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Tytuł oryginału: Down-regulation of nuclear receptor DNA-binding activity by nitric oxide - HNF4 as a model system.
Autorzy: Vossen Christine, Erard Monique
Źródło: Med. Sci. Monitor 2002: 8 (10) s.RA217-RA220, il., bibliogr. 22 poz.
Sygnatura GBL: 313,278

Hasła klasyfikacyjne GBL:
  • genetyka

    Typ dokumentu:
  • tytuł obcojęzyczny

    Streszczenie angielskie: The numerous physiological roles of nitric oxide (NO) are currently teh focus of intensive research. A major pathway by which NO mediates its biological effects is via S-nitrosylation of cysteine residues, and a growing body of evidence suggests that transcription factors are critical targets for such S-nitrosylation. Here we review the ability of NO to down-regulate the activity of transcription factors, and in particular nuclear receptors. Among the latter, the hepatocyte nuclear factor HNF4 stands out as a key regulator of cytochrome P45 (CYP) gene expression. We report on a series fo experients which show that inflammation-induced NO production decreases CYP mRNA transcription, and that NO suppresses the DNA-binding ability of HNF4. Together these data suggest that cysteine-nitrosylation of teh HNF4 DNA-binding domain is the primary molecular mechanism responsible for teh drop in oxydase activities of hepatic cytochrome P450 enzyems, and the consequent impairment in drug metabolism during inflammation. In order to discuss this hypothesis from a structural perspective, we have built a homology-derived model of the HNFe DNA-binding domain and computer-simulated the S-nitrosylation of its cysteine residues. Finally, bearing in mind the structural conservation of the nuclear receptor DNA-binding domain, we discuss to what extent results from HNF4 can be extended to other nuclear receptors.

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