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)

We recently reported that inhibition of NF-kappa B activation as a consequence of the overexpression of a degradation-resistant form of I kappa B alpha [I kappa B alpha(A32/36)] sensitized Ewing sarcoma cells to TNF alpha-induced killing. The c-Jun N-terminal kinases (JNK) have been shown to participate in death signaling triggered by certain stimuli and are activated by TNF alpha. To obtain insight into the mechanism of the anti-apoptotic effect of NF-kappa B, we compared the profiles of JNK activation by TNF alpha in control cells and in cells in which NF-kappa B activation was impaired. We show here that JNK activation was transient in control cells but remained elevated in I kappa B alpha(A32/36)-expressing cells. NF-kappa B repressed specifically the JNK pathway, since the kinetics of activation of the other TNF alpha-activated-MAP kinase p38 were identical in both cells. Prolongation of JNK activation in I kappa B alpha(A32/36)-expressing cells was not inhibited by the broad spectrum caspase inhibitor Z-VAD-FMK and thus was not the consequence of caspase activation. Pretreatment of control cells with the phosphatase inhibitor vanadate greatly prolonged JNK activation by TNF alpha and resulted in induction of apoptosis by this cytokine. Moreover, overexpression of a dominant-negative mutant of JNK1 decreased TNF alpha-induced apoptosis in cells expressing the super repressor of NF-kappa B, indicating that the sustained activation of JNK1 participated in death signaling triggered by TNF alpha. Our results provide evidence that the repression of JNK activation by NF-kappa B participates in the anti-apoptotic effect of this transcription factor in TNF alpha-treated Ewing sarcoma cells.
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PMID:NF-kappa B activation results in rapid inactivation of JNK in TNF alpha-treated Ewing sarcoma cells: a mechanism for the anti-apoptotic effect of NF-kappa B. 1146 17

Transcriptional activation of the human TNF gene involves multiple regulatory elements whose functional properties vary between stimuli and cell types. Here we have used a COS-7 expression system to dissect the transactivating potential of NF-kappa B binding sites in the human TNF promoter region from other regulatory influences. In this model, NF-kappa B acts largely through a dense cluster of three binding sites located 600 nt upstream of the transcription start site. We show that the transcriptional activity of this complex is highly sensitive to the p65:p50 ratio that is expressed. We demonstrate that the AP-1 complex c-Jun/Fra2 is capable of binding to this region and that this inhibits the transactivating effects of NF-kappa B. These results are suggestive of a complex regulatory element that mediates fine control rather than acting as a simple on-off switch for TNF gene expression.
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PMID:Interaction of AP-1 with a cluster of NF-kappa B binding elements in the human TNF promoter region. 1170 71

Insulin-like growth factor-2 (IGF-2) present in media conditioned by non-activated and interferon gamma (IFN gamma)-treated microglia reduces galactocerebroside(+) (GalC) oligodendrocyte apoptosis in cultures derived both from the CG4 cell line and primary rat cortices. Microglia-derived IGF-2 also acts in each culture system to block GalC(+) oligodendrocyte toxicity resulting from soluble microglial-derived tumour necrosis factor alpha (TNF alpha). IGF-2 inhibits TNF alpha-induced c-Jun kinase (JNK) activation of the CG4 cell line. Microglial activation results in the release of soluble factors that are potentially toxic to oligodendrocytes but this may be offset by the production of soluble factors that protect these vulnerable cells. Allowing for extrapolation of these in vitro findings to intact tissue, our observations suggest one mechanism for limiting bystander damage in the context of inflammatory brain disease.
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PMID:Microglia-derived IGF-2 prevents TNFalpha induced death of mature oligodendrocytes in vitro. 1195 20

