Identification of a cis-acting element that is responsible for cadmium-mediated induction of the human heme oxygenase gene.

Takeda, Kazuhisa; Ishizawa, S.; Sato, Michihiko; Yoshida, Tadashi; Shibahara, Shigeki

doi:10.1016/s0021-9258(17)31724-6

Cited by 123 publications

(11 citation statements)

References 46 publications

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“…A potential cadmium response element has been identified 5Ј to the transcriptional initiation site of the human HO-1 gene, between Ϫ4.5 and Ϫ4 kb (84). In the mouse HO-1 gene, Alam et al (86) have described two distal enhancers, one at Ϫ4.0 and another at Ϫ10 kb, that are required for induction of HO-1 in response to heme, heavy metals, hydrogen peroxide, and sodium arsenite.…”

Section: Molecular Regulation Of Ho-1mentioning

confidence: 99%

Renal Response to Tissue Injury

Agarwal

Nick

2000

Journal of the American Society of Nephrology

238

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Abstract. Heme oxygenase-1 (HO-1) is a microsomal enzyme involved in the degradation of heme, resulting in the generation of biliverdin, iron, and carbon monoxide. Recent attention has focused on the biologic effects of product(s) of this enzymatic reaction that have important antioxidant, anti-inflammatory, and cytoprotective functions. Induction of HO-1 occurs as an adaptive and beneficial response to a wide variety of oxidant stimuli, including heme, hydrogen peroxide, cytokines, growth factors, heavy metals, nitric oxide, and oxidized LDL. HO-1 has been implicated in several clinically relevant disease states, including transplant rejection, hypertension, acute renal injury, atherosclerosis, and others. Previous studies indicate a protective role for HO-1 in heme and non-heme-mediated models of acute renal injury using chemical inducers and inhibitors of HO-1. Studies in HO-1 knockout mice further corroborate these observations, highlighting the important role of HO-1 in the pathophysiology of acute renal injury. Expression of HO-1 has been linked to prolonged xenograft survival and is important in transplant rejection as well. More recently, the first known case of human HO-1 deficiency was reported with several phenotypical similarities to the mouse HO-1 knockout. The role of HO-1 has extended far beyond its initial description as an enzyme involved in heme degradation to being an important mediator in modulating adaptive and protective responses not only in renal injury, but in other organ systems as well.

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Section: Molecular Regulation Of Ho-1mentioning

confidence: 99%

Renal Response to Tissue Injury

Agarwal

Nick

2000

Journal of the American Society of Nephrology

238

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“…As such, it would be enlightening to have knowledge of any key factors, such as nutritive constituents present intracellularly, that could potentially influence the ability of cells to optimally express HO-1 upon cadmium exposure. It is well established that adequately nourished cells, which would be achieved when cells are cultured in media containing adequate amounts of all vital nutrients, have the ability to robustly express HO-1 upon exposure to cadmium, as exemplified by two previous studies (Takeda et al, 1994;Elbekai and El-Kadi, 2007). However, it is entirely unknown if cells can optimally express HO-1 when the cells are deficient in a single micronutrient and exposed to cadmium to induce HO-1.…”

