HIF hydroxylation and the mammalian oxygen-sensing pathway

Hypoxia refers to below-normal levels of oxygen in air, blood, or tissue.Tissue hypoxia leads to cellular dysfunction and ultimately can lead to cell death.Causes of tissue hypoxia include (a) decreased blood oxygenation (such as occurs in certain pulmonary disorders), (b) altered oxygen release from hemoglobin (associated with some hemoglobinopathies), and (c) impaired blood delivery leading to localized anemia (i.e., ischemia) as a result of low cardiac output or vascular obstruction.In order to adapt to hypoxia, mammals use a number of physiological responses.These include (a) increased production of erythropoietin (EPO), which augments the production of red blood cells; (b) induction of tyrosine hydroxylase, which facilitates the control of ventilation through the carotid body; and (c) the stimulation of new blood vessels by upregulation of VEGF (1).At the cellular level, hypoxia induces a number of metabolic changes that allow for continued energy generation despite decreased oxygen availability. Hypoxia-inducible factorOne of the most important factors in the cellular response to hypoxia is hypoxia-inducible factor (HIF), which transcriptionally activates genes encoding proteins that mediate adaptive responses to reduced oxygen availability.HIF is a heterodimer consisting of one of three α subunits (HIF1-α, HIF2-α, or HIF3-α) bound to the aryl hydrocarbon receptor nuclear translocator (ARNT), which is also known as HIF1-β.HIF-α is a member of the basic helix-loop-helix (bHLH) superfamily, in which the HLH domain mediates sub-unit dimerization while the basic domain binds to DNA.HIF-α, like some other bHLH family members, contains a Per/Arnt/Sim (PAS) domain that facilitates the heterodimerization of HIF-α with ARNT (2-4).HIF target genes play critical roles in metabolism, angiogenesis, cell proliferation, and cell survival.Examples of HIF target genes include VEGF, glucose transporter 1 (GLUT1), and EPO.HIF binds to the hypoxia-responsive element, which contains the core recognition sequence 5′-TACGTG-3′ (5), in the cis-regulatory regions of hypoxia-inducible genes.Transcriptional activation by HIF is linked to its ability to recruit coactivator proteins such as CREB-binding protein (CBP), p300, steroid receptor coactivator-1, and translation initiation factor 2 (6-8).Whereas changes in oxygen levels do not affect ARNT protein levels, hypoxia markedly increases the abundance of the HIF-α subunits (9-11).This increase is due primarily to protein stabilization.In some settings, hypoxia also leads to increased HIF1-α mRNA accumulation (12,13).von Hippel-Lindau disease von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome that affects approximately 1 in 35,000 individuals.The syndrome was first described in 1894 by Collins, who observed two siblings with bilateral retinal angiomas (now also called hemangioblastomas) (14).Later, the disease was mapped to chromosome 3p25 (15), and the VHL gene itself was isolated in 1993 (16).VHL behaves as a classical tumor suppressor gene.Almost all individuals with a clinical diagnosis of VHL disease can be shown to harbor a germline mutation of the VHL gene, with tumor development linked to somatic inactivation or loss of the remaining wild-type allele (17).The cardinal features of VHL disease are blood vessel tumors of the retina and central nervous system.Other tumors associated with VHL disease include clear cell carcinomas of the kidney, pheochromocytoma, endolymphatic sac tumors, pancreatic islet cell tumors, and papillary cystadenomas of the epididymis (in males) or broad ligament (in females) (18).In addition, patients with VHL often develop multiple visceral cysts involving organs such as the pancreas and kidneys (18).Biallelic VHL inactivation also occurs commonly in patients with sporadic hemangioblastoma or renal cell carcinoma,