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)

Tumour necrosis factor-alpha (TNF-alpha) deficient mice (TNF-alpha(-/-) mice) are resistant to skin carcinogenesis. Cellular signalling via the transcription factor complex AP-1 is thought to play a key role in tumour promotion. The induction of a specific subset of AP-1 responsive genes thought to be important for tumour development, namely GM-CSF, MMP-9 and MMP-3, was suppressed in TNF-alpha(-/-) compared to wild-type mouse skin in response to the tumour promotor TPA. The differential induction of these genes correlated with a temporal shift in AP-1 activation and c-Jun expression in TNF-alpha(-/-) compared to wild-type epidermis. The major receptor for TPA-induced signalling in basal keratinocytes, PKC alpha, was also differentially regulated in wild-type compared with TNF-alpha(-/-) epidermis. A marked delay in TPA-induced intracellular translocation and downregulation of PKC alpha was observed in TNF-alpha(-/-) epidermis, which correlated with the deregulated TPA-induced AP-1 activation and c-Jun expression. The frequency of DNA adduct formation and c-Ha-ras mutations was the same in wild-type and TNF-alpha(-/-) epidermis after DMBA treatment, suggesting that TNF-alpha was not involved in tumour initiation. These data suggest that the pro-inflammatory cytokine TNF-alpha is a critical mediator of tumour promotion, acting via a PKC alpha- and AP-1-dependent pathway. This may be one mechanism by which chronic inflammation increases susceptibility to cancer.
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PMID:Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha- and AP-1-dependent pathway. 1210 11

Tyrosine hydroxylase (TH) gene transcription rate increases in response to numerous pharmacological and physiological stimuli. The AP1 site within the TH gene proximal promoter is thought to play an important role in mediating many of these responses; however, it is unclear which AP1 factors are required. To investigate whether c-Fos is essential for the response of the TH gene to different stimuli, c-Fos-deficient PC12 cell lines were produced utilizing an antisense RNA strategy. In these cell lines, stimulus-induced increases in c-Fos protein levels were dramatically attenuated, while c-Jun and CREB levels remained unchanged. TH gene transcription rate increased from four- to eight-fold in control cells after treatment with either 50 mM KCl or TPA. These responses were dramatically decreased in the c-Fos-deficient cell lines. In contrast, c-Fos down-regulation had little effect on the response of the TH gene to forskolin. Stimulation of TH gene promoter activity, which was observed in control cell lines treated with either 50 mm KCl or TPA was also dramatically inhibited in the c-Fos-deficient cells. These results suggest that c-Fos induction is essential for maximal stimulation of the TH gene in response to either depolarization or PKC activation in PC12 cells.
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PMID:c-Fos is essential for the response of the tyrosine hydroxylase gene to depolarization or phorbol ester. 1278 62

We have used phospho-specific antibodies to re-examine the multisite phosphorylation of c-Jun in murine RAW macrophages and embryonic fibroblasts. Our results indicate that JNK isoforms are required and sufficient for the phosphorylation of Thr91 and Thr93, as well as the phosphorylation of Ser63 and Ser73, in response to LPS or anisomycin in macrophages and TNFalpha or anisomycin in fibroblasts. However, the phorbol ester (TPA) and EGF-induced phosphorylation of Ser63 and Ser73 is mediated by ERK1/ERK2, as well as JNK1/JNK2, in fibroblasts from wild-type mice and by ERK1/ERK2 alone in fibroblasts from JNK-deficient mice. The phosphorylation of Thr239 is catalysed by GSK3 and the phosphorylation of Ser243 by an as yet unidentified protein kinase. The inhibition of GSK3 is not required for the dephosphorylation of Thr239 in response to LPS, and nor is the phosphorylation of Thr91 and Thr93 required for the TPA- or EGF-induced dephosphorylation of Thr239 in fibroblasts. The agonist-induced dephosphorylation of Thr239 may involve a conformational change that exposes Thr239 to dephosphorylation and/or the activation of a Thr239 phosphatase.
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PMID:A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun. 1288 22

