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  • 1
    Keywords: ANGIOGENESIS ; APOPTOSIS ; FACTOR RECEPTOR ; GENES ; PROTEIN ; COLORECTAL-CANCER ; OXYGEN ; HIF ; INDUCIBLE FACTOR ; PROLYL HYDROXYLASES PHD1
    Abstract: Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. However, tumour cells are capable of counteracting these signals through mechanisms that are largely unknown. Here we show that the prolyl hydroxylase PHD3 restrains tumour growth in response to microenvironmental cues through the control of EGFR. PHD3 silencing in human gliomas or genetic deletion in a murine high-grade astrocytoma model markedly promotes tumour growth and the ability of tumours to continue growing under unfavourable conditions. The growth-suppressive function of PHD3 is independent of the established PHD3 targets HIF and NF-kappaB and its hydroxylase activity. Instead, loss of PHD3 results in hyperphosphorylation of epidermal growth factor receptor (EGFR). Importantly, epigenetic/genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification. Our findings reveal that PHD3 inactivation provides an alternative route of EGFR activation through which tumour cells sustain proliferative signalling even under conditions of limited oxygen availability.
    Type of Publication: Journal article published
    PubMed ID: 25420773
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Nephrology 7 (2002), S. 0 
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: SUMMARY: Studies of hypoxia-inducible cis-acting sequences from the erythropoietin gene have led to the recognition of a widespread transcriptional response to hypoxia based on the activation of a DNA-binding complex, hypoxia-inducible factor-1 (HIF). Genes with functions in cellular energy metabolism, iron metabolism, catecholamine metabolism, vasomotor control and angiogenesis have subsequently been shown to be responsive to HIF, indicating a role in the coordination of oxygen supply and cellular metabolism. Hypoxia-inducible factor-1 is a heterodimer of two basic helix-loop-helix proteins of the PAS family, HIF-1 alpha and HIF-1 beta, although different isoforms of each subunit are now known to exist. When oxygen tension is lowered, HIF-alpha subunits dimerize with HIF-beta and activate gene transcription. Hypoxia-inducible factor-1-mediated gene transcription is regulated predominantly by oxygen-dependent destruction of HIF-alpha via the ubiquitin-proteasome pathway. This destruction is mediated by a ubiquitin E3 ligase complex, in which the von Hippel-Lindau (VHL) protein (pVHL) recognizes and binds oxygen-dependent destruction domain(s) in HIF-alpha subunits. In VHL disease, the destruction of HIF-alpha is blocked, at least partly explaining the phenotype. the recognition of HIF-alpha by pVHL in normoxia has recently been shown to be conditional on enzymatic post-translational hydroxylation of critical prolyl residues. It is hoped that a detailed understanding of these gene regulatory mechanisms may lead to therapeutically useful interventions in the future, for example by up-regulating HIF activity in ischaemic disease or down-regulating it in cancer.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Pty
    Nephrology 7 (2002), S. 0 
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: SUMMARY: Studies of hypoxia-inducible cis-acting sequences from the erythropoietin gene have led to the recognition of a widespread transcriptional response to hypoxia based on the activation of a DNA-binding complex, hypoxia-inducible factor-1 (HIF). Genes with functions in cellular energy metabolism, iron metabolism, catecholamine metabolism, vasomotor control and angiogenesis have subsequently been shown to be responsive to HIF, indicating a role in the coordination of oxygen supply and cellular metabolism. Hypoxia-inducible factor-1 is a heterodimer of two basic helix–loop–helix proteins of the PAS family, HIF-1 alpha and HIF-1 beta, although different isoforms of each subunit are now known to exist. When oxygen tension is lowered, HIF-alpha subunits dimerize with HIF-beta and activate gene transcription. Hypoxia-inducible factor-1-mediated gene transcription is regulated predominantly by oxygen-dependent destruction of HIF-alpha via the ubiquitin-proteasome pathway. This destruction is mediated by a ubiquitin E3 ligase complex, in which the von Hippel-Lindau (VHL) protein (pVHL) recognizes and binds oxygen-dependent destruction domain(s) in HIF-alpha subunits. In VHL disease, the destruction of HIF-alpha is blocked, at least partly explaining the phenotype. The recognition of HIF-alpha by pVHL in normoxia has recently been shown to be conditional on enzymatic post-translational hydroxylation of critical prolyl residues. It is hoped that a detailed understanding of these gene regulatory mechanisms may lead to therapeutically useful interventions in the future, for example by up-regulating HIF activity in ischaemic disease or down-regulating it in cancer.
    Type of Medium: Electronic Resource
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