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

Many members of the cytokine receptor superfamily initiate intracellular signaling by activating members of the Jak family of tyrosine kinases. Activation of the same Jaks by multiple cytokines raises the question of how these cytokines activate distinct intracellular signaling pathways. Selection of particular substrates--the transcriptional activator Stat3 and protein tyrosine phosphatase PTP1D--that characterize responses to the ciliary neurotrophic factor-interleukin-6 cytokine family depended not on which Jak was activated, but was instead determined by specific tyrosine-based motifs in the receptor components--gp130 and LIFR--shared by these cytokines. Further, these tyrosine-based motifs were modular, because addition of a Stat3-specifying motif to another cytokine receptor, that for erythropoietin, caused it to activate Stat3 in a ligand-dependent fashion.
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PMID:Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. 787 33

Studies on erythropoietin (Epo) gene expression have been useful in investigating the mechanism by which cells and tissues sense hypoxia. Both in vivo and in Hep3B cells. Epo production is induced not only by hypoxia but also by certain transition metal (cobalt and nickel) and by iron chelation. When Hep3B cells were incubated in an iron deficient medium, Epo mRNA expression was enhanced fourfold compared to Hep3B cells in iron enriched medium. Epo induction by cobalt was inversely related to iron concentration in the medium, indicating competition between the two metals. Under hyperbaric oxygen, cobalt induction of erythropoietin mRNA was modestly suppressed while nickel induction was markedly enhanced. These recent observations support the proposal that the oxygen sensor is a heme protein in which cobalt and nickel can substitute for iron in the porphyrin ring. The up-regulation of Epo gene transcription by hypoxia depends on at least two known DNA binding transcription factors, HIF-1 and HNF-4, which bind to cognate response elements in a critical approximately 50 bp 3' enhancer. Hypoxia induces HIF-1 binding. HNF-4, an orphan nuclear receptor constitutively expressed in kidney and liver, binds downstream of HIF-1 and cooperates with HIF-1, contributing importantly to high level and perhaps tissue specific expression. The C-terminal activation domain of HNF-4 binds to the beta subunit of HIF-1. The C-terminal portion of the alpha subunit of HIF-1 binds specifically to p300, a general transcriptional activator. Hypoxic induction of the endogenous Epo gene in Hep3B cells as well as an Epo-reporter gene was fully inhibited by E1A, an adenovirus protein that binds to and inactivates p300, but only slightly by a mutant E1A that fails to bind to p300. Moreover, overexpression of p300 enhanced hypoxic induction. Thus, it is likely that in hypoxic cells, p300 or a related family member plays a critical role in forming a macromolecular assembly with HIF-1 and HNF-4, enabling transduction from the Epo 3' enhancer to the apparatus on the promoter responsible for the initiation of transcription.
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PMID:Erythropoietin gene regulation depends on heme-dependent oxygen sensing and assembly of interacting transcription factors. 902 36

The hypoxia-inducible factor 1 transcriptional activator complex (HIF-1) is involved in the activation of the erythropoietin and several other hypoxia-responsive genes. The HIF-1 complex is composed of two protein subunits: HIF-1beta/ARNT (aryl hydrocarbon receptor nuclear translocator), which is constitutively expressed, and HIF-1alpha, which is not present in normal cells but induced under hypoxic conditions. The HIF-1alpha subunit is continuously synthesized and degraded under normoxic conditions, while it accumulates rapidly following exposure to low oxygen tensions. The involvement of the ubiquitin-proteasome system in the proteolytic destruction of HIF-1 in normoxia was studied by the use of specific inhibitors of the proteasome system. Lactacystin and MG-132 were found to protect the degradation of the HIF-1 complex in cells transferred from hypoxia to normoxia. The same inhibitors were able to induce HIF-1 complex formation when added to normoxic cells. Final confirmation of the involvement of the ubiquitin-proteasome system in the regulated degradation of HIF-1alpha was obtained by the use of ts20TGR cells, which contain a temperature-sensitive mutant of E1, the ubiquitin-activating enzyme. Exposure of ts20 cells, under normoxic conditions, to the non-permissive temperature induced a rapid and progressive accumulation of HIF-1. The effect of proteasome inhibitors on the normoxic induction of HIF-1 binding activity was mimicked by the thiol reducing agent N-(2-mercaptopropionyl)-glycine and by the oxygen radical scavenger 2-acetamidoacrylic acid. Furthermore, N-(2-mercaptopropionyl)-glycine induced gene expression as measured by the stimulation of a HIF-1-luciferase expression vector and by the induction of erythropoietin mRNA in normoxic Hep 3B cells. These last findings strongly suggest that the hypoxia induced changes in HIF-1alpha stability and subsequent gene activation are mediated by redox-induced changes.
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PMID:Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. 927 21

The hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator involved in the expression of oxygen-regulated genes such as that for erythropoietin. Following exposure to low oxygen partial pressure (hypoxia), HIF-1 binds to an hypoxia-response element located 3' to the erythropoietin gene and confers activation of erythropoietin expression. The conserved core HIF-1 binding site (HBS) of the erythropoietin 3' enhancer (CGTG) contains a CpG dinucleotide known to be a potential target of cytosine methylation. We found that methylation of the HBS abolishes HIF-1 DNA binding as well as hypoxic reporter gene activation, suggesting that a methylation-free HBS is mandatory for HIF-1 function. The in vivo methylation pattern of the erythropoietin 3' HBS in various human cell lines and mouse organs was assessed by genomic Southern blotting using a methylation-sensitive restriction enzyme. Whereas this site was essentially methylation-free in the erythropoietin-producing cell line Hep3B, a direct correlation between erythropoietin protein expression and the degree of erythropoietin 3' HBS methylation was found in different HepG2 sublines. However, the finding that this site is partially methylation-free in human cell lines and mouse tissues that do not express erythropoietin suggests that there might be a general selective pressure to keep this site methylation-free, independent of erythropoietin expression.
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PMID:Oxygen-regulated erythropoietin gene expression is dependent on a CpG methylation-free hypoxia-inducible factor-1 DNA-binding site. 965 78

Control of gene expression is important to gene therapy for purposes of both dosing and safety. In vivo regulation of gene expression was demonstrated following co-injection of two separate recombinant adeno-associated virus vectors, one encoding an inducible murine erythropoietin transgene and the other a transcriptional activator, directly into the skeletal muscle of adult immunocompetent mice. Transcription was controlled by systemic administration or withdrawal of tetracycline over an 18 week period, demonstrating that the two vectors were capable of transducing the same cell. Cellular or humoral immune responses against the transactivator protein were not detected.
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PMID:Regulation of gene expression in vivo following transduction by two separate rAAV vectors. 970 75

Iron chelators are pluripotent neuronal antiapoptotic agents that have been shown to enhance metabolic recovery in cerebral ischemia models. The precise mechanism(s) by which these agents exert their effects remains unclear. Recent studies have demonstrated that iron chelators activate a hypoxia signal transduction pathway in non-neuronal cells that culminates in the stabilization of the transcriptional activator hypoxia-inducible factor-1 (HIF-1) and increased expression of gene products that mediate hypoxic adaptation. We examined the hypothesis that iron chelators prevent oxidative stress-induced death in cortical neuronal cultures by inducing expression of HIF-1 and its target genes. We report that the structurally distinct iron chelators deferoxamine mesylate and mimosine prevent apoptosis induced by glutathione depletion and oxidative stress in embryonic cortical neuronal cultures. The protective effects of iron chelators are correlated with their ability to enhance DNA binding of HIF-1 and activating transcription factor 1(ATF-1)/cAMP response element-binding protein (CREB) to the hypoxia response element in cortical cultures and the H19-7 hippocampal neuronal cell line. We show that mRNA, protein, and/or activity levels for genes whose expression is known to be regulated by HIF-1, including glycolytic enzymes, p21(waf1/cip1), and erythropoietin, are increased in cortical neuronal cultures in response to iron chelator treatment. Finally, we demonstrate that cobalt chloride, which also activates HIF-1 and ATF-1/CREB in cortical cultures, also prevents oxidative stress-induced death in these cells. Altogether, these results suggest that iron chelators exert their neuroprotective effects, in part, by activating a signal transduction pathway leading to increased expression of genes known to compensate for hypoxic or oxidative stress.
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PMID:Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin. 1055 91

Angiogenesis is essential for the increased delivery of oxygen and nutrients required for the reparative processes of bone healing. Vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, has been implicated in this process. We have previously shown that hypoxia specifically and potently regulates the expression of VEGF by osteoblasts. However, the molecular mechanisms governing this interaction remain unknown. In this study, we hypothesized that the hypoxic regulation of VEGF expression by osteoblasts occurs via an oxygen-sensing mechanism similar to the regulation of the erythropoietin gene (EPO). To test this hypothesis, we examined the kinetics of oxygen concentration on osteoblast VEGF expression. In addition, we analyzed the effects of nickel and cobalt on the expression of VEGF in osteoblastic cells because these metallic ions mimic hypoxia by binding to the heme portion of oxygen-sensing molecules. Our results indicated that hypoxia potently stimulates VEGF mRNA expression. In addition, we found that nickel and cobalt both stimulate VEGF gene expression in a similar time- and dose-dependent manner, suggesting the presence of a hemelike oxygen-sensing mechanism similar to that of the EPO gene. Moreover, actinomycin D, cycloheximide, dexamethasone, and mRNA stabilization studies collectively established that this regulation is predominantly transcriptional, does not require de novo protein synthesis, and is not likely mediated by the transcriptional activator AP-1. These studies demonstrate that hypoxia, nickel, and cobalt regulate VEGF expression in osteoblasts via a similar mechanism, implicating the involvement of a heme-containing oxygen-sensing molecule. This may represent an important mechanism of VEGF regulation leading to increased angiogenesis in the hypoxic microenvironment of healing bone.
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PMID:VEGF expression in an osteoblast-like cell line is regulated by a hypoxia response mechanism. 1075 33

