No abstract

Both hypoxia and insulin induce common target genes, including vascular endothelial growth factors and several glycolytic enzymes. However, these two signals eventually trigger quite different metabolic pathways. Hypoxia induces glycolysis, resulting in anaerobic ATP production, while insulin increases glycolysis for energy storage. Hypoxia-induced gene expression is mediated by the hypoxia-inducible factor-1 ( As oxygen levels decrease, cells generate ATP mainly from anaerobic glycolysis in the cytoplasm since the lack of oxygen diminishes the oxidative phosphorylation pathway in mitochondria. The hypoxic cells enhance glucose utilization by increasing transcription of glucose transporter proteins (Glut-1 and -3) 1 and several glycolytic enzymes. Other genes involved in systemic responses to prolonged hypoxic stress include vascular endothelial growth factor (VEGF), which induces blood vessel formation at hypoxic sites; erythropoietin, which elevates the production of red blood cells; and inducible nitricoxide synthase, which induces vasodilation (1). These diverse target genes are induced by a common transactivator, hypoxiainducible factor 1 (HIF-1). HIF-1 is composed of two subunits, HIF-1␣ and Arnt, both of which contain a basic-helix-loop-helix (bHLH) domain and Per, Arnt, AhR, Sim (PAS) domains. Recent studies demonstrated that hydroxylation of HIF-1␣ at the 564 proline residue is catalyzed by HIF-1␣ proline hydroxylase using molecular oxygen as the substrate. The tumor suppressor von Hippel-Lindau (VHL) protein specifically interacts with hydroxylated HIF-1␣ and mediates the assembly of a complex that activates a ubiquitin-dependent proteasome. Ubiquitinated HIF-1␣ is degraded by the proteasome. When cells lack oxygen, proline is not hydroxylated, and therefore HIF-1␣ protein is accumulated (2-5). Stabilized HIF-1␣ protein translocates into nuclei and makes a heterodimer with its partner Arnt. The HIF-1␣/Arnt heterodimer specifically contacts the hypoxia-responsive elements (HREs: -ANACGTGC-), recruits their coactivator p300/CBP, and increases transcription of their target genes. It is expected that the basic region of Arnt contacts CGTG sequences, whereas HIF-1␣ determines the half-site specificity of HRE (6).Besides hypoxia, the nutritional state and hormones of the cell also regulate transcription of many glycolytic enzymes required for maintaining metabolic homeostasis. Insulin plays a central role in regulating the metabolic pathways associated with energy storage and utilization. It triggers the conversion of glucose into glycogen and triglycerides and inhibits gluconeogenesis. Insulin has been known to modulate cellular metabolism by modifying the activity or changing the cellular location of preexisting enzymes. Recently the regulation of gene expression by insulin has been recognized as a major function of this hormone (7). Insulin increases the transcription of fatty-acid synthase and acetyl-CoA synthetase, both of which are involved in lipogenesis. Insulin also increases the transcription of Gl...

No abstract