Section: Discussionmentioning

confidence: 99%

“…How adequate amounts of iron enable cells to fully express HO-1 upon induction by cadmium exposure is not completely clear. But, the generation of ROS to function as signaling oxidants appears paramount considering that the HO-1 gene, which contains a stress response element (Alam and Cook, 2003), is activated when cells are exposed to stress-inducing agents (Li et al, 2006;Tyrrell, 2004;Chin et al, 2003;Takeda et al, 1994;Elbekai and El-Kadi, 2007) that typically induce ROS generation. A potential source of such ROS may come from the reaction catalyzed by non-phagocytic isoforms of NOX that are expressed in different tissues (Takeya and Sumimoto, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…To cope with the situation, cells express cytoprotective genes, such as heme oxygenase-1 (HO-1). Some inducers of HO-1 include strong oxidants (Li et al, 2006), UV radiation (Tyrrell, 2004), chemical carcinogens (Chin et al, 2003), and heavy metals (Takeda et al, 1994;Elbekai and El-Kadi, 2007). The HO-1 gene codes for a microsomal enzyme that catalyzes the degradation of heme to three main products (Kikuchi et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…For example, iron and cadmium are normally regarded as a vital micronutrient commonly deficient in humans (Zimmermann and Hurrell, 2007) and as a toxic environmental pollutant (Bertin and Averbeck, 2006), respectively. At certain concentrations (less than 100 µM), iron (i.e., Fe ++ ions) has not been demonstrated by anyone to significantly induce HO-1 in cells, whereas cadmium (i.e., Cd ++ ions) stimulates ROS production (Chen et al, 2008) and HO-1 gene activation (Takeda et al, 1994;Elbekai and El-Kadi, 2007). It is unclear whether these two effects of cadmium require iron, specifically in adequate amounts as a nutritive cellular component, in order to happen.…”

Section: Introductionmentioning

confidence: 99%

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Cellular iron depletion weakens induction of heme oxygenase-1 by cadmium

Lai

Loo

2011

The International Journal of Biochemistry & Cell Biology

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Heme oxygenase-1 is an inducible cytoprotective gene, although its induction by environmental factors is not completely understood. This study aimed to ascertain if specific nutritive factors or related compounds influence heme oxygenase-1 expression. In HCT-116 cells, cadmium increased heme oxygenase-1 enzymatic activity. This effect of cadmium was weaker in cells made iron-deficient with the iron chelator, desferrioxamine, which was associated with repression of heme oxygenase-1 protein and mRNA expression. The repression by desferrioxamine of cadmium-induced heme oxygenase-1 upregulation was reversed upon iron replenishment of the cells. Additionally, it was found that thiol antioxidants inhibited the heme oxygenase-1 upregulation caused by cadmium and also by ethacrynic acid, which each decreased intracellular glutathione as did buthionine sulfoxamine. Interestingly, cadmium and ethacrynic acid increased nuclear translocation of Nrf2 and subsequent heme oxygenase-1 expression, but buthionine sulfoxamine did not. Furthermore, NADPH oxidase inhibitors (diphenyleneiodonium and apocynin, and a superoxide scavenger (Tiron) inhibited cadmium-induced upregulation of heme oxygenase-1. Diphenyleneiodonium was the most potent and inhibited NADPH-cytochrome P450 reductase as well, whereas apocynin and Tiron did not. It is concluded that adequate amounts of iron, which at the atomic level can serve as the pivotal element of heme in NADPH oxidase, must be present in cells to permit what appears to be thiol redox-sensitive, NADPH oxidase-dependent upregulation of heme oxygenase-1. Thus, these findings are significant because they suggest that cells without adequate iron would be unable to fully express the stress gene, heme oxygenase-1, when confronted with the toxic metal, cadmium.

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Functional Analysis of the Heme Oxygenase‐1 Gene Promoter

Alam

2000

CP Toxicology

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Basal and inducer-dependent transcription activity of the heme oxygenase-1 gene promoter can be measured using the luciferase reporter gene in transfection assays. Methods are provided in this unit for purification of plasmid DNA, transient and stable transfection of DNA into cells, and measurement of luciferase and beta-galactosidase enzyme activities using chemiluminescent-based assays. These protocols can be used to identify inducer-activated cis elements.

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Identification of a cis-acting element that is responsible for cadmium-mediated induction of the human heme oxygenase gene.

Cited by 123 publications

References 46 publications

Renal Response to Tissue Injury

Renal Response to Tissue Injury

Cellular iron depletion weakens induction of heme oxygenase-1 by cadmium

Functional Analysis of the Heme Oxygenase‐1 Gene Promoter

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