Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxygen radicals are induced under various pathologic conditions associated with neovascularization. Oxygen radicals modulate angiogenesis in cultured human microvascular endothelial cells by an unknown mechanism. Treatment of human microvascular endothelial cells for 15 min with 0.1 to 0.5 mM hydrogen peroxide (H2O2) or 100 U of tumor necrosis factor alpha per ml induced tubular morphogenesis in type I collagen gels. Gel shift assays with nuclear extracts demonstrated that H2O2 increases the binding activities of two transcription factors, NF-kappaB and AP-1, but not of Spl. Tumor necrosis factor alpha increased the binding activities of all three factors. A supershift assay with specific antibodies against JunB, JunD, and c-Jun (Jun family) showed that the antibody against c-Jun supershifted the AP-1 complex after H2O2 treatment. Coadministration of the antisense sequence of NF-kappaB inhibited H2O2-dependent tubular morphogenesis, and the antisense c-Jun oligonucleotide caused partial inhibition. The angiogenic factor responsible for H2O2-induced tubular morphogenesis was examined. Cellular mRNA levels of vascular endothelial growth factor and interleukin-8 (IL-8), but not those of transforming growth factor alpha, were increased after treatment with 0.5 mM H2O2. Coadministration of anti-IL-8 antibody inhibited tubular morphogenesis enhanced by H2O2, and IL-8 itself also enhanced the formation of tube-like structures. Treatment with antisense NF-kappaB oligonucleotide completely blocked H2O2-dependent IL-8 production by endothelial cells. The tubular morphogenesis of vascular endothelial cells after treatment with oxidative stimuli and its possible association with NF-kappaB and IL-8, is examined.
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PMID:Involvement of the transcription factor NF-kappaB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress. 875 23

We have previously reported that hydrogen peroxide, an active oxygen species and a cellular oxidant, induces c-Fos and c-Jun mRNA expression and DNA synthesis in vascular smooth muscle cells and that these events require arachidonic acid release and metabolism through the lipoxygenase pathway. Here we have identified the eicosanoids that mediate the hydrogen peroxide-induced growth-related events in these cells. Hydrogen peroxide stimulated the production of 12- and 15-hydroperoxyeicosatetraenoic acids in vascular smooth muscle cells. Both 12- and 15-hydroperoxyeicosatetraenoic acids induced the expression of c-Fos and c-Jun protein and increased activating protein 1 (AP-1) activity, as measured by AP-1-DNA binding and AP-1-dependent human collagenase promoter-driven chloramphenicol acetyltransferase reporter gene transcription. Hydrogen peroxide and arachidonic acid also induced the expression of c-Fos and c-Jun protein and AP-1 activity. Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, significantly inhibited both hydrogen peroxide and arachidonic acid-stimulated c-Fos and c-Jun protein expression and AP-1 activity. Together, these findings suggest that hydrogen peroxide induces the production of eicosanoids and that the eicosanoids are potential mediators of the oxidative stress-stimulated growth-related events in vascular smooth muscle cells.
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PMID:Role of hydroperoxyeicosatetraenoic acids in oxidative stress-induced activating protein 1 (AP-1) activity. 891 Mar 70

Abasic sites in DNA are generated either spontaneously or after removal of altered bases during the base excision repair process. These as well as 3' damaged ends of DNA at single-strand breaks induced by reactive oxygen species are repaired by AP-endonucleases. The major human AP-endonuclease (named APE-1) has two unrelated activities. It may function as an activator of c-Fos and c-Jun transcription factors and as a repressor of the parathyroid hormone (PTH) gene by binding to the negative Ca(2+)-response elements (nCaRE) in its promoter. Preliminary studies indicate that the h-APE-1 gene is highly regulated. Analysis of its promoter activity by transient expression of the luciferase reporter gene in human, HeLa and TK6 cells suggested the presence of a negative regulatory element in the promoter. Two nCaRE-like sequences were identified in the promoter segment responsible for inhibiting reporter gene expression. Competitive electrophoretic mobility shift assay with HeLa nuclear extract indicated that the nCaRE sequences of the APE-1 and PTH genes are recognized by the APE-1 polypeptide. These results suggest that the APE-1 gene may be down-regulated by its own product.
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PMID:Negative regulation of the major human AP-endonuclease, a multifunctional protein. 894 27

