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)

Synaptic activation leads to the formation of arachidonic acid, platelet-activating factor (PAF, 1-O-alkyl-2-acyl-sn-3-phosphocholine) and other lipid messengers. PAF is a potent bioactive phospholipid in synaptic plasticity. PAF enhances presynaptic glutamate release, is a retrograde messenger in long-term potentiation and enhances memory formation. PAF also couples synaptic events with gene expression by stimulating a FOS/JUN/AP-1 transcriptional signaling system, as well as transcription of COX-2 (inducible prostaglandin synthase). Since the COX-2 gene is also involved in synaptic plasticity, the PAF-COX-2 pathway may have physiological significance. Seizures, ischemia and other forms of brain injury promote phospholipase A2 (PLA2) overactivation, resulting in the accumulation of bioactive lipids at the synapse. PAF, under these pathological conditions, behaves as a neuronal injury messenger by at least two mechanisms: (a) enhancing glutamate release; and, (b) by sustained augmentation of COX-2 transcription. These events link PAF with neurodegeneration. The upstream intracellular pathways of signal transduction involved in neuronal or photoreceptor cell apoptosis are not well understood and involve stress sensitive kinases. PAF is a transcriptional activator of the COX-2 gene. BN 50730, a potent intracellular PAF antagonist, blocks COX-2 induction. COX-2 transcription and protein expression are upregulated in the hippocampus in kainic acid induced epileptogenesis. There is a selectively elevated induction of COX-2 (72-fold) by kainic acid preceding neuronal cell death. BN 50730 administered by i.c.v. injection blocks seizure-induced COX-2 induction. Overall, PAF is a dual modulator of neural function and becomes an endogenous neurotoxin when over produced.
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PMID:The neuromessenger platelet-activating factor in plasticity and neurodegeneration. 993 49

Brain ischemia is a cause of substantial morbidity and mortality during the later decades of life. In light of this, many studies have used in vitro and in vivo models of acute necrosis to test candidate therapeutic agents. More recently, the existence of a genetically programmed component of ischemic death has become widely accepted. We have used molecular genetic approaches to investigate the potential link between hypoxia-induced gene transcription and the delayed death of ischemic neurons. Hypoxia-induced gene expression is an evolutionarily conserved response comprising both transcriptional activation and posttranscriptional and posttranslational stabilization events. Members of the PER-ARNT-SIM (PAS) family of basic helix-loop-helix transcription factors have been shown to regulate hypoxic transcripts in nonneuronal cultured lines. However, evidence for ischemic activation of PAS proteins within the neuronal compartment or possible involvement in neuronal death is lacking. The tumor-suppressor protein p53 is a known transcriptional activator within the central nervous system that is clearly involved in the pathologic response to ischemia. This article will provide data that implicate the coordinate activities of p53 and the PAS protein HIF-1alpha in driving ischemia-induced delayed neuronal death. Background regarding mechanisms of ischemic neuronal death will also be provided with special attention paid to the role of de novo gene expression in promoting this pathologic sequence. The identification of the HIF-1alpha/p53-mediated signaling pathway in neurons highlights a novel target toward which anti-ischemic neuroprotective drug discovery can be applied.
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PMID:HIF-1alpha and p53 promote hypoxia-induced delayed neuronal death in models of CNS ischemia. 1048 75

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator that mediates changes in gene expression in response to changes in cellular oxygen concentrations. HIF-1 is a heterodimer consisting of an oxygen-regulated HIF-1 alpha subunit and a constitutively expressed HIF-1 beta subunit. In mice, complete HIF-1 alpha deficiency results in embryonic lethality at midgestation because of cardiac and vascular malformations. Analyses of animal and cell culture models as well as human tissue have provided evidence that HIF-1 plays important roles in the pathophysiology of preeclampsia, intrauterine growth retardation, hypoxia-mediated pulmonary hypertension, and cancer. HIF-1 promotes neovascularization in response to myocardial or retinal ischemia by activating transcription of the gene encoding vascular endothelial growth factor. HIF-1 may also mediate the protective response to cerebral ischemia known as late-phase preconditioning.
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PMID:Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease. 1132 42

Formation of new blood vessels in the adult animal (i.e., angiogenesis) is an important event for tissue repair and for tumor growth and metastasis. Angiogenesis involves the migration and proliferation of endothelial cells. We have investigated the role of the growth suppressor p27(Kip1) (p27) on endothelial cell function in vitro and angiogenesis in vivo. We have generated Ad-TetON, a replication-deficient adenovirus that constitutively expresses the reverse tet-responsive transcriptional activator, and Ad-TRE-p27, which drives expression of p27 under the control of the tet response element. Western blot analysis demonstrated doxycycline-dependent overexpression of p27 in human umbilical vein endothelial cells (HUVECs) coinfected with Ad-TetON and Ad-TRE-p27, which resulted in a marked inhibition of DNA replication and cell migration in vitro. Inducible overexpression of p27 in cultured HUVECs inhibited the formation of tubelike structures and, when applied in a murine model of hind limb ischemia, reduced hind limb blood flow recovery and capillary density. These findings thus underscore a novel role of p27 in regulating endothelial cell migration in vitro and angiogenesis in vivo, suggesting a novel anti-angiogenic therapy based on inducible p27 overexpression.
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PMID:Overexpression of p27(Kip1) by doxycycline-regulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angiogenesis. 1153 67

