Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypoxia-inducible factor (HIF)-1 is a master transcriptional activator of oxygen-regulated genes involved in energy metabolism, angiogenesis, and erythropoiesis. HIF-1 is composed of the two subunits HIF-1alpha and HIF-1beta (also called ARNT). The destruction of HIF-1alpha in the presence of oxygen is initiated by prolyl-4-hydroxylation. In human cells three closely related prolyl hydroxylases (PHDs) have been identified. An age-dependent decrease in HIF-1alpha expression was reported previously in brain, liver and kidney, which may be associated with a reduced adaptation to hypoxia as found in aged animals and humans. We have determined the expression of HIF-1alpha and the PHDs in human atrial trabeculae under normoxic and hypoxic conditions, in samples of human left ventricles as well as in heart extracts from female mice of different age (5 up to 16 months). With increasing age we found a decreased expression of HIF-1alpha, which correlated to an increased PHD3 expression in mouse and human heart. PHD3 was the most prominent HIF modifying hydroxylase found in human heart samples. Additionally, we found a strong ischemia/hypoxia-inducibility of PHD3 compared to PHD1 and PHD2 in atrial trabeculae. These data may explain the previously reported reduction of HIF-1alpha and HIF-1 target genes such as the vascular endothelial growth factor in ageing tissue.
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PMID:Age-dependent increase of prolyl-4-hydroxylase domain (PHD) 3 expression in human and mouse heart. 1604 20

The transcriptional activator HIF (hypoxia-inducible factor) is a focal point of biomedical research because many situations in physiology and in pathology coincide with hypoxia. The effects of HIF activation may be a facet of normal growth, as in embryonic development, they may counterbalance a disease, as seen in the stimulation of erythropoiesis in anaemia, and they may be part of the pathological processes, as exemplified by tumour angiogenesis. The oxygen-sensitive alpha-subunits of HIF are primarily regulated by the enzymatic hydroxylation that induces rapid proteasomal degradation. The HIFalpha hydroxylases belong to a superfamily of dioxygenases that require the co-substrates oxygen and 2-oxoglutarate as well as the cofactors Fe2+ and ascorbate. The regulation of enzyme turnover by the concentration of the cosubstrate oxygen constitutes the interface between tissue oxygen level and the activity of HIF. The HIFalpha prolyl hydroxylases, termed PHDs/EGLNs (prolyl hydroxylase domain proteins/EGL nine homologues), bind to a conserved Leu-Xaa-Xaa-Leu-Ala-Pro motif present in all substrates identified so far. This recognition motif is present twice in HIF1alpha, which gives rise to a NODD [N-terminal ODD (oxygen-dependent degradation domain)] containing Pro402 of HIF1alpha and a CODD (C-terminal ODD) where Pro564 is hydroxylated. PHD1/EGLN2 and PHD2/EGLN1 hydroxylate both ODDs with higher activity towards CODD, whereas PHD3/EGLN3 is specific for CODD. The reason for this behaviour has been unclear. In this issue of the Biochemical Journal, Villar and colleagues demonstrate that distinct PHD/EGLN domains, that are remote from the catalytic site, function in substrate discrimination. This elegant study improves our understanding of the interaction of the oxygen-sensing PHDs/EGLNs with their substrates, which include, but are not limited to, the HIFalpha proteins.
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PMID:Enzyme substrate recognition in oxygen sensing: how the HIF trap snaps. 1772 46

Caloric restriction remains the most reproducible measure known to extend life span or diminish age-associated changes. Previously, we have described an elevated expression of the prolyl-4-hydroxylase domain (PHD) 3 with increasing age in mouse and human heart. PHDs modulate the cellular response towards hypoxia by regulating the stability of the alpha-subunit of the transcriptional activator hypoxia inducible factor (HIF). In the present study we demonstrate that elevated PHD3, but not PHD1 or PHD2, expression is not restricted to the heart but does also occur in rat skeletal muscle and liver. Elevated expression of PHD3 is counteracted by a decrease in caloric intake (40% caloric restriction applied for 6 months) in all three tissues. Age-associated changes in PHD3 expression inversely correlated with the expression of the HIF-target gene macrophage migration inhibitory factor (MIF), which has been previously described to be involved in cellular HIF-mediated anti-ageing effects. These data give insight into the molecular consequences of caloric restriction, which influences hypoxia-mediated gene expression via PHD3.
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PMID:Caloric restriction counteracts age-dependent changes in prolyl-4-hydroxylase domain (PHD) 3 expression. 1823 68