Inflammatory mediators such as TNF and bacterial LPS do not cause significant apoptosis of endothelial cells unless the expression of cytoprotective genes is blocked. In the case of TNF, the transcription factor NF-kappaB conveys an important survival signal. In contrast, even though LPS can also activate NF-kappaB, this signal is dispensable for LPS-inducible cytoprotective activity. LPS intracellular signals are transmitted through a member of the Toll-like receptor family, TLR4. This family of receptors transduces signals through a downstream molecule, TNFR-associated factor 6 (TRAF6). In this study, we demonstrate that the C-terminal fragment of TRAF6 (TRAF6-C) inhibits LPS-induced NF-kappaB nuclear translocation and c-Jun NH(2)-terminal kinase (JNK) activation in endothelial cells. In contrast, LPS activation of p38 kinase is not inhibited by TRAF6-C. TRAF6-C also inhibits LPS-initiated endothelial apoptosis, but potentiates TNF-induced apoptosis. LPS-induced loss of mitochondrial transmembrane potential, cytochrome c release, and caspase activation are all blocked by TRAF6-C. We demonstrate that TRAF6 signals apoptosis via JNK activation, since inhibition of JNK activation using a dominant-negative mutant also inhibits apoptosis. JNK inhibition blocks caspase activation, but the reverse is not true. Hence, JNK activation lies upstream of caspase activation in response to LPS stimulation.
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PMID:Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH2-terminal kinase. 1219 32

Adult T-cell leukemia is caused by human T-cell leukemia virus type I (HTLV-I). The HTLV-I Tax protein is essential for clinical manifestations because it activates viral and cellular gene transcription. Tax enhances production of tumor necrosis factor-alpha (TNF-alpha), which may lead to bone and joint destruction. Because estrogens might prevent osteoporosis by repressing TNF-alpha gene transcription, we investigated whether estrogens inhibit the transcriptional effects of Tax on the TNF-alpha promoter. Tax activated the -1044, -163, and -125 TNF-alpha promoters by 9-25-fold but not the -82 promoter, demonstrating that Tax activation requires the -125 to -82 region, known as the TNF response element (TNF-RE). Three copies of the TNF-RE upstream of the minimal thymidine kinase promoter conferred a similar magnitude of activation by Tax. We demonstrated that c-Jun, NFkappaB, p50, and p65 interact with and activate the TNF-RE by using mutational analysis of the TNF-RE, Tax mutants that selectively activate NFkappaB or the cAMP-response element binding protein/activating transcription factor pathway, and gel shift assays with nuclear extracts. Estradiol markedly repressed Tax-activated transcription of the TNF-alpha gene with estrogen receptor (ER) alpha or beta. Nuclear extracts from U2OS cells stably transfected with ER(alpha) demonstrated that ERs interact with the TNF-RE. Our studies provide evidence that ERs repress Tax-activated TNF-alpha transcription by interacting with a c-Jun and NFkappaB platform on the TNF-RE. Estrogens may ameliorate bone and inflammatory joint diseases in patients infected with HTLV-I by repressing transcription of the TNF-alpha gene.
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PMID:Estradiol represses human T-cell leukemia virus type 1 Tax activation of tumor necrosis factor-alpha gene transcription. 1223 95

Bacterial lipopolysaccharide (LPS) elicits inflammation and endotoxic shock by inducing proinflammatory cytokine gene expression. The purpose of this study was to test the hypothesis that differential activation of transcription factor binding in the spleen correlates with proinflammatory cytokine gene expression in mice exposed to LPS. When proinflammatory cytokine expression in spleen was evaluated in mice injected ip with 4 mg/kg LPS over an 8-h period, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 mRNAs were elevated up to 5-, 6-, and 300-fold, respectively, over vehicle controls. Both TNF- alpha and IL-6 mRNA peaked at 2 h and begin to decline thereafter, whereas IL-1beta mRNA remained elevated from 2 to 8 h. The capacities of splenic nuclear proteins to bind to six different consensus transcriptional control motifs associated with proinflammatory cytokine promoters were also measured over 8 h. Electrophoretic mobility shift assay (EMSA) revealed that binding activity was markedly increased at 0.5 to 8 h for activator protein-1 (AP-1) as were CCAAT enhancer-binding protein (C/EBP) and nuclear factor kappaB (NF-kappaB) at 0.5 to 1.5 h. At 0.5 h, cyclic AMP response element (CRE)-binding protein (CREB) and binding was slightly elevated, whereas activator protein- 2 (AP-2) and specificity protein 1 (Sp1) binding were not affected. Antibody supershift EMSA and Western blot analysis confirmed that increased binding of these factors correlated with LPS-induced increases in nuclear concentrations of AP-1 (c-Jun, phosphorylated c-Jun, Jun D, and Jun B), C/EBPbeta, NF-kappaB (p50, p65, and c-Rel), CREB (CREB-1, CREB-2, and ATF-2), and AP-2alpha proteins. Remarkably, after 8 h, C/EBP, CREB, AP-2, and Sp1 binding activities were greatly depleted relative to both naive and corresponding vehicle controls. When mice were exposed to a second dose of LPS, 8 h after a 4 mg/kg priming dose, TNF-alpha and IL-6 mRNA responses were markedly impaired, suggesting that the mice were endotoxin tolerant at this time point. Taken together, the quiescent, active, and suppressive phases of transcription factor binding observed in this model were highly consistent with the rapid transient nature of LPS-induced proinflammatory cytokine expression in vivo as well as tolerance to secondary LPS exposure.
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PMID:Kinetics of lipopolysaccharide-induced transcription factor activation/inactivation and relation to proinflammatory gene expression in the murine spleen. 1266 98

