Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents.
Recent work has indicated that oxygen-sensing mechanism(s) resembling those controlling erythropoietin production operate in many non-erythropoietin-producing cells. To pursue the implication that such a system might control other genes, we studied oxygen-regulated expression of mRNAs for vascular endothelial growth factor, platelet-derived growth factor (PDGF) A and B chains, placental growth factor (PLGF), and transforming growth factor in four different cell lines and compared the characteristics with those of erythropoietin regulation. Oxygen-regulated expression was demonstrated for each gene in at least one cell type. However, the response to hypoxia (1% oxygen) varied markedly, ranging from a 13-fold increase (PDGF-B in Hep G2 cells) to a 2-fold decrease (PLGF in the trophoblastic line BeWo). For each gene/cell combination, both the magnitude and direction of the response to hypoxia were mimicked by exposure to cobaltous ions or two different iron-chelating agents, desferrioxamine and hydroxypyridinones. These similarities with established characteristics of erythropoietin regulation indicate that a similar mechanism of oxygen sensing is operating on a variety of vascular growth factors, and they suggest that chelatable iron is closely involved in the mechanism.
Gleadle
J M
JM
Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
Ebert
B L
BL
Firth
J D
JD
Ratcliffe
P J
PJ
D043925:Angiogenesis Inducing Agents / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular; D015687:Cell Hypoxia; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology*; D003676:Deferoxamine / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004921:Erythropoietin / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006133:Growth Substances / Q000096:biosynthesis*; D006801:Humans; D008113:Liver Neoplasms; D008222:Lymphokines / Q000096:biosynthesis; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D000072483:Placenta Growth Factor; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D011257:Pregnancy Proteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D012342:RNA, Small Nuclear / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D043925:Angiogenesis Inducing Agents; D002614:Chelating Agents; D016228:Endothelial Growth Factors; D006133:Growth Substances; D008222:Lymphokines; C000608036:PGF protein, human; D010982:Platelet-Derived Growth Factor; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D012342:RNA, Small Nuclear; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004921:Erythropoietin; D000072483:Placenta Growth Factor; D003035:Cobalt; D003676:Deferoxamine