Hypoxia and reoxygenation are principal components of myocardial ischemia and reperfusion and have distinctive effects on the tissue. Both conditions have been associated with inflammation, necrosis, apoptosis, and myocardial infarction. Using a cell culture model of ischemia and reperfusion in which cardiac myocytes were exposed to cycles of hypoxia and reoxygenation, we report here that reoxygenation, but not hypoxia alone, caused sustained approximately 10-fold increases in phosphorylation of the amino-terminal domain of the c-jun transcription factor. The activation was similar to treatments with anisomycin or okadaic acid and correlated with the hypoxia-mediated depression of intracellular glutathione. Reoxygenation-induced c-Jun kinase activity was reduced by preincubating myocytes during the hypoxia phase with the spin-trap agent alpha-phenyl N-tert-butylnitrone or with N-acetylcysteine. The kinase activation was also inhibited by the tyrosine kinase inhibitor genistein but not by other protein kinase inhibitors. These results implicate unquenched reactive oxygen intermediates as the stimulus that initiates a kinase pathway involving the stress-activated protein kinases (JNKs/SAPKs) in reoxygenated cardiac myocytes.
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PMID:Hypoxia/reoxygenation stimulates Jun kinase activity through redox signaling in cardiac myocytes. 904 53

Manganese superoxide dismutase (MnSOD) has been found to be depleted in a variety of tumor cells as well as in in vitro transformed cell lines, suggesting that MnSOD may function as an anticarcinogen by protecting the cell from oxidant-induced carcinogenesis. The relationship between MnSOD expression and tumor promotion was studied by transfection of a human MnSOD cDNA into the promotable mouse epidermal cell line JB6 clone41. The effect of MnSOD overexpression on the promotion-sensitive phenotype of JB6 cells was assessed by measuring growth characteristics such as growth rate and the ability to form colonies in soft agar. Compared with the parental and vector-transfected (gpt) control cells, MnSOD-overexpressing cells had a slower growth rate and their ability to form colonies in soft agar was significantly decreased in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. Since the transformation-sensitive phenotype of JB6 clone41 cells is associated with increased expression of the transcription factor AP-1, we compared c-jun and c-fos mRNA expression in MnSOD-transfected and control JB6 cells. Overexpression of MnSOD led to a significant decrease in c-jun and c-fos expression in response to treatment with TPA or the oxidant promoter superoxide. These findings indicate that the promotion-sensitive phenotype of JB6 clone41 cells can be reverted by increasing MnSOD intracellularly. A possible mechanism is that elevated MnSOD expression might change the intracellular redox state by altering the balance of reactive oxygen species. This could lead to a modulation of TPA and oxidant-induced signal transduction pathways controlling cell growth and differentiation.
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PMID:Manganese superoxide dismutase expression inhibits soft agar growth in JB6 clone41 mouse epidermal cells. 906 45

Oxygen plays such a critical role in the central nervous system that a specialized mechanism of oxygen delivery to neurons is required. Reduced oxygen tension, or hypoxia, may have severe detrimental effects on neuronal cells. Several studies suggest that hypoxia can induce cellular adaptive responses that overcome apoptotic signals in order to minimize hypoxic injury or damage. Adaptive responses of neuronal cells to hypoxia may involve activation of various ion channels, as well as induction of specific gene expression. For example, ATP sensitive K+ channels are activated by hypoxia in selective neuronal cells, and may play a role in cell survival during hypoxia/anoxia. Additionally, hypoxia-induced c-Jun, bFGF and NGF expression appear to be associated with prevention (or delay) of neuronal cell apoptosis. In this paper, these adaptive responses to hypoxia in neuronal cells are discussed to examine the possible role of hypoxia in pathophysiology of diseases.
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PMID:Cellular adaptive responses to low oxygen tension: apoptosis and resistance. 913 Feb 64

Ultraviolet A (UVA: 320-400 nm) radiation activates c-Jun-N-terminal kinase (JNK 2) in human skin fibroblasts. Exposure of cells to UVA (300 kJ/m2) led to a 5-fold induction of JNK-activity which was significantly increased in the presence of D2O, an enhancer of the lifetime of singlet oxygen. Sodium azide, a quencher of singlet oxygen, abolished the activation of JNK. A hydroxyl radical scavenger, mannitol, had no effect. Furthermore, photochemically produced singlet oxygen (Rose Bengal plus white light) was found to induce JNK activity. This was enhanced by D2O and inhibited by azide. Thus, singlet oxygen activates and mediates the UVA-induced activation of JNK.
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PMID:Singlet oxygen mediates the activation of JNK by UVA radiation in human skin fibroblasts. 918 78

