title: Hypoxia-inducible factor-1alpha enhances haptoglobin gene expression by improving binding of STAT3 to the promoter.
abstract: Haptoglobin (Hp) is known to play a role in angiogenesis as well as in anti-inflammation. STAT3 is a major transcription factor for expression of human Hp. We investigated whether hypoxia-inducible factor-1α (HIF-1α), a key mediator of angiogenesis, participates in Hp gene expression. HIF-1α overexpression by gene transfection or hypoxia augmented Hp transcription in HepG2 human hepatoma cells. Conversely, knockdown of HIF-1α by specific siRNA transfection diminished Hp expression, although the level of STAT3 phosphorylation remained unchanged. A luciferase reporter assay using mutant Hp promoters demonstrated that two adjacent DNA elements, a STAT3-binding element (SBE) and a cAMP-response element (CRE)-like site in human Hp promoter -120/-97, were required for HIF-1α-stimulated transactivation of the Hp gene. HIF-1α, STAT3, and p300/CBP were simultaneously bound to the SBE/CRE as a complex form. When HIF-1α was knocked down, STAT3 binding to the SBE in the Hp promoter was attenuated. Our findings suggest that HIF-1α assists STAT3 in strong binding to the proximal SBE in the Hp promoter. The CRE-like site located near the SBE may contribute to the formation of a stable complex of STAT3, HIF-1α, and p300/CBP, which leads to maximum transcription of the Hp gene.
authors.affiliation: Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Oh
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Nam-Hoon
authors.initials: NH
authors.lastname: Kim
authors.forename: Seon-Joo
authors.initials: SJ
authors.lastname: Park
authors.forename: In-Yang
authors.initials: IY
authors.lastname: Park
authors.forename: In-Sook
authors.initials: IS
authors.lastname: Kim
mesh_terms: D005786:Gene Expression Regulation / Q000502:physiology*; D006242:Haptoglobins / Q000096:biosynthesis* / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology; D010766:Phosphorylation; D020218:Response Elements / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; C485359:HP protein, human; D006242:Haptoglobins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050880:p300-CBP Transcription Factors