HIF-1 signaling pathway

Hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix-PAS domain transcription factor, plays an integral role in the body's response to low oxygen concentrations, or hypoxia. It consists of two subunits: an oxygen-regulated α-subunit and a constitutively expressed β-subunit. It is expressed in all metazoan organisms. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxic conditions, HIF-1 regulates the transcription of hundreds of genes in a cell type–specific manner. The HIF-1α subunit is regulated by O2-dependent hydroxylation of proline residue 402, 564, or both, by prolyl hydroxylase domain protein 2 (PHD2), which promotes binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation; and O2-dependent hydroxylation of asparagine residue 803 by factor inhibiting HIF-1 (FIH-1), which blocks the binding of the 300-kilodalton coactivator protein (p300) and CREB binding protein (CBP). Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors.

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