VEGF mRNA is stabilized by ras and tyrosine kinase oncogenes, as well as by UV radiation--evidence for divergent stabilization pathways.
Vascular Endothelial Growth Factor (VEGF) is a pivotal endothelial cell mitogen that mediates both normal and pathological angiogenesis. Although expressed at very low levels in cells not undergoing vascularization, VEGF mRNA is transiently upregulated and stabilized by a variety of extracellular stimuli, and is persistently upregulated and stabilized in many human tumor cell lines (White et al., 1995). Here we demonstrate that oncogenic activation of tyrosine protein kinases and Ras proteins induce a 6- to 16-fold increase in the abundance of VEGF mRNA and a 3- to 5-fold increase in the stability of VEGF mRNA, suggesting that persistent activation of signaling pathways induced by these oncoproteins accounts for overexpression of VEGF in a significant fraction of human tumors. In addition to these oncoproteins, ultraviolet (UV) radiation upregulated and stabilized VEGF mRNA 15- and 5-fold, respectively. While the tyrosine kinase inhibitor, genistein, blocked VEGF upregulation by activated tyrosine protein kinases, and the Ras inhibitor, N-Acetyl-S-trans-farnesyl-L-cysteine (AFC), eliminated VEGF expression in cells transformed by v-Ras, neither agent blocked upregulation by hypoxia or UV radiation. These data argue that multiple divergent pathways upregulate and stabilize VEGF mRNA.
White
F C
FC
Department of Pathology, UCSD School of Medicine, La Jolla 92093-0612, USA.
Benehacene
A
A
Scheele
J S
JS
Kamps
M
M
D016475:3T3 Cells; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics*; D011905:Genes, ras; D019833:Genistein; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007529:Isoflavones / Q000494:pharmacology; D008222:Lymphokines / Q000235:genetics*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins / Q000235:genetics; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018631:ras Proteins / Q000235:genetics / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007529:Isoflavones; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; C068268:N-acetyl-S-farnesylcysteine; D013755:Tetradecanoylphorbol Acetate; D000111:Acetylcysteine