dChan - Q Origins Project Archive

HYPOXIA INDUCIBLE FACTOR 1

HIF-1 is involved in embryonic development,15–17 tumour growth, metastasis,18,19 and apoptosis.12,20 HIF-1 is a heterodimer composed of the rate limiting factor HIF1α and the constitutively expressed HIF-1β.21 HIF-1β is also called the aryl hydrocarbon receptor nuclear translocator. It heterodimerises with several other factors, such as the Ahr transcription factor.22 HIF-1α is induced by hypoxia, and also by oncogenes, such as HER-2/neu, v-src, and ras, as reviewed by Semenza.23 The induction of HIF-1 by hypoxia takes place at the protein level, because HIF-1α mRNA expression remains unchanged. During normoxia, HIF-1α protein is expressed but is unstable. Rapid degradation of HIF-1 by the proteasome results from its ubiquitination by the product of the Von Hippel Lindau tumour suppressor gene (VHL). In patients with loss of the VHL gene, HIF-1α and HIF-1 dependent genes, such as angiogenesis factors, are also expressed during normoxia.24 Vascular tumours are often seen in these patients, who suffer from the von Hippel Lindau syndrome. The binding of HIF-1α to pVHL requires a modification of HIF-1α by proline hydroxylases in the oxygen dependent degradation domain (ODD) within the HIF-1α protein.25–27 These enzymes are oxygen dependent and therefore HIF-1α cannot be hydroxylated during hypoxia. In those circumstances, HIF-1α accumulates and is translocated to the nucleus. Here it binds to HIF-1β to form the active transcription factor HIF-1.

Stabilisation of HIF-1α by the ODD domain is not only caused by prolyl hydroxylases. HIF-1α becomes unstable when bound to p53.28 Jab1 (jun activation domain binding protein 1) directly interferes with the HIF-1α-p53 complex and leads to stabilisation of the HIF-1α protein during hypoxia.29

In addition to it regulation by stabilisation, HIF-1α is also regulated at the translational level. Recently, internal ribosome entry site (IRES) sequences were detected in the promoters of various hypoxia inducible genes, such as VEGF and HIF-1.30,31 During hypoxia, the translation of classic cap dependent mRNA transcription is reduced, and only mRNA containing an IRES sequence will be translated. To become active, HIF-1α complexes with HIF-1β. The HIF-1 complex can bind to hypoxia response element (HRE; 5′-RCGTG-3′) sequences in the promoter of HIF-1 target genes to initiate gene expression.32 Many genes regulated by HIF-1α are involved in several adaptive pathways including metabolism, angiogenesis, and survival to overcome hypoxic stress.1 However, in the presence of different environmental factors HIF-1 is involved in apoptosis.33

https://jcp.bmj.com/content/57/10/1009