IGF-I is a major anabolic hormone for skeletal muscle in vivo. Yet the mechanisms by which GH and cytokines regulate IGF-I expression remain obscure. Lipopolysaccharide (LPS) dramatically alters the circulating concentration of both TNF alpha and IGF-I, and TNF alpha in part mediates the cachectic activity of LPS. Little is known about the local synthesis of IGF-I and TNF alpha in skeletal muscle per se. The purpose of the present study was to determine whether LPS alters the expression of TNF alpha and IGF-I in mouse skeletal muscle and whether TNF alpha directly inhibits IGF-I mRNA expression in C2C12 myoblasts. Intraperitoneal injection of LPS in C3H/SnJ mice increased the expression of TNF alpha protein in plasma (16-fold) and TNF alpha mRNA in skeletal muscle (8-fold). LPS also decreased the plasma concentration of IGF-I (30%) and IGF-I mRNA in skeletal muscle (50%, between 6 and 18 h after LPS administration). Addition of LPS or TNF alpha directly to C2C12 myoblasts decreased IGF-I mRNA by 50-80%. The TNF alpha-induced decrease in IGF-I mRNA was both dose and time dependent and occurred in both myoblasts and differentiated myotubes. TNF alpha selectively decreased IGF-I but not IGF-II mRNA levels, and the effect of TNF alpha was blocked by a specific TNF-binding protein. TNF alpha did not alter IGF-I mRNA levels in the presence of the protein synthesis inhibitor cycloheximide. TNF alpha did not change the half-life of IGF-I mRNA. TNF alpha completely prevented GH-inducible IGF-I mRNA expression, but this GH resistance was not attributable to impairment in signal transducer and activator of transcription-3 or -5 phosphorylation. TNF alpha increased both nitric oxide synthase-II mRNA and protein, and the nitric oxide donor sodium nitroprusside decreased IGF-I mRNA levels in C2C12 cells. Yet inhibitor studies indicate that nitric oxide did not mediate the effect of TNF alpha on IGF-I mRNA expression. TNF alpha stimulated the phosphorylation of c-Jun and specific inhibition of the Jun N-terminal kinase pathway, but not other MAPK pathways, completely prevented the TNF alpha-induced drop in IGF-I mRNA. These data suggest that LPS stimulates TNF alpha expression in mouse skeletal muscle and autocrine-derived cytokines may contribute to the reduced expression of IGF-I in this tissue.
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PMID:Tumor necrosis factor-alpha decreases insulin-like growth factor-I messenger ribonucleic acid expression in C2C12 myoblasts via a Jun N-terminal kinase pathway. 1269 82

Impaired ability to undergo programmed cell death in response to a wide range of external stimuli acquires melanomas a selective advantage for progression and metastasis as well as their notorious resistance to therapy. Better understanding of mechanisms that govern apoptosis has enabled identification of diverse routes by which melanomas manage to escape stimuli of apoptosis. Changes at genomic, transcriptional and post-translational levels of G-proteins and protein kinases (Ras, B-Raf) and their transcription factor effectors (c-Jun, ATF2, Stat3 and NF-kappaB) affects TNF, Fas and TRAIL receptors, which play important roles in acquiring melanoma's resistance to apoptosis. Here, we summarize our current understanding of changes that alters the regulation of death receptors during melanoma development.
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PMID:Death receptors and melanoma resistance to apoptosis. 1278 91

