Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Curcumin (CCM), a major yellow pigment of turmeric obtained from powdered rhizomes of the plant Curcuma longa Linn, is commonly used as coloring agent in foods, drugs and cosmetics. In this study we report that gavage administration of 200 mg/kg or 600 mg/kg CCM effectively suppressed diethylnitrosamine (DEN)-induced liver inflammation and hyperplasia in rats, as evidenced by histopathological examination. Immunoblotting analysis showed that CCM strongly inhibited DEN-mediated the increased expression of oncogenic p21(ras) and p53 proteins in liver tissues of rats. In cell-cycle-related proteins, CCM selectively reduced the expression of proliferating cell nuclear antigen (PCNA), cyclin E and p34(cdc2), but not Cdk2 or cyclin D1. Moreover, CCM also inhibited the DEN-induced increase of transcriptional factor NF-kappa B. However, CCM failed to affect DEN-induced c-Jun and c-Fos expression. It has become widely recognized that the development of human hepatocellular carcinoma (HCC) is predominantly due to the chronic inflammation by virus, bacteria or chemical. Our results suggest a potential role for CCM in the prevention of HCC.
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PMID:Inhibition by curcumin of diethylnitrosamine-induced hepatic hyperplasia, inflammation, cellular gene products and cell-cycle-related proteins in rats. 1103 36

The Sma and Mad related (Smad) family proteins are critical mediators of the transforming growth factor-beta (TGF-beta) superfamily signaling. After TGF-beta-mediated phosphorylation and association with Smad4, Smad2 moves to the nucleus and activates expression of specific genes through cooperative interactions with DNA-binding proteins, including members of the winged-helix family of transcription factors, forkhead activin signal transducer (FAST)-1 and FAST2. TGF-beta has also been described to activate other signaling pathways, such as the c-Jun N-terminal Kinase (JNK) pathway. Here, we show that activation of JNK cascade blocked the ability of Smad2 to mediate TGF-beta-dependent activation of the FAST proteins. This inhibitory activity is mediated through the transcriptional factor c-Jun, which enhances the association of Smad2 with the nuclear transcriptional corepressor TG-interacting factor (TGIF), thereby interfering with the assembly of Smad2 and the coactivator p300 in response to TGF-beta signaling. Interestingly, c-Jun directly binds to the nuclear transcriptional corepressor TGIF and is required for TGIF-mediated repression of Smad2 transcriptional activity. These studies thus reveal a mechanism for suppression of Smad2 signaling pathway by JNK cascade through transcriptional repression.
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PMID:c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity. 1137 41

Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, have been examined following intracortical injection of the glutamate analogue quinolinic acid (QA). Increased JNK(P) and p38(P) immunoreactivity has been found in the core at 1 h following QA injection, whereas increased MAPK(P) immunoreactivity occurs in neurons and glial cells localised around the lesion and in neurons in remote cortical regions. This is accompanied by strong phosphorylated Ser63 c-Jun (c-Jun(P)) immunoreactivity in the core at 3 h, and by strong phosphorylated CREB, Elk-1 and ATF-2 (CREB(P), Elk-1(P) and ATF-2(P)) immunoreactivity mainly in neurons around the core at 24 h following QA injection. Examination with the method of in situ end-labelling of nuclear DNA fragmentation has revealed large numbers of positive cells with no apoptotic morphology in the core at 24 h, thus indicating that JNK(P), p38(P) and c-Jun(P) over-expression precedes cell death. In contrast, MAPK(P), CREB(P), Elk-1(P) and ATF-2(P), but not phosphorylated c-Myc (c-Myc(P)), over-expression correlates with cell survival. Examination of cleaved, active caspase-3 has shown specific immunoreactivity restricted to a few hematogenous cells in the area of injection. Since cleaved caspase-3 is not expressed by dying cells in the present paradigm, JNK(P), p38(P) and c-Jun(P) expression is not associated with caspase-3 activation. The present results demonstrate selective activation of specific MAPK signals which are involved either in cell death or cell survival triggered by excitotoxic insult.
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PMID:Differential expression of active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates following quinolinic acid excitotoxicity in the rat. 1159 64