Vascular development involves vasculogenesis, in which endothelial cells form a primary tubular network, as well as angiogenesis, in which vessel size and structure are modified based upon flow and branching occurs to insure that all cells receive adequate O2 delivery. In adults, angiogenesis occurs in response to tissue hypoxia/ischemia and plays an important role in determining the progression of ischemic heart disease and cancer. A critical molecular pathway induced by hypoxia/ischemia is the activation of hypoxia-inducible factor 1, a transcriptional activator of genes encoding vascular endothelial growth factor and other important mediators of angiogenesis. Novel therapeutic approaches that involve stimulating angiogenesis in ischemic tissue and inhibiting angiogenesis in neoplastic tissue are currently being evaluated in clinical trials.
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PMID:Angiogenesis in ischemic and neoplastic disorders. 1235 28

The cardiovascular and respiratory systems play key roles in O(2) homeostasis. Physiological responses to hypoxia involve changes in gene expression that are mediated by the transcriptional activator hypoxia-inducible factor (HIF)-1. Analysis of mice heterozygous for a knockout allele at the locus encoding the O(2)-regulated HIF-1alpha or HIF-2alpha subunit has revealed that these proteins are required for multiple physiological responses to chronic hypoxia, including erythrocytosis and pulmonary vascular remodeling. In mice with partial HIF-2alpha deficiency, hypoxia-induced expression of endothelin-1 and norepinephrine is dramatically impaired, and the mice fail to develop pulmonary hypertension after 4 wk of exposure to 10% O(2). In mice with partial HIF-1alpha deficiency, the ability of the carotid body to sense and/or respond to acute or chronic hypoxia is lost. In wild-type mice, brief episodes of intermittent hypoxia are sufficient to induce production of erythropoietin (EPO), which protects the heart against apoptosis after ischemia-reperfusion, whereas in mice with partial HIF-1alpha deficiency, intermittent hypoxia does not induce EPO production or cardiac protection. Parenteral administration of EPO to rodents is sufficient to induce dramatic protection against ischemia-reperfusion injury in the heart. Thus HIF-1 mediates critical physiological responses to hypoxia, and the elucidation of these homeostatic mechanisms may lead to novel therapies for the most common causes of mortality in the US population.
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PMID:O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1. 1476 67

Inadequate angiogenic response to ischemia in diabetic myocardium could result in poor collateral formation. Because hypoxia-inducible factor (HIF)-1alpha is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating angiogenic responses to hypoxia, we investigated the expression of HIF-1alpha and VEGF in specimens of human heart tissue to elucidate the molecular responses to myocardial ischemia in diabetic patients during unstable angina. Moreover, accumulation of a marker of protein nitration nitrotyrosine, as well as the superoxide anion (O(2)(-)) levels and inducible nitric oxide synthase (iNOS), were evaluated. Ventricular biopsy specimens from 15 type 2 diabetic and 14 nondiabetic patients presenting with unstable angina (ischemic group) and from 20 patients (11 type 2 diabetic and 9 nondiabetic patients) who underwent coronary bypass surgery without angina within the preceding 10 days (control group) were collected during coronary bypass surgery. Nondiabetic patients had higher HIF-1alpha and VEGF expressions compared with diabetic patients (P < 0.001). As compared with nondiabetic specimens, diabetic specimens showed higher levels of both iNOS mRNA and protein levels (P < 0.001) associated with the highest tissue levels of nitrotyrosine and O(2)(-) (P < 0.001). Diabetes is associated with increased myocardial tissue levels of iNOS, O(2)(-), and nitrotyrosine and reduced expression of myocardial angiogenesis factors during ischemia.
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PMID:Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes. 1533 49

Effective therapies for stroke must interdict multiple parallel and sequential pathophysiological events. A paradigm which offers insight into multivalent but thoughtfully coordinated protective programs is ischemic preconditioning. A central hypothesis of our group and others is that pharmacological agents that activate programs of gene expression normally induced by ischemic preconditioning will be effective agents for the prevention and treatment of stroke. Inhibitors of a class of enzymes, the hypoxia inducible factor-1 (HIF-1) prolyl hydroxylases stabilize the transcriptional activator HIF-1 and activate target genes involved in compensation for ischemia, including erythropoeitin (Epo) and vascular endothelial growth factor (VEGF). Here, we review evidence suggesting that the HIF-1 prolyl hyroxylases are inhibited during ischemic preconditioning and that pharmacological inhibitors of these enzymes are viable targets for stroke therapy.
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PMID:Translation of ischemic preconditioning to the patient: prolyl hydroxylase inhibition and hypoxia inducible factor-1 as novel targets for stroke therapy. 1547 13

The putative amino acid sequence of ringed seal (Phoca hispida) hypoxia-inducible factor 1alpha (HIF-1alpha) derived from DNA sequence analysis of the single-copy gene has been investigated. The rationale for these studies was to determine the reasons for the presence of HIF-1alpha at relatively high levels in seal tissues, and its possible role in protection against diving-related oxidative damage. Sequence analysis indicated that the bHLH/PAS and TAD functional domains are very similar to those in terrestrial mammals, although there were significant sequence differences between the mouse and seal proteins in a region of the ODD domain. Some of these results indicate that seal HIF-1alpha protein can bind HIF-Ibeta, DNA, transcriptional coactivators, and von Hippel-Lindau protein (pVHL). The presence of HIF-1alpha in seal tissues was not related to the absence of pVHL, which was found to be present in all seal tissues examined. It is concluded that seal HIF-1alpha may act as a transcriptional activator and that its presence in seal tissues is probably not caused by its inability to interact with pVHL. It is suggested that seal HIF-1 may serve two functions in the postdiving period, namely, to attenuate ischemia/reperfusion-induced oxidative stress and to allow efficient lung reinflation.
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PMID:Hypoxia-inducible factor 1 proteomics and diving adaptations in ringed seal. 1596 12

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


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