Two genes (MAT1A and MAT2A) encode for methionine adenosyltransferase (MAT), an essential cellular enzyme responsible for S-adenosylmethionine biosynthesis. MAT1A is expressed mostly in the liver, whereas MAT2A is widely distributed. We showed a switch from MAT1A to MAT2A expression in human hepatocellular carcinoma (HCC), which facilitates cancer cell growth. Using DNase I footprinting analysis, we previously identified a region in the MAT2A promoter protected from DNase I digestion in HCC. This region contains NF-kappa B and AP-1 elements, and the present study examined whether they regulate MAT2A promoter activity. We found nuclear binding of NF-kappa B and AP-1 to the MAT2A promoter increased in HCC. Tumor necrosis factor alpha (TNFalpha), which activates both NF-kappa B and AP-1, increased MAT2A expression in a dose- and time-dependent manner, binding of both NF-kappa B and AP-1 to the MAT2A promoter and MAT2A promoter activity, with the latter effect blocked by site-directed mutagenesis of the NF-kappa B and AP-1 binding sites. Blocking NF-kappa B with I kappa B super-repressor or AP-1 with dominant-negative c-Jun led to decreased basal MAT2A expression and prevented the TNF alpha-induced increase in MAT2A expression. Although blocking NF-kappa B had no influence on the ability of TNF alpha to increase AP-1 nuclear binding, blocking AP-1 with dominant-negative c-Jun prevented the TNF alpha-mediated increase in NF-kappa B binding. In conclusion, both NF-kappa B and AP-1 are required for basal MAT2A expression in HepG2 cells and mediate the increase in MAT2A expression in response to TNF alpha treatment. Increased trans-activation of these two sites also contributes to MAT2A up-regulation in HCC.
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PMID:Induction of human methionine adenosyltransferase 2A expression by tumor necrosis factor alpha. Role of NF-kappa B and AP-1. 1453 Feb 85

Inflammatory osteolysis induced by implant-derived wear debris is associated with infiltration of various cell-types to the implant-bone interface leading to abundant secretion of pro-inflammatory cytokines and activation of proteinases that together lead to propagation of the localized inflammatory response and periprosthetic bone erosion. Tumor necrosis factor family members are considered to be direct mediators of inflammation and osteolysis. These cytokines exert their osteoclastic effects via activation of the transcription factor NF-kappaB and certain MAP kinases, including c-Jun, Erks and p38, all known to be essential for the development of osteoclasts. We have recently documented that the osteoclastogenic cytokines TNF and RANKL play a pivotal role in the development of inflammatory osteolysis. We have also found that PMMA particles stimulate osteoclastogenesis, at least in part, by induction of RANKL, TNF, and by activation of the transcription factor NF-kappaB. More importantly, our data indicate that inhibitors of the osteoclastogenic factors, TNF and RANKL abrogate particle-induced osteoclastogenesis. In the current study, we investigated if PMMA particles activate MAP kinases, and the potential role of these kinases as mediators of osteolysis. Using kinase assays, we show that in osteoclast precursors, PMMA particles markedly and rapidly activate p38 and ERK MAP kinases. This activation was specific, evident by complete blockade with specific inhibitory compounds. Similarly, we show that PMMA particles activate the JNK pathway, which is known to be involved in inflammatory and osteoclastogenic events. We also show that p38 MAP kinase regulates PMMA-activation of NF-kappaB, thus providing a possible mechanism for particle action in osteoclast precursors. Finally, we provide evidence that specific inhibitors of MAP kinases are capable of inhibiting PMMA-stimulated osteoclastogenesis. These data provide evidence that MAP kinases are potent mediators of particle-induced osteoclastogenesis.
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PMID:Mitogen-activated protein (MAP) kinases mediate PMMA-induction of osteoclasts. 1455 17


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