Open AccessDiphenylene Iodonium Inhibits the Induction of Erythropoietin and Other Mammalian Genes by Hypoxia
Author(s) -
Gleadle Jonathan M.,
Ebert Benjamin L.,
Ratgliffe Peter J.
Publication year - 1995
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1995.092_c.x
Subject(s) - erythropoietin , hypoxia (environmental) , lactate dehydrogenase , mechanism of action , chemistry , vascular endothelial growth factor , gene expression , oxygen , glucose transporter , gene , biochemistry , medicine , biology , endocrinology , enzyme , vegf receptors , organic chemistry , insulin , in vitro
Recent studies on the induction of erythropoietin gene expression by hypoxia have indicated that erythropoietin forms part of a widely operative system of gene regulation by oxygen. Similar responses to hypoxia, cobaltous ions and desferrioxamine have indicated that the action of these agents is closely connected with the mechanism of oxygen sensing. To consider further the mechanisms underlying these responses, the effect of iodonium compounds was tested on five genes which show oxygen‐regulated expression; erythropoietin, vascular endothelial growth factor (VEGF), lactate dehydrogenase‐A (LDH‐A), glucose transporter‐1 (GLUT‐1) and placental growth factor (PLGF). In each case, the response to hypoxia was specifically inhibited by low doses of diphenylene iodonium (Ph 2 I + ). This occurred irrespective of whether the hypoxic response was induction of gene expression (erythropoietin, vascular endothelial growth factor, lactate dehydrogenase‐A, glucose transporter‐1) or inhibition of gene expression (PLGF). In contrast, the induction of gene expression by cobaltous ions or desferrioxamine was not inhibited by PhJ + . The differential action of Ph 2 I + on the response to hypoxia versus the response to cobaltous ions or desferrioxamine must reflect a difference in the mechanism of action of these stimuli, which will require accommodation in any model of the oxygen‐sensing mechanism. Based on the known properties of Ph 2 I + , the implication of these findings is that the mechanism of oxygen sensing most probably involves the operation of a flavoprotein oxidoreductase