HIF1alpha

HIF-1alpha, or hypoxia-inducible factor 1 alpha, is a subunit of the transcription factor HIF-1, which mediates cellular responses to low oxygen. HIF-1 is a heterodimer consisting of HIF-1alpha and HIF-1beta (ARNT). HIF-1alpha is regulated by oxygen levels: under normal oxygen, it is hydroxylated by prolyl hydroxylases, recognized by the Von Hippel-Lindau (VHL) E3 ubiquitin ligase, ubiquitinated, and degraded. In hypoxia, hydroxylation is suppressed, stabilizing HIF-1alpha, which accumulates, translocates to the nucleus, and dimerizes with HIF-1beta. The complex binds hypoxia-response elements in target gene promoters and activates transcription.

Target genes include those driving angiogenesis (VEGF), erythropoiesis (EPO), and glycolytic metabolism (GLUT1, LDHA, and other glycolytic enzymes), as well as genes involved in cell survival and iron metabolism. Through these targets, HIF-1alpha promotes new blood vessel formation, metabolic reprogramming toward glycolysis, and adaptive responses to low oxygen.

Physiological roles span development, wound healing, and adaptation to hypoxic stress in tissues. In disease, HIF-1alpha is frequently dysregulated; overexpression is linked to tumor growth, invasion, and metastasis in many cancers and often associates with poorer prognosis. It also participates in ischemic responses and inflammatory processes. Because of its central role, the HIF pathway is a focus of therapeutic strategies for cancer, anemia, and ischemic diseases.

Genetics and regulation: HIF1A is the gene encoding HIF-1alpha. The protein can be post-translationally modified by hydroxylation, acetylation, and phosphorylation, and its activity is modulated by coactivators such as p300/CBP. Members of the HIF family, including HIF-2alpha, have overlapping yet distinct roles.