. J., and Motterlini R. (1997) J. Biol. Chem. 272, 18411-18417). Here, we report that up-regulation of HO-1 in aortic endothelial cells by severe hypoxic conditions (pO(2) = 2 mm Hg) is preceded by increased inducible NO synthase and NO synthase activity. This effect is accompanied by oxidation of intracellular glutathione and formation of S-nitrosothiols. Incubation of cells with a selective inhibitor of inducible NO synthase (S-(2-aminoethyl)-isothiourea) or a NO scavenger ([2-(4-carboxyphenyl)-4,4,5, 5-tetramethylimidazoline-1-oxyl-3-oxide]) significantly attenuated the increase in heme oxygenase activity caused by reduced oxygen availability. A series of antioxidant agents did not prevent the elevation in heme oxygenase activity by hypoxia; however, the precursor of glutathione synthesis and thiol donor, N-acetylcysteine, completely abolished HO-1 induction. We also found that the hypoxia-mediated increase in endothelial heme oxygenase activity was potentiated by the presence of S-nitrosoglutathione. These results indicate that intracellular interaction of thiols with NO is an important determinant in the mechanism leading to HO-1 induction by reduced oxygen levels. We suggest that in addition to oxidative stress, HO-1 gene expression can be regulated by redox reactions involving NO and S-nitrosothiols (nitrosative stress), emphasizing a versatile role for the heme oxygenase pathway in the cellular adaptation to a variety of stressful conditions. 相似文献
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Marcel Kramer Christoph Sponholz Monique Slaba Bianka Wissuwa Ralf A. Claus Uwe Menzel Klaus Huse Matthias Platzer Michael Bauer 《PloS one》2013,8(10)
The single nucleotide polymorphism rs2071746 and a (GT)n
microsatellite within the human gene encoding heme oxygenase-1 (HMOX1) are associated with incidence or outcome in a variety of diseases. Most of these associations involve either release of heme or oxidative stress. Both polymorphisms are localized in the promoter region, but previously reported correlations with heme oxygenase-1 expression remain not coherent. This ambiguity suggests a more complex organization of the 5’ gene region which we sought to investigate more fully.We evaluated the 5‘ end of HMOX1 and found a novel first exon 1a placing the two previously reported polymorphisms in intronic or exonic positions within the 5’ untranslated region respectively. Expression of exon 1a can be induced in HepG2 hepatoma cells by hemin and is a repressor of heme oxygenase-1 translation as shown by luciferase reporter assays. Moreover, minigene approaches revealed that the quantitative outcome of alternative splicing within the 5’ untranslated region is affected by the (GT)n
microsatellite.This data supporting an extended HMOX1 gene model and provide further insights into expression regulation of heme oxygenase-1. Alternative splicing within the HMOX1 5'' untranslated region contributes to translational regulation and is a mechanistic feature involved in the interplay between genetic variations, heme oxygenase-1 expression and disease outcome. 相似文献
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Hock TD Liby K Wright MM McConnell S Schorpp-Kistner M Ryan TM Agarwal A 《The Journal of biological chemistry》2007,282(9):6875-6886
Heme oxygenase-1 is a highly inducible gene, the product of which catalyzes breakdown of the prooxidant heme. The purpose of this study was to investigate the regulation of the human heme oxygenase-1 gene in renal epithelial cells. DNase I hyper-sensitivity studies identified three distal sites (HS-2, -3, and -4) corresponding to approximately -4.0, -7.2, and -9.2 kb, respectively, of the heme oxygenase-1 promoter in addition to one proximal region, HS-1, which we have shown previously to be an E box. In vivo dimethyl sulfate footprinting of the HS-2 region revealed six individual protected guanines. Two mutations within HS-2 combined with a third mutation of the proximal E box abolished hemin- and cadmium-driven heme oxygenase-1 promoter activation, suggesting that these three sites synergized for maximal heme oxygenase-1 induction. Jun proteins bound to the antioxidant response element in the HS-2 region in vitro and associated with the heme oxygenase-1 promoter in vivo. JunB and JunD contribute opposing effects; JunB activated whereas JunD repressed heme oxygenase-1 expression in human renal epithelial cells, results that were corroborated in junB(-)(/)(-) and junD(-)(/)(-) cells. We propose that heme oxygenase-1 induction is controlled by a dynamic interplay of regulatory proteins, and we provide new insights into the molecular control of the human heme oxygenase-1 gene. 相似文献