HIF-1α

Abstract

Angiogenesis is regulated by the oxygen demand in local tissue, with the hypoxia-inducible factor-1 (HIF-1) being the primary factor mediating this response. HIF-1 is a transcriptional activator which is active in hypoxic environments. It is composed of two subunits, HIF-1α and HIF-1β. Under normal conditions, HIF-1α protein is constantly synthesized and degraded, a protective mechanism to help our body respond rapidly to hypoxic stress. In hypoxia, HIF-1α degradation is inhibited, this leads to the accumulation HIF-1α. The HIF complex then binds to hypoxia response elements resulting rapid increase in oxygen supply. For long-term adaptation, HIF pathway stimulates angiogenesis by regulating several pro-angiogenic genes such as angiopoietin-1, angiopoietin-2, Tie2, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and monocyte chemoattractant protein-1 (MCP-1). HIF-1α expression in cancer is linked with unfavourable prognosis which is mainly due to therapeutic resistance. There is a hypothesis that increased levels of HIF-1α has a selective advantage for tumor survival. This makes the HIF angiogenic pathway an attractive target for cancer therapies as it regulates several pro-angiogenic pathways.