The tetracycline (Tet)-dependent regulatory system has been widely used for controlling gene expression. The Tet-on version of the system, in which the reverse Tet-responsive transcriptional activator (rtTA) is positively regulated by Tet or its analogs, such as doxycycline (Dox), is of potential utility for gene therapy applications in humans. However, rtTA may display a high basal activity, especially when delivered in vivo by using episomal vectors such as plasmids. Two novel Dox-inducible activators, called rtTA2(S)-S2 and rtTA2(S)-M2, which have a significantly lower basal activity than rtTA in stably transfected cell lines, have been described. In this study we tested the capability of these trans-activators to control expression of mouse erythropoietin (mEpo) and to modulate hematocrit (Hct) increase in vivo on delivery of plasmids into quadriceps muscles of adult mice by DNA electroinjection. Both rtTA2(S)-M2 and rtTA2(S)-S2 displayed a considerably lower background activity and higher window of induction than rtTA in vivo. Moreover, a stringent control of mEpo gene expression and Hct levels in the absence of any background activity was maintained over a 10-month period by injecting as little as 1 microg of a single plasmid containing the rtTA2(S)-S2 expression cassette and the Tet-responsive mEpo cDNA. This constitutes the first report of a stringent ligand-dependent control of gene expression in vivo obtained by delivering a single plasmid encoding both the trans-activator and the regulated gene. Notably, the rtTA2(S)-S2-based system was induced by oral doses of doxycycline comparable to those normally used in clinical practice in humans.
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PMID:Stringent control of gene expression in vivo by using novel doxycycline-dependent trans-activators. 1181 77

Heme and its metabolism fulfill significant roles in many homeostatic and adaptative reactions. For example, heme (protein) senses oxygen concentration to regulate hypoxia response genes such as erythropoietin, and free heme, a proxidant, controls levels of several oxidative stress response proteins as well as that of a few enzymes in the heme metabolic pathway. Heme oxygenase (HO) is the key enzyme in heme catabolism, which degrades heme to Fe, CO, and biliverdin. CO is known as a gaseous messenger in the vascular and nervous systems. Biliverdin is rapidly converted to bilirubin, whose antioxidative effect is proposed to protect cells against reactive oxygen species. HO-1, the inducible isozyme of HO, is induced not only by its substrate heme, but also NO, metals, hypoxia, and various other stimuli. Studies on HO-1 deficiency indicate that induction of HO-1 is essential to homeostasis, at least in humans. Heme response elements (HREs), which mediate the induction of HO-1 expression by heme, are identified in enhancer regions of the mouse HO-1 gene. HRE shares a nucleotide sequence with the Maf recognition element (MARE). A transcriptional activator, Nrf2, has been shown to participate in HO-1 induction by several stimuli, including heme via HRE. A heme-binding transcription factor such as yeast Hap1 had been supposed to also exist in vertebrates, however, no such factor had been identified. Recently, we found that a mammalian transcription repressor, Bach1, directly binds heme, and that the DNA binding activity of Bach1 is negatively regulated by heme. Bach1 is capable of competing the binding to MARE with activators including Nrf2, therefore, HO-1 and other stress response genes bearing MARE may be regulated by heme via the MARE-binding transcription factors. Further analyses on the gene regulatory mechanism by heme would help us to understand the stress response system, especially against oxidative stress.
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PMID:[Heme metabolism in stress response]. 1186 90

Included in the acute response of lowlanders exposed to reduced oxygen availability is an elevated red blood cell count due to increased erythropoietin (Epo) synthesis. According to current thinking, hypoxia is "sensed" by hydroxylases that permit Hypoxia Inducible Factor 1alpha (HIF-1alpha) to complex with HIF-1beta to form a transcriptional activator (HIF-1) that drives expression of hypoxia-sensitive genes (such as EPO) under hypoxic conditions. In altitude-adapted Andean natives, the Epo hypoxic response may be blunted; however, our data indicate that the DNA sequences of the genes encoding Epo (including the 3' regulatory region) and HIF-1alpha appear to be conserved. Hence, adaptive changes in the Andean hypoxic response are not a consequence of changes in the primary sequence of these proteins or of known transcriptional regulatory domains of EPO. These results suggest that the altered erthropoietic response in Andean natives reflects adaptations in hypoxia sensing, rather than hypoxia response, mechanisms.
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PMID:Fine tuning the HIF-1 'global' O2 sensor for hypobaric hypoxia in Andean high-altitude natives. 1271 22


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