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Type: Journal article
Title: Hypoxic Regulation of Vascular Endothelial Growth Factor mRNA Stability Requires the Cooperation of Multiple RNA Elements
Author: Dibbens, J.
Miller, D.
Damert, A.
Risau, W.
Vadas, M.
Goodall, G.
Citation: Molecular Biology of the Cell, 1999; 10(4):907-919
Publisher: American Society for Cell Biology (ASCB)
Issue Date: 1999
ISSN: 1059-1524
Statement of
J. A. Dibbens, D. L. Miller, A. Damert, W. Risau, M. A. Vadas and G. J. Goodall
Abstract: Vascular endothelial growth factor (VEGF) is a key regulator of developmental, physiological, and tumor angiogenesis. Upregulation of VEGF expression by hypoxia appears to be a critical step in the neovascularization of solid cancers. The VEGF mRNA is intrinsically labile, but in response to hypoxia the mRNA is stabilized. We have systematically analyzed the regions in the VEGF mRNA that are responsible for its lability under normoxic conditions and for stabilization in response to hypoxia. We find that the VEGF mRNA not only contains destabilizing elements in its 3' untranslated region (3'UTR), but also contains destabilizing elements in the 5'UTR and coding region. Each region can independently promote mRNA degradation, and together they act additively to effect rapid degradation under normoxic conditions. Stabilization of the mRNA in response to hypoxia is completely dependent on the cooperation of elements in each of the 5'UTR, coding region, and 3'UTR. Combinations of any of two of these three regions were completely ineffective in responding to hypoxia, whereas combining all three regions allowed recapitulation of the hypoxic stabilization seen with the endogenous VEGF mRNA. We conclude that multiple regions in the VEGF mRNA cooperate both to ensure the rapid degradation of the mRNA under normoxic conditions and to allow stabilization of the mRNA in response to hypoxia. Our findings highlight the complexity of VEGF gene expression and also reveal a mechanism of gene regulation that could become the target for strategies of therapeutic intervention.
Keywords: 3T3 Cells
Human Growth Hormone
Vascular Endothelial Growth Factors
Vascular Endothelial Growth Factor A
Endothelial Growth Factors
Recombinant Fusion Proteins
RNA, Messenger
3' Untranslated Regions
5' Untranslated Regions
Culture Media
Cell Hypoxia
Transcription, Genetic
Gene Expression Regulation
Genes, Reporter
Time Factors
Description: Copyright © 1999 by The American Society for Cell Biology
DOI: 10.1091/mbc.10.4.907
Appears in Collections:Aurora harvest
Medicine publications

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