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A Fenton Reaction at the Endoplasmic Reticulum Is Involved in the Redox Control of Hypoxia-Inducible Gene Expression

Liu, Qing ; Berchner-Pfannschmidt, Utta ; Möller, Ulrike ; Brecht, Martina ; Wotzlaw, Christoph ; Acker, Helmut ; Jungermann, Kurt ; Kietzmann, Thomas ; Forster, Robert E.

Proceedings of the National Academy of Sciences - PNAS, 2004-03, Vol.101 (12), p.4302-4307 [Periódico revisado por pares]

United States: National Academy of Sciences

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  • Título:
    A Fenton Reaction at the Endoplasmic Reticulum Is Involved in the Redox Control of Hypoxia-Inducible Gene Expression
  • Autor: Liu, Qing ; Berchner-Pfannschmidt, Utta ; Möller, Ulrike ; Brecht, Martina ; Wotzlaw, Christoph ; Acker, Helmut ; Jungermann, Kurt ; Kietzmann, Thomas ; Forster, Robert E.
  • Assuntos: Anatomy & physiology ; Biological Sciences ; Cell culture techniques ; Cell Nucleus - metabolism ; Cultured cells ; Endoplasmic Reticulum - metabolism ; Fluorescence ; Gene expression ; Gene Expression Regulation ; Genes, Reporter ; Hep G2 cells ; Humans ; Hypoxia ; Hypoxia - metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit ; In Vitro Techniques ; Messenger RNA ; Oxidation-Reduction ; Reactive oxygen species ; Rhodamine 123 - metabolism ; Rhodamines - metabolism ; Scavenging ; Transactivation ; Transcription Factors - genetics ; Transcription Factors - metabolism
  • É parte de: Proceedings of the National Academy of Sciences - PNAS, 2004-03, Vol.101 (12), p.4302-4307
  • Notas: ObjectType-Article-2
    SourceType-Scholarly Journals-1
    ObjectType-Feature-1
    content type line 23
    ObjectType-Article-1
    ObjectType-Feature-2
    Communicated by Robert E. Forster, University of Pennsylvania School of Medicine, Philadelphia, PA, January 13, 2004
    To whom correspondence should be addressed. E-mail: tkietzm@gwdg.de.
    Q.L. and U.B.-P. contributed equally to this work.
    Abbreviations: ·OH, hydroxyl radical; HIF-1, hypoxia-inducible factor 1; DHR, dihydrorho-damine; ER, endoplasmic reticulum; VHL, von Hippel–Lindau; TADx; transactivation domain x; ROS, reactive oxygen species; EPO, erythropoietin; HRE, hypoxia response element; ECFP, enhanced cyan fluorescent protein; RH, rhodamine; GM, Golgi membrane; 2P-CLSM, two-photon laser confocal microscopy.
    Deceased May 10, 2002.
  • Descrição: It has been proposed that hydroxyl radicals (·OH) generated in a perinuclear iron-dependent Fenton reaction are involved in O2-dependent gene expression. Thus, it was the aim of this study to localize the cellular compartment in which the Fenton reaction takes place and to determine whether scavenging of ·OH can modulate hypoxia-inducible factor 1 (HIF-1)-dependent gene expression. The Fenton reaction was localized by using the nonfluorescent dihydrorhodamine (DHR) 123 that is irreversibly oxidized to fluorescent rhodamine 123 while scavenging ·OH together with gene constructs allowing fluorescent labeling of mitochondria, endoplasmic reticulum (ER), Golgi apparatus, peroxisomes, or lysosomes. A 3D two-photon confocal laser scanning microscopy showed ·OH generation in distinct hot spots of perinuclear ER pockets. This ER-based Fenton reaction was strictly pO2-dependent. Further colocalization experiments showed that the O2-sensitive transcription factor HIF-1α was present at the ER under normoxia, whereas HIF-1α was present only in the nucleus under hypoxia. Inhibition of the Fenton reaction by the ·OH scavenger DHR attenuated HIF-prolyl hydroxylase activity and interaction with von Hippel-Lindau protein, leading to enhanced HIF-1α levels, HIF-1α transactivation, and activated expression of the HIF-1 target genes plasminogen activator inhibitor 1 and heme oxygenase 1. Further, ·OH scavenging appeared to enhance redox factor 1 (Ref-1) binding and, thus, recruitment of p300 to the transactivation domain C because mutation of the Ref-1 binding site cysteine 800 abolished DHR-induced transactivation. Thus, the localized Fenton reaction appears to impact the expression of hypoxia-regulated genes by means of HIF-1α stabilization and coactivator recruitment.
  • Editor: United States: National Academy of Sciences
  • Idioma: Inglês
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