Nerve growth factor induces innervation and epidermal hyperplasia in inflammatory skin diseases like psoriasis. Nerve growth factor production by keratinocytes is increased in the inflammatory lesions. Nerve growth factor induces histamine release from mast cells. We examined the in vitro effects of histamine on nerve growth factor production in human keratinocytes. Histamine enhanced nerve growth factor secretion, mRNA expression, and promoter activity in keratinocytes. Two TPA-response elements on the nerve growth factor promoter were responsible for the activation by histamine. Histamine enhanced transcriptional activity and DNA binding of activator protein 1 at the two TPA-response elements. It shifted the TPA-response-element-binding activator protein 1 composition from c-Jun homodimers to c-Fos/c-Jun heterodimers. Histamine transiently induced c-Fos mRNA expression, which was not detectable in unstimulated keratinocytes, whereas c-Jun mRNA expression was constitutive and was not altered by histamine. Histamine-induced enhancement of nerve growth factor secretion, promoter activity, activator protein 1 transcriptional activity, and c-Fos expression was suppressed by H1 antagonist pyrilamine, protein kinase C inhibitor calphostin C, and PD98059, an inhibitor of mitogen-activated protein kinase kinase 1. Histamine induced the translocation of protein kinase C activity from cytosol to membrane, which was suppressed by phospholipase C inhibitor U73122. It stimulated the phosphorylation of extracellular signal-regulated kinase, which was blocked by pyrilamine, calphostin C, and PD98059. These results suggest that histamine may enhance nerve growth factor production by inducing c-Fos expression in keratinocytes. These effects may be mediated by the H1-receptor-induced signaling cascade of phospholipase C-protein kinase C-mitogen-activated protein kinase kinase 1-extracellular signal-regulated kinase.
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PMID:Histamine enhances the production of nerve growth factor in human keratinocytes. 1292 17

Mammalian mismatch repair (MMR) plays a prominent role in genomic stability and toxicity induced by some DNA damaging agents. Advance in the appreciation of regulation mechanisms of the key MMR protein hMSH2 would certainly lead to valuable information on its role and to a better understanding of MMR system dysfunctions with respect to their consequences in cells. We have previously reported that, in myeloid leukemic U937 cell line, the expression of hMSH2 MMR protein is regulated by protein kinase C (PKC) activity. Here we show that the increase of protein level following PKC activation by phorbol ester (TPA) treatment parallels that of hMSH2 mRNA. Our results support the view that the hMSH2 gene is prone to transcriptional regulation upon TPA induction, and that AP-1 is a factor implicated in the transactivation. When losing the AP-1-dependent hMSH2 promoter activity, either by mutating the AP-1 binding sites of the hMSH2 promoter or by using a dominant negative c-Jun factor, the hMSH2 overexpression induced by TPA is abolished both in vitro and in vivo. Thus the control of hMSH2 expression by PKC appears to be dependent, at least partially, on an up-regulation mediated by AP-1 transactivation.
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PMID:hMSH2 expression is driven by AP1-dependent regulation through phorbol-ester exposure. 1450 Aug 26

Vimentin exhibits a complex pattern of developmental- and tissue-specific expression. Since it is aberrantly expressed in metastatic tumors, which have progressed through the epithelial-mesenchymal transition, it has been cited as a marker for tumor progression. Previous studies have indicated that the transcription factor activator protein (AP1) is important in tumor progression. The stable transformation of the MCF7 cell line with the oncogene c-Jun resulted in a cell line (MCF7Jun), which displayed a change in morphology, enhanced migratory and invasive properties, and metastatic behavior. Of the 21 genes whose expression levels were altered in the MCF7Jun cell line, the greatest change in expression occurred for the vimentin gene. Previously, tandem AP1 sites in the promoter were reported to be important for the serum and TPA inducibility of the vimentin gene. However, we find that the AP1 elements only contribute in part to c-Jun activation. Moreover, this activation can be duplicated in COS-1 or S2 cells by expression of c-Jun or TAM67, and is dependent only on the leucine-zipper region of c-Jun. Transient transfection analyses, electrophoretic mobility shift assays, DNA precipitation assays, and coimmunoprecipitation studies suggest that c-Jun is able to synergize with the activator protein Sp1 in binding to GC-box1 to enhance vimentin gene expression.
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PMID:c-Jun and the dominant-negative mutant, TAM67, induce vimentin gene expression by interacting with the activator Sp1. 1465 85