Calcium antagonists (CAs) are widely prescribed for patients with cardiovascular diseases. CAs have been reported to inhibit smooth muscle cell (SMC) proliferation in addition to their effects on vascular tone. To determine whether CAs potentially affect vascular remodeling, we measured the expression of matrix-degrading enzymes in growth factor-stimulated SMC. Human cultured SMC were stimulated with 10 ng/ml of platelet-derived growth factor (PDGF)-BB with or without a calcium antagonist, diltiazem. In the cell counting assay, diltiazem (10-5 M) alone had no effect on the proliferation of quiescent SMC, however 10-6-10-5 M of diltiazem dose-dependently inhibited PDGF-stimulated SMC proliferation. The inhibitory effects of diltiazem on SMC proliferation were further confirmed by a 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and flow cytometry. In Western blotting, matrix metalloproteinase (MMP)-1 (tissue collagenase) but not MMP-2 (72-kDa gelatinase) expression was upregulated by PDGF and phorbol ester (TPA), which were reduced by diltiazem in a dose-dependent manner. The downregulation of MMP-1 expression was consistent with the reduction of collagenolytic activity measured by a FITC-conjugated type I collagen breakdown assay. PDGF-stimulated c-Jun/AP-1 expression, a major transcriptional factor for MMP-1, was not affected by diltiazem. In contrast, intracellular calcium ions measured with a fluorometric assay of Fluo-3AM-loaded cells revealed that the PDGF-stimulated increase in the intracellular calcium content was dose-dependently reduced by diltiazem. Our data suggest that diltiazem inhibits not only proliferation but also MMP-1 expression and collagenolytic activity in PDGF-stimulated SMC. The administration of CAs potentially influences the process of vascular remodeling, and this possibility should be further verified in vivo.
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PMID:Diltiazem, a calcium antagonist, inhibits matrix metalloproteinase-1 (tissue collagenase) production and collagenolytic activity in human vascular smooth muscle cells. 1160 28

Cellular responses to xenobiotic-induced stress can signal proliferation, differentiation, homeostasis, apoptosis, or necrosis. To better understand the underlying molecular mechanisms after exposure to xenobiotics or drugs, we studied the signal transduction pathways, the mitogen-activated protein kinase (MAPK), and the basic leucine zipper transcription factor Nrf2, activated by different agents in the induction of Phase II drug metabolizing enzymes (DMEs). The MAPKs, characterized as proline-directed serine/threonine kinases, are essential components of signaling pathways that convert various extracellular signals into intracellular responses through serial phosphorylation cascades. Once activated, MAPKs can phosphorylate many transcription factors, such as c-Jun, ATF-2, and ultimately lead to changes in gene expression. Two classes of Phase II gene inducers, which are also cancer chemopreventive agents, were studied: (1) the phenolic antioxidants, namely butylated hydroxyanisole (BHA) and its active de-methylated metabolite t-butylhydroquinone (tBHQ), and phenolic flavonoids such as green tea polyphenols (GTP) and (-)-epigallocatechin-3-gallate (EGCG); and (2) the naturally occurring isothiocyanates, namely phenethyl isothiocyanate (PEITC), and sulforaphane. BHA and tBHQ are both well-known phenolic antioxidants used as food preservatives, and strongly activate c-Jun N-terminal kinase 1 (JNK1), extracellular signal-regulated protein kinase 2 (ERK2), or p38, in a time- and dose-dependent fashion. Free radical scavengers N-acetyl-L-cysteine (NAC), or glutathione (GSH), inhibited ERK2 activation and, to a much lesser extent, JNK1 activation by BHA/tBHQ, implicating the role of oxidative stress. Under conditions where MAPKs were activated, BHA or GTP also activated ARE/EpRE (antioxidant/electrophile response element), with the induction of Phase II genes such as NQO. Transfection studies with various cDNAs encoding wild-type or dominant-negative mutants of MAPKs and/or transcription factor Nrf2, substantially modulated ARE-mediated luciferase reporter activity in the presence or absence of phenolic compounds. Other phytochemicals including PEITC, and sulforaphane, also differentially regulated the activities of MAPKs, Nrf2, and ARE-mediated luciferase reporter gene activity and Phase II enzyme induction. A model is proposed where these xenobiotics (BHA, tBHQ, GTP, EGCG, PEITC, sulforaphane) activate the MAPK pathway via an electrophilic-mediated stress response, leading to the transcription activation of Nrf2/Maf heterodimers on ARE/EpRE enhancers, with the subsequent induction of cellular defense/detoxifying genes including Phase II DMEs, which may protect the cells against toxic environmental insults and thereby enhance cell survival. The studies of these signaling pathways may yield insights into the fate of cells upon exposure to xenobiotics.
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PMID:Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE). 1176 69

