Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing

Abstract

This article outlines the need for a homeostatic response to alterations in cellular oxygenation. It describes work on erythropoietin control that led to the discovery of the hypoxia-inducible transcription factor (HIF-1) and the parallel recognition that this system was responsive to a widespread oxygen-sensing mechanism. Subsequently, multiple HIF isoforms have been shown to have overlapping but non-redundant functions, controlling expression of genes involved in diverse processes such as angiogenesis, vascular tone, metal transport, glycolysis, mitochondrial function, cell growth and survival. The major role of prolyl and asparaginyl hydroxylation in regulating HIFs is described, as well as the identification of PHD1-3 and FIH as the oxygen-sensing enzymes responsible for these hydroxylations. Current understanding of other processes that modulate overall HIF activity, including influences from other signalling mechanisms such as kinases and nitric oxide levels, and the existence of a variety of feedback loops are outlined. The effects of some mutations in this pathway are documented as is knowledge of other substrates for these enzymes. The importance of PHD1-3 and FIH, and the large family of 2-oxoglutarate and iron(II)-dependent dioxygenases of which they are a part, in biology and medicine are discussed.

Identification of an AAA ATPase VPS4B-Dependent Pathway That Modulates Epidermal Growth Factor Receptor Abundance and Signaling during Hypoxia

“…To adapt to hypoxic conditions, cells typically activate HIF-1 to mediate gene transcription of a large number of genes and in particular those regulating cell metabolism (reviewed in reference 5). Accumulating reports have also suggested that there are hypoxic adaptations other than the HIF response (6,54,64,67). For example, there is evidence to support a functional role for the induction of a lysoanalyses, pairs of SKBR3:SKBR3/sh-VPS4B and NR6-EGFRvIII:NR6-EGFRvIII/sh-VPS4B cells were serum starved and treated with vehicle or EGF (100 ng/ml) for the indicated times prior to RNA isolation.…”

Curcumin suppresses HIF1A synthesis and VEGFA release in pituitary adenomas

“…To study the effect of hypoxia on VEGFA and HIF1A production, cells were treated with cobalt chloride (CoCl 2 ), a well-established substance used to mimic hypoxic conditions (Ebert & Bunn 1999, Masson & Ratcliffe 2003, Yuan et al 2003, Webb et al 2009). In a previous study, we have shown that CoCl 2 treatment and hypoxia (1% O 2 ) had similar effects on HIF1A and VEGFA production in pituitary tumour cells (Shan et al 2012).…”

“…Tumour neovascularisation is induced by intratumoural hypoxia, which leads to an increase in hypoxia inducible factor 1a (HIF1A), the regulated subunit of the transcription factor HIF1 (Harris 2002, Hickey & Simon 2006. The latter is composed of two subunits, the constitutively expressed HIF1B and HIF1A, which is absent under normoxic conditions but is rapidly up-regulated under hypoxia (Webb et al 2009) and stabilised in pituitary tumour cells by RSUME (Carbia-Nagashima et al 2007, Shan et al 2012. HIF1 regulates multiple genes to induce mechanisms to overcome cellular hypoxia; among them angiogenesis, a complex process in which multiple angiogenic factors induce, in a coordinated manner, the sprouting of new vessels from already existing ones and direct their growth into the expanding tumour (Carmeliet 2003).…”

RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells

“…It is composed of the constitutively expressed HIF-1b subunit, and the oxygen-regulated HIF-1a subunit. Although HIF-1a protein is continuously synthesised, it is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions (Jaakkola et al 2001, Appelhoff et al 2004, Wei & Yu 2007, Webb et al 2009). Thus, little or no heterodimeric HIF-1 protein is available under normoxia.…”

“…Thus, little or no heterodimeric HIF-1 protein is available under normoxia. However, when the oxygen availability declines, HIF-1a degradation is rapidly inhibited and thus intracellular HIF-1 protein levels strongly increase (Wei & Yu 2007, Webb et al 2009. HIF-1 then induces genes involved in multi-facetted actions in tissues that have impaired oxygen supply due to ischaemia of different origin (Hickey & Simon 2006).…”