OXYGEN-REGULATED CONTROL ELEMENTS IN THE PHOSPHOGLYCERATE KINASE-1 AND LACTATE-DEHYDROGENASE-A GENES - SIMILARITIES WITH THE ERYTHROPOIETIN3' ENHANCER

Production of the glycoprotein hormone erythropoietin (Epo) in respons e to hypoxic stimuli is almost entirely restricted to particular cells within liver and kidney, yet the transcriptional enhancer lying 3' to the Epo gene shows activity inducible by hypoxia after transfection i nto a wide variety of cultured cells. The implication of this finding is that many cells which do not produce Epo contain a similar, if not identical, oxygen regulated control system, suggesting that the same s ystem is involved in the regulation of other genes. We report that the human phosphoglycerate kinase 1 and mouse lactate dehydrogenase A gen es are induced by hypoxia with characteristics which resemble inductio n of the Epo gene. In each case expression is induced by cobalt, but n ot by cyanide, and hypoxic induction is blocked by the protein-synthes is inhibitor cycloheximide. We show that the relevant cis-acting contr ol sequences are located in the 5' flanking regions of the two genes, and we define an 18-bp element in the 5' flanking sequence of the phos phoglycerate kinase 1 gene which is both necessary and sufficient for the hypoxic response, and which has sequence and protein-binding simil arities to the hypoxia-inducible factor 1 binding site within the Epo 3' enhancer.