Corpora amylacea (CAm) are regarded as a hallmark of brain ageing, but little is known about their role in normal and pathological circumstances. CAm contain, in addition to glucose polymers, ageing-, stress- and proinflammatory proteins. In view of their almost universal occurrence and their cumulation with time, formation of CAm may represent a basic mechanism for the management of metabolic degradation products. In this context, we studied samples from post-mortem cases with repetitive brain hypoxic episodes in the past history. We investigated, by immunohistochemistry, the presence of Bcl-2, c-jun and bax in CAm. CAm showed immunoreactivity for the mitochondrial membrane associated protein Bcl-2, and for the major component of activator protein 1 transcriptional factor c-Jun. We found higher numbers of CAm in the hippocampus and the dentate gyrus in cases with repetitive cerebral hypoxia than in controls. We conclude that: (1) the presence of C-Jun and Bcl-2 within the glucose polymer mass of CAm may be related to mitochondrial damage and/or a transient overload of proteolytic systems during cellular injury; and (2) repetitive cellular stress during life may cause the age-related increase of CAm in elderly subjects.
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PMID:Immunoreactivity for Bcl-2 and C-Jun/AP1 in hippocampal corpora amylacea after ischaemia in humans. 1190 30

Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet the mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress-activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active, phosphorylation-dependent specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, has been examined following systemic administration of kainic acid (KA) at convulsant doses to rats. Increased phosphorylated MAPK (MAPK(P)) immunoreactivity has been found at 3 and 6 h in the vulnerable regions entorhinal cortex and CA3, in which neurons are committed to die, as well as in sensitive regions dentate gyrus and gyrus cinguli, in which neurons will survive. JNK(P) has been observed in the entorhinal cortex and dentate gyrus, and p38(P) immunoreactivity occurs in the entorhinal cortex. Strong c-Myc(P) expression parallels MAPK(P) immunoreactivity in the entorhinal cortex, CA3, dentate gyrus and gyrus cinguli, showing that enhanced c-Myc(P) expression does not preclude cell death or cell survival. Selective decrease of CREB(P) immunoreactivity in entorhinal cortex and CA3 indicates CREB(P) reduction associated with cell death. Strong c-Jun(P) immunoreactivity has been found in the entorhinal cortex, CA3 and dentate gyrus, thus suggesting that regulation of two opposing cellular programs (cell death or cell survival) of c-Jun(P) depends on c-Jun interactions with other factors. Interestingly, ATF-2(P), and to a lesser extent Elk-1(P), is selectively increased in the dentate gyrus. These results suggest ATF-2(P) involvement in cell survival of dentate gyrus granule cells. The present results demonstrate activation of specific MAPK pathways in association with either cell death or cell survival triggered by KA. Furthermore, increased Ras activation, as seen with p21 Ras activation assay, indicates a crucial role for Ras in activating MAP kinases following excitotoxic insult.
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PMID:Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat. 1190 60