Thioredoxin (Trx) is a small ubiquitous dithiol protein which together with the FAD-containing enzyme thioredoxin reductase (TR) and NADPH (the Trx system) is a hydrogen donor for ribonucleotide reductase essential for DNA synthesis and a general protein disulfide reductase involved in redox regulation. Selenite, selenodiglutathione (GS-Se-SG) and selenocystine are efficiently reduced by thioredoxins and also directly by NADPH and mammalian TR but not by the E. coli enzyme. Incubation of selenite or GS-Se-SG with the Trx system or with mammalian TR results in a rapid formation of selenide, which by redox cycling with oxygen may cause a large non-stoichiometric oxidation of NADPH. Selenocystine is efficiently reduced into two molecules of the selenol amino acid selenocysteine by mammalian TR with a K(m)-value (6 mumol.L-1) and a high turnover number (kappa cat 3200 min-1) almost identical to the natural substrate Trx-S2. TR also directly reduces lipid hydroperoxides and this peroxidase reaction is strongly stimulated by the presence of catalytic amounts of free selenocysteine. Glutaredoxin (Grx) which catalyzes GSH-dependent disulfide reduction also via a redox-active disulfide and Trx are both efficient electron donors to the human plasma glutathione peroxidase providing a mechanism by which human plasma glutathione peroxidase may reduce hydroperoxides in an environment almost free from glutathione. Selenate is reduced by Grx and Trx in the presence of GSH. The DNA-binding of the transcription factor AP-1 is strongly inhibited by GS-Se-SG and selenite. Furthermore, selenide formed by TR-mediated reduction of selenite and GS-Se-SG inhibits lipoxygenase and changes the electron spin resonance spectrum of the active site iron. Mammalian TR with two subunits of 57 kDa has recently been cloned and shown to be homologous to glutathione reductase. The rat enzyme contains a selenocysteine residue in a unique Cterminal position and a conserved SECIS sequence directing insertion of the selenocysteine. The discovery of selenocysteine in mammalian TR may explain the broad substrate specificity of the enzyme and the requirement of selenium for cell proliferation.
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PMID:Selenium and the thioredoxin and glutaredoxin systems. 931 20

The effect of angiotensin II (Ang II) to activate c-Jun amino-terminal kinase (JNK) was studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type-1a Ang II receptor (CHO-AT1a). Ang II treatment induced a time-dependent activation of JNK. Ang II (10(-7) mol/L) activated JNK activity, with a peak at 30 minutes (9.39 +/- 2.52-fold, n = 7, P < .02 versus control), which was maintained until 3 hours (2.7 +/- 0.65-fold, n = 3, P < .02 versus control). Ang II-induced JNK activation at 30 minutes was inhibited by a specific lipoxygenase (LO) pathway inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (1 mumol/L) by 87.5% (n = 4, P < .01 versus Ang II-induced JNK activity). The direct addition of 12-HETE also induced a time-dependent JNK activation. 12-HETE (10(-7) mol/L) activated JNK activity, with a peak at 10 minutes (3.43 +/- 0.87-fold, n = 6, P < .02 versus control), which remained elevated until 1 hour. These results suggest that the LO pathway is a mediator of Ang II-induced JNK activation. 15-HETE can also activate JNK at 5 minutes, but this activity was reduced at 30 minutes and could not be seen at 1 hour, indicating that the time course was different from that seen with 12-HETE. N-Acetylcysteine (NAC), an antioxidant, was used to perturb intracellular reactive oxygen intermediate (ROI) levels to assess the role of endogenous ROIs in regulating JNK activity. Pretreatment of cells with 500 mumol/L NAC for 1 hour attenuated approximately 50% of Aug II-induced JNK activation, suggesting that ROIs, at least partially, mediate Ang II-induced JNK activation. Furthermore, 12-HETE-induced JNK activation was reduced by approximately 90% by NAC. Finally, pertussis toxin completely blocked 12-HETE-induced JNK activation, suggesting that Gi-protein signaling participates in 12-HETE-induced effects. These results suggest that LO activation plays a role in mediating Ang II-induced JNK activation in part by altering the redox tone and Gi-protein signaling of cells.
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PMID:Evidence that angiotensin II and lipoxygenase products activate c-Jun NH2-terminal kinase. 935 37

The expression of c-Fos, c-Jun and Hsp70 was examined in the hippocampus at 6, 12, 24, 48, 72 h, 4, 7 and 42 days following a combination of unilateral common carotid artery ligation and 60 min of systemic hypoxia (8% oxygen, 92% nitrogen) in 25-day-old male rats. While pyknotic cells were not visible in the hippocampus of control animals, pyknosis was evident in the ipsilateral, but not the contralateral hippocampus, of hypoxic-ischemic animals beginning at 24 h post-hypoxia. Immunohistochemical analysis revealed no c-Fos-, c-Jun- or Hsp70-immunoreactivity (IR) in any control animals. However, at 6 h post-hypoxia, Fos- and Jun-IR was evident throughout the injured ipsilateral hippocampus and later appeared throughout the contralateral hippocampus, which never showed signs of pyknosis. In contrast, Hsp70-IR was first observed at 24 h post-hypoxia and was restricted to the injured ipsilateral hippocampus. Hsp70-IR was not, however, limited to dying neurons. H-I/seizure animals did not express these proteins at any time point. These results suggest that, even in irreversibly injured neurons, Fos, Jun and Hsp70 appear to be involved in the aftermath of ischemia but probably do not play a pivotal role in the outcome of H-I compromised cells. Furthermore, compounded injury (H-I/seizure) appears to block the synthesis these proteins.
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PMID:The effects of hypoxia-ischemia on expression of c-Fos, c-Jun and Hsp70 in the young rat hippocampus. 937 54


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