Isoenzyme-specific regulation of genes involved in energy metabolism by hypoxia: similarities with the regulation of erythropoietin

Abstract

Recent studies have indicated that regulatory mechanisms underlying the oxygen-dependent expression of the haematopoietic growth factor erythropoietin are widely operative in non-erythropoietin-producing cells and are involved in the regulation of other genes. An important characteristic of this system is that the inducible response to hypoxia is mimicked by exposure to particular transition metals such as cobaltous ions, and by iron chelation. We have investigated the extent of operation of this system in the regulation of a range of genes concerned with energy metabolism. The effects of hypoxia (1% oxygen), cobaltous ions and desferrioxamine on gene expression in tissue-culture cells was studied using RNase protection assays. Hypoxia induced the expression of glucose transporters in an isoform-specific manner; GLUT-1 and GLUT-3 were induced by hypoxia, whereas expression of GLUT-2 was decreased. Isoenzyme-specific regulation by hypoxia was also observed for genes encoding phosphofructokinase, aldolase and lactate dehydrogenase. For all of these genes, responses to cobaltous ions and desferrioxamine correlated in both direction and magnitude with the response to hypoxia. In contrast, a reduction in mitochondrial transcripts was observed in hypoxia, but these changes were not mimicked by either cobaltous ions or desferrioxamine. These findings indicate that similarities with erythropoietin regulation extend to the oxygen-dependent regulation of genes encoding glucose transporters and glycolytic enzymes but not to the regulation of mitochondrial transcripts, and they show that in glucose metabolism regulation by this system is isoenzyme- or isoform-specific.

Oxygen sensing and signaling: impact on the regulation of physiologically important genes

“…The response to cobalt is not specific for the Epo gene or for Epo producing cells. For example, cobalt has been shown to mimic hypoxia in stimulating the expression of VEGF (Goldberg and Schneider, 1994;Ladoux and Frelin, 1994;Minchenko et al, 1994) and glycolytic enzymes (Firth et al, 1994;Semenza et al, 1994;Ebert et al, 1996) in a number of different types of cells Moreover, reporter gene experiments show that Epo's 3′ enhancer (discussed in detail below) is responsive to both hypoxia and cobalt in a variety of cell lines from different tissues (Maxwell et al, 1993). The fact that CO does not block the induction of Epo by cobalt or nickel (Goldberg et al, 1988;Huang et al, 1999) is consistent with the inability of cobalt and nickel substituted hemes to bind to CO.…”

Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival

“…Hypoxia has been recognized as a key factor involved in the regulation of a cascade of physiological responses such as erythropoiesis (Gopfert et al, 1996), glycolysis (Ebert et al, 1996), glucose transport (Tagaki et al, 1998), angiogenesis and vasodilatation (Griffiths et al, 1997;Carmeliet et al, 1998;Faller, 1999). A large group of genes that includes erythropoietin (Goldberg et al, 1988), nitric oxide synthase (Palmer et al, 1998), tyrosine hydroxylase (Norris and Millhorn, 1995), VEGF (Forsythe et al, 1996;Ema et al, 1997), lactate dehydrogenase, haem oxygenase, transferin receptor and others are regulated by hypoxia (Blancher and Harris, 1998).…”

The influence of nickel and cobalt on putative members of the oxygen‐sensing pathway of erythropoietin‐producing HepG2 cells

“…Cobalt and/ or nickel substituted for the hypoxic stimulus to induce endothelin-1 in early passages of human umbilical endothelial cells [3], the human phosphoglycerate kinase 1 and mouse lactate dehydrogenase A genes [4]. Cobalt and desferrioxamine increased the expression of mRNAs for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) A and B chains, placental growth factor (PLGF), transforming growth factor [5] and mRNAs encoding phosphofructokinase, aldolase, lactate de-hydrogenase and the glucose transporters GLUT-1 and GLUT-3 [6]. Ho and Bunn [7] have put forward the notion that iron and cobalt compete for the heme protein, since Hep3B cells incubated in low iron medium required less cobalt for EPO stimulation than those exposed to iron-enriched medium.…”