Heat shock response has been implicated in cytoprotective effects from cellular damage and in the regulation of cytokine expression. We report the effect of heat shock on LPS-induced expression of IL-18, an important cytokine that has diverse immune regulatory effects on T cells, B cells, NK cells, and nonimmune cells. The augmentation of LPS-induced IL-18 mRNA and protein was significantly suppressed in murine peritoneal macrophages after 43 degrees C heat shock treatment. In addition, the JNK MAPK inhibitor SP600125 inhibited IL-18 mRNA transcription in a dose-dependent manner. To examine the possibility that the inhibition of IL-18 may be mediated through the inactivation of JNK, the activity of JNK was measured by using Western blot and kinase assays. Our data show that heat shock response decreased LPS-induced phosphorylation of JNK and its downstream substrate c-Jun. AP-1, a transcriptional factor composed of c-Jun, could regulate the expression of IL-18. Also, its DNA-binding activity was reduced by the heat shock response. These findings suggest that treatment of heat stress results in inhibition of IL-18 production in macrophages mainly through the JNK/AP-1 signaling pathway.
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PMID:Heat shock response inhibits IL-18 expression through the JNK pathway in murine peritoneal macrophages. 1217 45

Stat3 mediates cellular responses associated with proliferation, survival and differentiation, but the mechanisms underlying the diverse effects of this signaling molecule remain unknown. M1 mouse myeloid leukemia cells arrest growth and differentiate into macrophages following treatment with interleukin 6 (IL-6) or leukemia inhibitory factor (LIF), and recent studies have shown that Stat3 plays a central role in this process. Utilizing representational difference analysis, we demonstrate that expression of the mouse BATF gene is upregulated as an early response to IL-6/LIF stimulation and Stat3 activation in this cell system. Immunoblots using antibodies to BATF detected an increase in BATF protein in response to LIF/IL-6 stimulation. BATF is a member of the AP-1 family of basic leucine zipper transcription factors and functions to inhibit the transcriptional and biological functions of AP-1 activity in mammalian cells. BATF forms complexes with c-Jun in M1 cells and forced expression of BATF in the absence of Stat3 signaling results in a reduced rate of cellular growth. These results indicate that Stat3 mediates cellular growth by modulating AP-1 activity through the induction of BATF.
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PMID:Stat3-dependent induction of BATF in M1 mouse myeloid leukemia cells. 1244 55

Hydrogen peroxide (H(2)O(2)) has been shown to act as a second messenger that activates chemokine expression. In the present study, we investigated the mechanisms underlying this cellular regulation in the murine macrophage cell line B10R. We report that H(2)O(2) increases mRNA expression of various chemokines, macrophage-inflammatory protein (MIP)-1alpha/CC chemokine ligand (CCL)3, MIP-1beta/CCL4, MIP-2/CXC chemokine ligand 2, and monocyte chemoattractant protein-1/CCL2, by activating the extracellular signal-regulated kinase (ERK) pathway and the nuclear translocation of the transcription factors NF-kappaB, AP-1, and CREB. Blockage of the ERK pathway with specific inhibitors against mitogen-activated protein kinase kinase 1/2 and ERK1/ERK2 completely abolished both the H(2)O(2)-mediated chemokine up-regulation and the activation of all NF studied. Similarly, selective inhibition of cAMP and NF-kappaB strongly down-regulated the induction of all chemokine transcripts as well as CREB and NF-kappaB activation, respectively. Of interest, we detected a significant decrease of NF-kappaB, AP-1, and CREB DNA binding activities by reciprocal competition for these binding sites when either specific cold oligonucleotides (NF-kappaB, AP-1, and CREB) or Abs against various transcription factor subunits (p50, p65, c-Fos, Jun B, c-Jun, and CREB-1) were added. These findings indicate that cooperation between ERK- and cAMP-dependent pathways seems to be required to achieve the formation of an essential transcriptional factor complex for maximal H(2)O(2)-dependent chemokine modulation. Finally, experiments performed with actinomycin D suggest that H(2)O(2)-mediated MIP-1beta mRNA up-regulation results from transcriptional control, whereas that of MIP-1alpha, MIP-2, and monocyte chemoattractant protein-1 is due to both gene transcription activation and mRNA posttranscriptional stabilization.
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PMID:Hydrogen peroxide induces murine macrophage chemokine gene transcription via extracellular signal-regulated kinase- and cyclic adenosine 5'-monophosphate (cAMP)-dependent pathways: involvement of NF-kappa B, activator protein 1, and cAMP response element binding protein. 1247 Nov 38


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