Cell-specific and hypoxia-dependent regulation of human HIF-3α: inhibition of the expression of HIF target genes in vascular cells.
Hypoxia-inducible factors (HIF) are transcription factors responding to reduced oxygen levels and are of utmost importance for regulation of a widespread of cellular processes, e.g., angiogenesis. In contrast to HIF-1α/HIF-2α, the relevance of HIF-3α for the regulation of the HIF pathway in human vascular cells is largely unknown. HIF-3α mRNA increases under hypoxia in endothelial and vascular smooth muscle cells. Analysis of HIF-3α isoforms revealed a cell type-specific pattern, but only one isoform, HIF-3α2, is hypoxia-inducible. Reporter gene assays of the appropriate promoter localized a 31-bp fragment, mediating this hypoxic regulation. The contribution of HIF-1/2 and NFκB to the HIF-3α induction was verified. Functional studies focused on overexpression of HIF-3α isoforms, which decrease the hypoxia-mediated expression of VEGFA and Enolase2. These data support the notion of a hypoxia-induced inhibitory function of HIF-3α and demonstrate for the first time the existence of this negative regulation of HIF-signaling in vascular cells.
Department of Internal Medicine and Cardiology, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany. antje.augstein@tu-dresden.de
Antje
A
Augstein
David M
DM
Poitz
Rüdiger C
RC
Braun-Dullaeus
Ruth H
RH
Strasser
Alexander
A
Schmeisser
D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D016328:NF-kappa B; D020033:Protein Isoforms; D012097:Repressor Proteins; C116973:HIF3A protein, human