Keratinocyte-derived TNF-alpha acts as an endogenous tumour promoter and can also regulate AP-1 activity in mouse epidermis. To gain further insight into TNF-alpha signalling during skin tumour formation, mice deficient in TNFR1 (TNFR1-/- mice) or TNFR2 (TNFR2-/- mice) were subjected to chemical carcinogenesis. Tumour multiplicity was significantly reduced in TNFR1-/- and TNFR2-/- mice compared to wild-type (wt) mice, suggesting that both receptors have protumour activity. However, TNFR1-/- mice were markedly more resistant to tumour development than TNFR2-/- mice indicating that TNFR1 is the major mediator of TNF-alpha-induced tumour formation. TNFR1 and TNFR2 were both expressed in wt epidermis during tumour promotion and by primary keratinocytes in vitro. TPA-induced c-Jun expression was transient in TNFR1-/- and TNFR2-/- compared to wt epidermis and this was reflected by reduced induction of the AP-1-responsive genes granulocyte/macrophage-colony stimulating factor, matrix metalloproteinase-9 and matrix metalloproteinase-3. These genes were differentially regulated in TNFR1-/- compared to TNFR2-/- epidermis, suggesting that the TNF-alpha receptors act independently via different AP-1 complexes to transduce TNF-alpha signals during tumour promotion. In addition, TNFR2 cooperated with TNFR1 to optimise TNFR1-mediated TNF-alpha bioactivity on keratinocytes in vitro. Our data provide further insight into TNF-alpha signalling in malignancy and provide some rationale for the use of TNF-alpha antagonists in the treatment of cancer.
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PMID:Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development. 1466 Oct 63

Surfactant protein A (SP-A), the most abundant pulmonary surfactant protein, plays a role in innate host defense and blocks the inhibitory effects of serum proteins on surfactant surface tension-lowering properties. SP-A mRNA and protein are downregulated by phorbol esters (TPA) via inhibition of gene transcription. We evaluated the TPA signaling pathways involved in SP-A inhibition in a lung cell line, H441 cells. TPA caused sustained phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), p38 MAPK, and c-Jun-NH(2)-terminal kinase. An inhibitor of conventional and novel isoforms of protein kinase C (PKC) and two inhibitors of p44/42 MAPK kinase partially or completely blocked the inhibitory effects of TPA on SP-A mRNA levels. In contrast, inhibitors of conventional PKC-alpha and -beta, stress-activated protein kinases, protein phosphatases, protein kinase A, and the phosphatidylinositol 3-kinase pathway had no effect on the TPA-mediated inhibition of SP-A mRNA. TPA also stimulated the synthesis of c-Jun mRNA and protein in a time-dependent manner. Inhibitors of the p44/42 MAPK signaling pathway and PKC blocked the TPA-mediated phosphorylation of p44/42 MAPK and the increase in c-Jun mRNA. We conclude that TPA inhibits SP-A gene expression via novel isoforms of PKC, the p44/42 MAPK pathway, and the activator protein-1 complex.
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PMID:Signal transduction events involved in TPA downregulation of SP-A gene expression. 1475 51

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

Activation of the transcription factor AP-1 (activator protein-1) is required for tumor promotion and maintenance of malignant phenotype. A number of AP-1-regulated genes that play a role in tumor progression have been identified. However, AP-1-regulated genes driving tumor induction are yet to be defined. Previous studies have established that expression of a dominant-negative c-Jun (TAM67) inhibits phorbol 12-tetradecanoyl-13-acetate (TPA)-induced AP-1 transactivation as well as transformation in mouse epidermal JB6/P+ cells and tumor promotion in mouse skin carcinogenesis. In this study, we utilized the tumor promotion-sensitive JB6/P+ cells to identify AP-1-regulated TAM67 target genes and to establish causal significance in transformation for one target gene. A 2700 cDNA microarray was queried with RNA from TPA-treated P+ cells with or without TAM67 expression. Under conditions in which TAM expression inhibited TPA-induced transformation, microarray analysis identified a subset of six genes induced by TPA and suppressed by TAM67. One of the identified genes, the high-mobility group protein A1 (Hmga1) is induced by TPA in P+, but not in transformation-resistant P cells. We show that TPA induction of the architectural transcription factor HMGA1 is inhibited by TAM67, is extracellular-signal-regulated kinase (ERK)-activation dependent, and is mediated by AP-1. HMGA1 antisense construct transfected into P+ cells blocked HMGA1 protein expression and inhibited TPA-induced transformation indicating that HMGA1 is required for transformation. HMGA1 is not however sufficient as HMGA1a or HMGA1b overexpression did not confer transformation sensitivity on P- cells. Although HMGA1 expression is ERK dependent, it is not the only ERK-dependent event required for transformation because it does not suffice to rescue ERK-deficient P- cells. Our study shows (a) TAM 67 when it inhibits AP-1 and transformation, targets a relatively small number of genes; (b) HMGA1, a TAM67 target gene, is causally related to transformation and therefore a potentially important target for cancer prevention.
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PMID:Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation. 1506 52


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