Genetic Analysis of the Role of the Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-inducible Factor (HIF) in Regulating HIF Transcriptional Target Genes

Stolze, Ineke; Tian, Ya-Min; Appelhoff, Rebecca J.; Turley, Helen; Wykoff, Charles C.; Gleadle, Jonathan; Ratcliffe, Peter J.

doi:10.1074/jbc.m406713200

Cited by 149 publications

(165 citation statements)

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“…During hypoxia, when oxygen is limiting, FIH is unable to efficiently catalyse the hydroxylation of the CAD, enabling binding of CBP/p300 to the non-hydroxylated CAD and transactivation of target genes oxygen concentration, whereas the PHDs were found to be inactive under the same conditions. 34 However, more recent studies using larger peptides suggest that the K m of FIH-1 for oxygen in vitro is closer to 250 mM like the PHDs, depending on the length of peptide used. 35 More importantly, cell-based assays examining the activity of endogenous FIH-1 and the PHDs indicate that FIH-1 was less sensitive to decreasing oxygen levels than the PHDs in some cell types, whereas in other cells types it was more sensitive, thus demonstrating that the oxygen-dependent sensitivity of FIH-1 can vary between different cell types independently of the PHDs.…”

Section: Oxygen-dependent Regulation Of Hif-cad By Fih-1mentioning

confidence: 99%

“…36 Localisation and Expression of FIH FIH-1 protein expression has been detected at similar levels in all tissue culture cell lines investigated to date. 34,36 Immunohistochemical interrogation of an extensive range of human tissues revealed widespread and predominantly cytoplasmic staining of varying intensity for FIH-1 protein. 42 During normoxia, FIH-1 is localised predominantly in the cytoplasm, and is available for modification and silencing of HIF-a.…”

Section: Oxygen-dependent Regulation Of Hif-cad By Fih-1mentioning

confidence: 99%

“…Treatment of cultured cells with hypoxia or hypoxia mimetics does not appear to alter the cytoplasmic localisation of FIH-1. 34,40,43 Other FIH-1 Substrates and HIF Regulation…”

Section: Oxygen-dependent Regulation Of Hif-cad By Fih-1mentioning

confidence: 99%

“…Although the authors argue that it represents a hypoxia-dependent degradation mechanism for FIH-1 and thus a way of enhancing HIF transactivation under oxygen stress, there is no discernable increase in FIH-1 protein levels in hypoxia in this or previous studies. 34,47 A novel mechanism of regulation of FIH-1 transcription in renal carcinoma cells has been put forth following an earlier finding that FIH-1 message was increased with knockdown of protein kinase C-z (PKCz), or overexpression of a dominantnegative form. 48 Li and co-workers identified a cis-regulatory element in the FIH-1 promoter that binds phosphorylated CDP/Cut proteins and thus represses transcription.…”

Section: Regulation Of Fih-1mentioning

confidence: 99%

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Turn me on: regulating HIF transcriptional activity

