Transcriptional regulation of human xanthine dehydrogenase/xanthine oxidase

Hoidal, John R.; Xu, Ping; Huecksteadt, Thomas P.; Sanders, Karl; Pfeffer, Kathleen D.

doi:10.1042/bst0250796

Cited by 15 publications

(5 citation statements)

References 3 publications

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“…The human XOR promoter carries putative HIF-1␣ and activator protein (AP-1) sites (13,44), known to mediate effects of changes in oxygen tension. To study the transcriptional activation of XOR, we prepared a set of constructs containing variable lengths of the human XOR promoter coupled to a luciferase reporter gene (Fig.…”

Section: Resultsmentioning

confidence: 99%

Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions

Linder

Martelin

Lapatto

et al. 2003

American Journal of Physiology-Cell Physiology

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O. Raivio. Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions. Am J Physiol Cell Physiol 285: C48-C55, 2003. First published March 12, 2003 10.1152/ajpcell.00561.2002 catalyzes the final reactions of purine catabolism and may account for cell damage by producing reactive oxygen metabolites in cells reoxygenated after hypoxia. We found a three-to eightfold higher XOR activity in cultured human bronchial epithelial cells exposed to hypoxia (0.5-3% O 2) compared with cells grown in normoxia (21% O 2) but no difference in XOR protein or mRNA. XOR promoter constructs failed to respond to hypoxia. The cellular XOR activity at 3% O 2 returned to basal levels when the cells were returned to 21% O 2, and hyperoxia (95% O2) abolished enzyme activity with no change in XOR protein.Our data suggest reversible enzyme inactivation by oxygen or its metabolites. NADH was normally oxidized by the oxygen-inactivated enzyme, which rules out damage to the flavin adenine dinucleotide cofactor. Hydrogen peroxide partially inactivated the molybdenum center of XOR, as shown by a parallel decrease in XOR-catalyzed xanthine oxidation and dichlorophenolindophenol reduction. We conclude that the transcription or translation of XOR is not influenced by hypoxia or hyperoxia. Instead, the molybdenum center of XOR is posttranslationally inactivated by oxygen metabolites in "normal" (21% O 2) cell culture atmosphere. This inactivation is reversed in hypoxia and accounts for the apparent induction. xanthine oxidase; hypoxia; hyperoxia; ischemia reperfusion

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Section: Resultsmentioning

confidence: 99%

Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions

Linder

Martelin

Lapatto

et al. 2003

American Journal of Physiology-Cell Physiology

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“…Hypoxia has been reported as the main transcriptional and post-translational regulator of XOR in several animal models. Putative binding sites for the oxygen-regulated transcription factors NF-Y, NF-B, AP-1 and HIF-1 have been identified in the promoter for the human XOR gene (Hoidal et al, 1997;Xu et al, 1996). Interferon-g is also a potent upregulator of XOR mRNA and activity in rat lung endothelium, in part because of increased transcription XOR (Dupont et al, 1992).…”

Section: Purine Metabolism Increases With Fastingmentioning

confidence: 99%

Prolonged fasting increases purine recycling in post-weaned northern elephant seals

Soñanez‐Organis

Vázquez‐Medina

Zenteno‐Savín³

et al. 2012

Journal of Experimental Biology

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SUMMARYNorthern elephant seals are naturally adapted to prolonged periods (1-2months) of absolute food and water deprivation (fasting). In terrestrial mammals, food deprivation stimulates ATP degradation and decreases ATP synthesis, resulting in the accumulation of purines (ATP degradation byproducts). Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) salvages ATP by recycling the purine degradation products derived from xanthine oxidase (XO) metabolism, which also promotes oxidant production. The contributions of HGPRT to purine recycling during prolonged food deprivation in marine mammals are not well defined. In the present study we cloned and characterized the complete and partial cDNA sequences that encode for HGPRT and xanthine oxidoreductase (XOR) in northern elephant seals. We also measured XO protein expression and circulating activity, along with xanthine and hypoxanthine plasma content in fasting northern elephant seal pups. Blood, adipose and muscle tissue samples were collected from animals after 1, 3, 5 and 7weeks of their natural post-weaning fast. The complete HGPRT and partial XOR cDNA sequences are 771 and 345bp long and encode proteins of 218 and 115 amino acids, respectively, with conserved domains important for their function and regulation. XOR mRNA and XO protein expression increased 3-fold and 1.7-fold with fasting, respectively, whereas HGPRT mRNA (4-fold) and protein (2-fold) expression increased after 7weeks in adipose tissue and muscle. Plasma xanthine (3-fold) and hypoxanthine (2.5-fold) levels, and XO (1.7-to 20-fold) and HGPRT (1.5-to 1.7-fold) activities increased during the last 2weeks of fasting. Results suggest that prolonged fasting in elephant seal pups is associated with increased capacity to recycle purines, which may contribute to ameliorating oxidant production and enhancing the supply of ATP, both of which would be beneficial during prolonged food deprivation and appear to be adaptive in this species.

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“…1), he might be XDH deficient. Unfortunately, family members antioxidant defense mechanisms [14], reactive oxygen species generated by XO, the oxidase form of the enzyme [15][16][17], have been implicated as mediators of cellular injury in a wide range of clinical conditions such as ische-DISCUSSION mia reperfusion [18], hypertension [19], and inflamma-Following the initial finding of a homozygous XDHtion [20,21]. XDH/XO is also involved in the metabolism linked haplotype, we identified a novel 1658insC mutaof N-heterocyclic compounds of pharmacological and tion in the XDH gene in a female patient affected by toxicological importance.…”

Section: The Forward Primer and The Pcr Reaction Conditionsmentioning

confidence: 99%

XDH gene mutation is the underlying cause of classical xanthinuria: A second report

Levartovsky¹,

Lagziel²,

Sperling³

et al. 2000

Kidney International

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A molecular approach to the diagnosis of classical xanthinuria type I in a female patient with profound hypouricemia is described. Linkage of xanthinuria to the XDH locus was demonstrated by homozygosity mapping, and a 1658insC mutation, predicting a truncated inactive XDH protein, was identified. These results reinforce the notion that mutations in the XDH gene are the underlying cause of classical xanthinuria type I.

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Transcriptional regulation of human xanthine dehydrogenase/xanthine oxidase

Cited by 15 publications

References 3 publications

Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions

Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions

Prolonged fasting increases purine recycling in post-weaned northern elephant seals

XDH gene mutation is the underlying cause of classical xanthinuria: A second report

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