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 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

Polycythemia is often associated with erythropoietin (EPO) overexpression and defective oxygen sensing. In normal cells, intracellular oxygen concentrations are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins, which tag hypoxia-inducible factor (HIF) alpha subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show that different PHD isoforms differentially regulate HIF-alpha stability in the adult liver and kidney and suppress Epo expression and erythropoiesis through distinct mechanisms. Although Phd1(-/-) or Phd3(-/-) mice had no apparent defects, double knockout of Phd1 and Phd3 led to moderate erythrocytosis. HIF-2alpha, which is known to activate Epo expression, accumulated in the liver. In adult mice deficient for PHD2, the prototypic Epo transcriptional activator HIF-1alpha accumulated in both the kidney and liver. Elevated HIF-1alpha levels were associated with dramatically increased concentrations of both Epo mRNA in the kidney and Epo protein in the serum, which led to severe erythrocytosis. In contrast, heterozygous mutation of Phd2 had no detectable effects on blood homeostasis. These findings suggest that PHD1/3 double deficiency leads to erythrocytosis partly by activating the hepatic HIF-2alpha/Epo pathway, whereas PHD2 deficiency leads to erythrocytosis by activating the renal Epo pathway.
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PMID:Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. 1805 38

When humans are exposed to hypoxia, systemic and intracellular changes operate together to minimise hypoxic injury and restore adequate oxygenation. Emerging evidence indicates that the hypoxia-inducible factor (HIF) family of transcription factors plays a central regulatory role in these homeostatic changes at both the systemic and cellular levels. HIF was discovered through its action as the transcriptional activator of erythropoietin, and has subsequently been found to control intracellular hypoxic responses throughout the body. HIF is primarily regulated by specific prolyl hydroxylase-domain enzymes (PHDs) that initiate its degradation via the von Hippel-Lindau tumour suppressor protein (VHL). The oxygen and iron dependency of PHD activity accounts for regulation of the pathway by both cellular oxygen and iron status. Recent studies conducted in patients with rare genetic diseases have begun to uncover the wider importance of the PHD-VHL-HIF axis in systems-level human biology. These studies indicate that, in addition to regulating erythropoiesis, the system plays an important role in cardiopulmonary regulation. This article reviews our current understanding of the importance of HIF in human systems-level physiology, and is modelled around the classic physiological response to high-altitude hypoxia.
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PMID:The human side of hypoxia-inducible factor. 1841 May 68

Hypoxia-inducible factor (HIF) is a transcriptional activator that promotes death or survival in neurons. The regulators and targets of HIF-1alpha-mediated death remain unclear. We found that prodeath effects of HIF-1 are not attributable to an imbalance in HIF-1alpha and HIF-1beta expression. Rather, the synergistic death caused by oxidative stress and by overexpression of an oxygen-resistant HIF-VP16 in neuroblasts was attributable to transcriptional upregulation of BH3-only prodeath proteins, PUMA or BNIP3. By contrast, overexpression of BNIP3 was not sufficient to potentiate oxidative death. As acidosis is known to activate BNIP3-mediated death, we examined other secondary stresses, such as oxidants or prolyl hydroxylase activity are necessary for exposing the prodeath functions of HIF in neurons. Antioxidants or prolyl hydroxylase inhibition prevented potentiation of death by HIF-1alpha. Together, these studies suggest that antioxidants and PHD inhibitors abrogate the ability of HIF-mediated transactivation of BH3-only proteins to potentiate oxidative death in normoxia. The findings offer strategies for minimizing the prodeath effects of HIF-1 in neurologic conditions associated with hypoxia and oxidative stress, such as stroke and spinal cord injury.
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PMID:Antioxidants, HIF prolyl hydroxylase inhibitors or short interfering RNAs to BNIP3 or PUMA, can prevent prodeath effects of the transcriptional activator, HIF-1alpha, in a mouse hippocampal neuronal line. 1877

Red blood cells deliver O(2) from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O(2)-regulated alpha subunit and a constitutively expressed beta subunit. Hydroxylation of HIF-1alpha or HIF-2alpha by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1alpha or HIF-2alpha by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2alpha have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.
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PMID:Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. 1949 50

Hypoxia-inducible factor 1 (HIF-1) plays essential roles in tumor angiogenesis and growth by regulating the transcription of several key genes in response to hypoxic stress and growth factors. HIF-1 is a heterodimeric transcriptional activator consisting of inducible alpha and constitutive beta subunits. In oxygenated cells, proteins containing the prolyl hydroxylase domain (PHD) directly sense intracellular oxygen concentrations. PHDs tag HIF-1alpha subunits for polyubiquitination and proteasomal degradation by prolyl hydroxylation using 2-oxoglutarate (2-OX) and dioxygen. Our recent studies showed that 2-OX reduces HIF-1alpha, erythropoietin, and vascular endothelial growth factor (VEGF) expression in the hepatoma cell line Hep3B when under hypoxic conditions in vitro. Here, we report that similar results were obtained in Lewis lung cancer (LLC) cells in in vitro studies. Furthermore, 2-OX showed potent antitumor effects in a mouse dorsal air sac assay and a murine tumor xenograft model. In the dorsal air sac assay, 2-OX reduced the numbers of newly formed vessels induced by LLC cells. In a murine tumor xenograft model, intraperitoneal injection of 2-OX significantly inhibited tumor growth and angiogenesis in tumor tissues. Moreover, 5-fluorouracil combined with 2-OX significantly inhibited tumor growth in this model, which was accompanied by reduction of Vegf gene expression and inhibited angiogenesis in tumor tissues. These results suggest that 2-OX is a promising anti-angiogenic therapeutic agent.
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PMID:Antitumor effects of 2-oxoglutarate through inhibition of angiogenesis in a murine tumor model. 1957 48

Candida albicans reversibly switches between yeast and hyphal morphologies, with hyphae being associated with virulence. Hyphal initiation and maintenance depend on host environment sensing. Hyphal maintenance in vitro requires chromatin remodeling of hypha-specific gene promoters, although disrupting chromatin-remodeling does not disrupt C. albicans hyphal elongation and virulence during invasive infection. We find that the combination of hypoxia and high CO2, but neither condition alone, maintains hyphal elongation, even in mutants lacking the nutrient-responsive chromatin-remodeling pathway. Ume6, the transcriptional activator of hypha-specific genes, is stabilized via regulation by Ofd1, a prolyl hydroxylase family member inhibited by hypoxia, and by an uncharacterized pathway that senses high CO2. Virulence and hyphal elongation in vivo are attenuated only when the parallelly acting Ume6 stabilization and chromatin-remodeling pathways are both blocked. The evolution of redundant signaling pathways allowing C. albicans to adapt to varied host environments may explain this commensal's success as a pathogen.
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PMID:Synergistic regulation of hyphal elongation by hypoxia, CO(2), and nutrient conditions controls the virulence of Candida albicans. 2423 92