Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor

Bruick, Richard K.

doi:10.1101/gad.1145503

Cited by 399 publications

(321 citation statements)

References 95 publications

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“…HIF targets include members of stress-response gene families that mediate acute and chronic hypoxic adaptations, such as glucose transporters, glycolytic enzymes, angiogenic factors, haematopoietic growth factors, and molecules that affect cell growth, survival, and motility 4 , 130 , 136 ,137 . This panel has been adapted from a review article written by Bruick (2003 (A) Diagrammatic representation of the differentiation pathway that cytotrophoblast stem cells undertake in vivo. These cells detach from the underlying uterine basement membrane and either fuse to form multinucleated syncytiotrophoblasts or columns of mononuclear cells that attach the conceptus to the uterine wall.…”

Section: Box 2 Regulation Of Hypoxia-inducible Factor By O 2 Deprivationmentioning

confidence: 99%

“…A connection between mammalian embryogenesis and O 2 levels was first appreciated in the 1970s, when Morriss and New demonstrated that successful development of the neural fold by ex utero mouse embryos was dependent on the creation of low O 2 culture conditions 7 . Since then, discrete molecular mechanisms through which O 2 levels modulate embryonic development have been elucidated by the cloning and subsequent characterization of HIFs, dimeric transcription factors (see Boxes 1 and 2) that regulate many hypoxic responses in cells and tissues 1,8 . Genetic analysis of HIF function in multiple species and the multiple developmental defects exhibited by HIF-deficient embryos have revealed the importance of O 2 as a key regulator of ontogeny.…”

Section: Introductionmentioning

confidence: 99%

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The role of oxygen availability in embryonic development and stem cell function

Simon¹,

Keith²

2008

Nat Rev Mol Cell Biol

839

770

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Low levels of oxygen (O 2 ) occur naturally in developing embryos. Cells respond to their hypoxic microenvironment by stimulating several hypoxia-inducible factors (and other molecules that mediate O 2 homeostasis), which then coordinate the development of the blood, vasculature, placenta, nervous system, and other organs. Furthermore, embryonic stem and progenitor cells frequently occupy hypoxic 'niches' and low O 2 regulates their differentiation. Recent work has revealed an important link between factors involved in regulating stem/progenitor cell behaviour and hypoxiainducible factors, which provides a molecular framework for hypoxic control of differentiation and cell fate. These findings have important implications for the development of therapies for tissue regeneration and disease.

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Section: Box 2 Regulation Of Hypoxia-inducible Factor By O 2 Deprivationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The role of oxygen availability in embryonic development and stem cell function

Simon¹,

Keith²

2008

Nat Rev Mol Cell Biol

839

770

View full text Add to dashboard Cite

show abstract

“…These enzymes were identified on the principle that other mammalian PHDs such as those which target extracellular collagen were 2-oxoglutarate dependent [24], and it was predicted that the HIF PHDs would also belong to this family of enzymes. Based on conserved structural features [24], a candidate molecular approach was used to define HIF-modifying enzymes.…”

Section: Hif Is Protective For Mucosal Inflammationmentioning

confidence: 99%

Hypoxia and gastrointestinal disease

2007

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The gastrointestinal mucosa is a richly perfused vascular bed directly juxtaposed with the anaerobic and nonsterile lumen of the gut. As such, intestinal epithelial cells, which line the mucosa, experience a uniquely steep physiologic oxygen gradient in comparison with other cells of the body. Inflammation associated with a loss of epithelial barrier function and unregulated exposure of the mucosal immune system to luminal antigens leads to inflammatory bowel disease (IBD), a relatively common disorder with severe morbidity and a limited therapeutic repertoire. During IBD, increased tissue metabolism and vasculitis renders the chronically inflamed mucosa and particularly the epithelium hypoxic, giving rise to the activation of the hypoxia-responsive transcription factor hypoxia-inducible factor (HIF). Recent studies utilizing conditional intestinal epithelial hif1a-null mice have revealed a protective role for epithelial HIF-1α in murine models of IBD. Such protection occurs, at least in part, through HIF-dependent induction of barrier-protective genes in the epithelium. More recently, studies employing pharmacologic activation of HIF via inhibition of HIF prolyl hydroxylases revealed a profoundly protective effect of these agents in murine models of colitis. In this paper, we review this pathway in detail and examine the therapeutic potential for targeting HIF hydroxylases in intestinal mucosal inflammatory disease.

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“…There are several clinical trials involving pharmaceutical agents (Bevacizumab and Sunitinib) that are aimed at targeting VEGF secretion or inhibition of the VEGF receptor [7]. Hypoxia is a major regulator of angiogenesis, mediated in part via up-regulation of hypoxia-inducible factor (HIF)-1 α [8]. The purine nucleoside adenosine, released from hypoxic tissues, appears to be a key mediator in this pathway, accounting for up to 70% of hypoxiainduced angiogenesis in some situations [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A and A2B receptor expression in neuroendocrine tumours: potential targets for therapy

Kalhan

Gharibi

Vazquez

et al. 2011

Purinergic Signalling

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The clinical management of neuroendocrine tumours is complex. Such tumours are highly vascular suggesting tumour-related angiogenesis. Adenosine, released during cellular stress, damage and hypoxia, is a major regulator of angiogenesis. Herein, we describe the expression and function of adenosine receptors (A 1 , A 2A , A 2B and A 3 ) in neuroendocrine tumours. Expression of adenosine receptors was investigated in archival human neuroendocrine tumour sections and in two human tumour cell lines, BON-1 (pancreatic) and KRJ-I (intestinal). Their function, with respect to growth and chromogranin A secretion was carried out in vitro. Immunocytochemical data showed that A 2A and A 2B receptors were strongly expressed in 15/15 and 13/18 archival tumour sections. Staining for A 1 (4/18) and A 3 (6/18) receptors was either very weak or absent. In vitro data showed that adenosine stimulated a three-to fourfold increase in cAMP levels in BON-1 and KRJ-1 cells. The non-selective adenosine receptor agonist (adenosine-5′N-ethylcarboxamide, NECA) and the A 2A R agonist (CGS21680) stimulated cell proliferation by up to 20-40% which was attenuated by A 2B (PSB603 and MRS1754) and A 2A (SCH442416) receptor selective antagonists but not by the A 1 receptor antagonist (PSB36). Adenosine and NECA stimulated a twofold increase in chromogranin A secretion in BON-1 cells. Our data suggest that neuroendocrine tumours predominantly express A 2A and A 2B adenosine receptors; their activation leads to increased proliferation and secretion of chromogranin A. Targeting adenosine signal pathways, specifically inhibition of A 2 receptors, may thus be a useful addition to the therapeutic management of neuroendocrine tumours.

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Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor

Cited by 399 publications

References 95 publications

The role of oxygen availability in embryonic development and stem cell function

The role of oxygen availability in embryonic development and stem cell function

Hypoxia and gastrointestinal disease

Adenosine A2A and A2B receptor expression in neuroendocrine tumours: potential targets for therapy

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