Regulation of HIF: Prolyl Hydroxylases

Stolze, Ineke; Mole, David R.; Ratcliffe, Peter J.

doi:10.1002/9780470035009.ch3

Cited by 50 publications

(43 citation statements)

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“…When activated, they enhance the hydroxylation of specific prolyl and asparagyl residues of the transcription protein, Hypoxia Inducible Factor (HIF) (Fig 2). It is this family of proteins that respond to the oxemic status and through their interaction with HIF regulate glycolysis as well as a number of related cellular activities [16][17][18]. Indeed, in an earlier study we showed the presence of PHD isoenzymes in isolated chondrocytes and the growth plate itself [19].…”

Section: Regulation Of the Oxemic Response By Phd And Hif Proteinsmentioning

confidence: 99%

Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment

Shapiro¹,

Srinivas²

2007

Bone

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The goal of this review is to examine some of the metabolic features of the maturing chondrocyte within the epiphyseal growth plate. The energy status of the tissue is examined in light of the energy needs of the tissue and the availability of oxygen. The role of HIF, PHD's and other proteins concerned with transduction of the oxemic response is considered and related to chondrocyte survival in a complex extracellular matrix.

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Section: Regulation Of the Oxemic Response By Phd And Hif Proteinsmentioning

confidence: 99%

Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment

Shapiro¹,

Srinivas²

2007

Bone

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“…This process is facilitated by a family of prolyl hydroxylases (PHDs). 2 Following hydroxylation, HIF-1a binds to the von Hippel-Lindau protein (pVHL) which is part of an E3-ubiquitin ligase complex that marks HIF-1a for proteasomal degradation through ubiquitination. 3 Oxygen is required for the function of PHDs.…”

Section: Introductionmentioning

confidence: 99%

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

et al. 2012

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The heterodimer HIF-1a (hypoxia inducible factor)/HIF-b (also known as ARNT-aryl hydrocarbon nuclear translocator) is a key mediator of cellular response to hypoxia. The interaction between these monomer units can be modified by the action of small molecules in the binding interface between their C-terminal heterodimerization (PasB) domains. Taking advantage of the presence of several cysteine residues located in the allosteric cavity of HIF-1a PasB domain, we applied a cysteine-based reactomics ''hotspot identification'' strategy to locate regions of HIF1a PasB domain critical for its interaction with ARNT. COMPOUND 5 was identified using a mass spectrometry-based primary screening strategy and was shown to react specifically with Cys255 of the HIF-1a PasB domain. Biophysical characterization of the interaction between PasB domains of HIF-1a and ARNT revealed that covalent binding of COMPOUND 5 to Cys255 reduced binding affinity between HIF-1a and ARNT PasB domains approximately 10-fold. Detailed NMR structural analysis of HIF-1a-PasB-COMPOUND 5 conjugate showed significant local conformation changes in the HIF-1a associated with key residues involved in the HIF-1a/ARNT PasB domain interaction as revealed by the crystal structure of the HIF-1a/ARNT PasB heterodimer. Our screening strategy could be applied to other targets to identify pockets surrounding reactive cysteines suitable for development of small molecule modulators of protein function.

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“…Under normoxia, HIF-1α is continuously synthesized and its protein levels and transcriptional activity are finely regulated by different mechanisms . The most important regulatory system is proteolysis by different oxygen-dependent mechanisms including hydroxylation by prolyl-hydroxylases Stolze et al, 2006) that allows its ubiquitination and proteosomal degradation (Cockman et al, 2000). Once protein is stabilized, it dimerizes with the constitutively expressed HIF-1β subunit, leading to its translocation to the nucleus where it switches on a series of genes participating in compensatory mechanisms including regulation of angiogenesis (Forsythe et al, 1996), vasomotor control (Palmer et al, 1998), erythropoiesis (Wang and Semenza, 1993), iron metabolism (Mukhopadhyay et al, 2000), cell cycle control (Carmeliet et al, 1998) and energy metabolism (Ebert et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

HIF-1α is neuroprotective during the early phases of mild hypoxia in rat cortical neurons

López-Hernández

Posadas

Podlesniy

et al. 2012

Experimental Neurology

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Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a key role regulating the adaptive response to hypoxia. HIF-1α is stabilised during hypoxia and, after dimerization with HIF-1β, triggers the expression of different genes involved in cell cycle control and energy metabolism associated with cell survival. However, HIF-1α also regulates the expression of proapoptotic genes. The aim of this work is to ascertain the influence of HIF-1α on neurotoxicity evoked by hypoxia in rat cortical neurons. We found that mild hypoxia induces a time-dependent neuronal death that involves free radical production, mitochondrial depolarization, cytochrome c release and caspase 3 activation. Lentiviral mediated knockdown of HIF-1α markedly potentiated all these effects during the initial 24 hours of hypoxia suggesting that HIF-1α plays a neuroprotective role on hypoxia-mediated neuronal death. After this period, the protective actions of HIF-1α disappeared in agreement with the time-course of hypoxia-mediated HIF-1α stabilization. On the other hand, lentiviral mediated over expression of HIF-1α increased lactate dehydrogenase A, one of the target genes for HIF-1α, but did not show protective actions on hypoxia-mediated neuronal death indicating that the level of endogenous HIF-1α stabilization achieved during hypoxia is already the maximal required for the transcription activities of HIF-1α. These results indicate that HIF-1α is neuroprotective in the early phases of hypoxia.3

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Regulation of HIF: Prolyl Hydroxylases

Cited by 50 publications

References 0 publications

Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment

Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

HIF-1α is neuroprotective during the early phases of mild hypoxia in rat cortical neurons

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