Identification of a human VPF/VEGF 3' untranslated region mediating hypoxia-induced mRNA stability

Mol Biol Cell. 1998 Feb;9(2):469-81. doi: 10.1091/mbc.9.2.469.


Hypoxia is a prominent feature of malignant tumors that are characterized by angiogenesis and vascular hyperpermeability. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) has been shown to be up-regulated in the vicinity of necrotic tumor areas, and hypoxia potently induces VPF/VEGF expression in several tumor cell lines in vitro. Here we report that hypoxia-induced VPF/VEGF expression is mediated by increased transcription and mRNA stability in human M21 melanoma cells. RNA-binding/electrophoretic mobility shift assays identified a single 125-bp AU-rich element in the 3' untranslated region that formed hypoxia-inducible RNA-protein complexes. Hypoxia-induced expression of chimeric luciferase reporter constructs containing this 125-bp AU-rich hypoxia stability region were significantly higher than constructs containing an adjacent 3' untranslated region element without RNA-binding activity. Using UV-cross-linking studies, we have identified a series of hypoxia-induced proteins of 90/88 kDa, 72 kDa, 60 kDa, 56 kDa, and 46 kDa that bound to the hypoxia stability region element. The 90/88-kDa and 60-kDa species were specifically competed by excess hypoxia stability region RNA. Thus, increased VPF/VEGF mRNA stability induced by hypoxia is mediated, at least in part, by specific interactions between a defined mRNA stability sequence in the 3' untranslated region and distinct mRNA-binding proteins in human tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Cell Hypoxia / genetics*
  • Cloning, Molecular
  • DNA, Complementary / genetics
  • Endothelial Growth Factors / genetics*
  • Gene Expression Regulation, Neoplastic / genetics
  • Half-Life
  • Humans
  • Lymphokines / genetics*
  • Melanoma
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • RNA
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA, Neoplasm / chemistry
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • RNA-Binding Proteins / metabolism
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Sequence Analysis, DNA
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • DNA, Complementary
  • Endothelial Growth Factors
  • Lymphokines
  • RNA, Messenger
  • RNA, Neoplasm
  • RNA, recombinant
  • RNA-Binding Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • RNA

Associated data

  • GENBANK/AF022375