Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1.
Hypoxia regulates expression of vascular endothelial growth factor (VEGF) by increasing its transcription and by stabilizing its mRNA. Despite the pivotal role of hypoxia-inducible factor 1 (HIF-1) in transcriptional activation of hypoxia-responsive genes, it is not known whether HIF-1 mediates hypoxia-induced stabilization of VEGF mRNA. We constructed adenoviral vectors expressing either the wild-type HIF-1 alpha (Ad2/HIF-1 alpha/FL), a constitutively stable hybrid form of HIF-1 alpha (Ad2/HIF-1 alpha/VP16), or no transgene (Ad2/CMVEV). In rat glioma (C6) cells and human cardiac, vascular smooth muscle, and endothelial cells, infection with Ad2/HIF-1 alpha/VP16 or Ad2/HIF-1 alpha/FL increased VEGF expression at both the mRNA and protein levels. Under normoxic conditions, the half-life of VEGF mRNA was 42 min in C6 cells. Hypoxia and Ad2/HIF-1 alpha/VP16 increased the half-life of VEGF mRNA to 3.3 and 2.7 h, respectively, while Ad2/CMVEV had no effect. These studies are the first to demonstrate that overexpression of HIF-1 alpha increases VEGF mRNA stability. Our results also suggest that stabilization of VEGF mRNA by hypoxia is mediated, at least in part, by HIF-1.
Liu
Louis X
LX
Genzyme Corporation, 31 New York Avenue, Framingham, Massachusetts 01701, USA.
Lu
Hsienwie
H
Luo
Yuxia
Y
Date
Taro
T
Belanger
Adam J
AJ
Vincent
Karen A
KA
Akita
Geoffrey Y
GY
Goldberg
Mark
M
Cheng
Seng H
SH
Gregory
Richard J
RJ
Jiang
Canwen
C
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D005822:Genetic Vectors; D006207:Half-Life; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007700:Kinetics; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors