Complex role of protein phosphorylation in gene activation by hypoxia

Complex role of protein phosphorylation in gene activation by hypoxia. Mammalian cells are able to sense decreased oxygen tension in their environment and turn-on the expression of specific hypoxia responsive genes. The best studied of these hypoxia regulated genes is the one that encodes for erythropoietin, the glycoprotein hormone that regulates red cell production [1]. The response of the erythropoietin gene to hypoxia is mediated by an enhancer sequence located at the 3′ flanking region of the gene [2–4]. A hypoxia inducible DNA-binding protein complex, termed HIF-1, regulates the transcriptional function of the erythropoietin enhancer [5]. Most interestingly, identical HIF-1 complexes also control the responses of other hypoxia regulated genes, in what appears to be a general mechanism of oxygen sensing and response [6, 7]. These other hypoxia regulated genes include vascular endothelial growth factor, glycolytic enzymes such as pyruvate kinase and aldolase A, glucose transporter 1 and endothelin, among others. All these genes are transcriptionally activated by hypoxia and also by transition metals such as cobalt (Co) and by iron chelators such as desferrioxamine (Dfx) [reviewed in 8]