2008

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The hypoxia-inducible factors (HIFs) are critical for cellular adaptation to limiting oxygen and regulate a wide array of genes when cued by cellular oxygen-sensing mechanisms. HIF is able to direct transcription from either of two transactivation domains, each of which is regulated by distinct mechanisms. The oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF-1a (FIH-1) is a key regulator of the HIF C-terminal transactivation domain, and provides a direct link between oxygen sensation and HIFmediated transcription. Additionally, there are phosphorylation and nitrosylation events reported to modulate HIF transcriptional activity, as well as numerous transcriptional coactivators and other interacting proteins that together provide cell and tissue specificity of HIF target gene regulation. The maintenance of oxygen homeostasis is a crucial physiological requirement that involves coordinated regulation of a plethora of genes. The hypoxia-inducible transcription factors (HIFs) are responsible for a major genomic response to hypoxia, where cellular oxygen demand exceeds supply. The HIFs directly regulate the transcription of more than 70 genes involved in cellular processes that act to directly address this deficit by decreasing oxygen dependence and consumption by cells, and by increasing the efficiency of oxygen delivery to cells. These processes include vasculogenesis and angiogenesis, metabolism, vasodilation, cell migration, signalling and cell fate decisions. As such, the HIFs are fundamental to embryonic development and the pathophysiology of many serious human diseases, and are therefore subject to strict regulatory mechanisms that act to limit transcriptional activity to periods of cellular oxygen stress. The HIF proteins are subject to oxygen-dependent regulation, both at the level of protein stability (reviewed in this issue by R Bruick) and transcriptional activity, rendering them almost inactive at normoxia, but potently inducible in hypoxia. The regulation of the transcriptional activity of the HIF proteins, both via oxygen-dependent and oxygen-independent mechanisms, will be discussed in this review. The HIFsHIF is assembled from a-and b-subunits to become a transcriptionally active heterodimer. 1 Both subunits are members of the bHLH/PAS (basic helix-loop-helix/Per-ArntSim homology) family of transcription factors, and both contain transactivation domains (Figure 1). 2,3 Whereas HIF1b, also known as the aryl hydrocarbon receptor nuclear translocator (Arnt1), is a constitutively expressed nuclear protein, the a-subunit is strictly regulated in an oxygendependent manner. There are three paralogues of the HIF-a subunit, HIF-1a, HIF-2a and HIF-3a, and three paralogues of HIF-1b (Arnt1, Arnt2 and Arnt3), with either HIF-1a or HIF-2a being able to heterodimerize with HIF-1b to form the functional HIF transcription factor complexes responsible for the hypoxic shift in gene expression. HIF-3a has no known role as an active transcription factor, and is instead postulated to behave as a negative reg...

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Section: Oxygen-dependent Regulation Of Hif-cad By Fih-1mentioning

confidence: 99%

Section: Oxygen-dependent Regulation Of Hif-cad By Fih-1mentioning

confidence: 99%

“…Treatment of cultured cells with hypoxia or hypoxia mimetics does not appear to alter the cytoplasmic localisation of FIH-1. 34,40,43 Other FIH-1 Substrates and HIF Regulation…”

Section: Oxygen-dependent Regulation Of Hif-cad By Fih-1mentioning

confidence: 99%

Section: Regulation Of Fih-1mentioning

confidence: 99%

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Turn me on: regulating HIF transcriptional activity

2008

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“…39,40 Inhibition of FIH can result in increased HIF target gene expression even under severe hypoxia or in certain VHL-deficient cell lines. 41 …”

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confidence: 99%

The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

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The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

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Modeling the regulation of p53 activation by HIF‐1 upon hypoxia

et al. 2019

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As a famous tumor suppressor, p53 is also activated under hypoxic conditions. Hypoxia‐inducuble factor 1, HIF‐1, is involved in the activation of p53 upon hypoxia. However, how p53 is modulated by the HIF‐1 pathway to decide cell fate is less understood. In this work, we developed a network model including p53 and HIF‐1 pathways to clarify the mechanism of cell fate decision in response to hypoxia. We found that HIF‐1α and p53 are activated under different conditions. Under moderate hypoxia, HIF‐1α is activated to induce glycolysis or angiogenesis, and promotes partial accumulation of p53 by inducing PNUTS. Under severe hypoxia, p53 rises to high levels due to ATR‐dependent stabilization and promotes Mdm2‐dependent HIF‐1α degradation. As a result, fully activated p53 triggers apoptosis. Of note, competition for p300 between HIF‐1α and p53 plays a key role in regulating their transcriptional activities. This work may advance the understanding of the mechanism for p53 regulation by HIF‐1 in the hypoxic response.

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Genetic Analysis of the Role of the Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-inducible Factor (HIF) in Regulating HIF Transcriptional Target Genes

Cited by 149 publications

References 32 publications

Turn me on: regulating HIF transcriptional activity

Turn me on: regulating HIF transcriptional activity

The VHL tumor suppressor and HIF: insights from genetic studies in mice

Modeling the regulation of p53 activation by HIF‐1 upon hypoxia

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