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)

Stimulation of mesangial cells with insulin-like growth factor-1 (IGF-1) resulted in the rapid tyrosyl phosphorylation of nuclear proteins as indicated by fluorescence microscopy of cells stained with anti-phosphotyrosine antibodies. Immunoprecipitation of nuclear extracts with anti-phosphotyrosine antibodies revealed that IGF-1 induced a transient increase in immunoreactive phosphotyrosine in nuclear proteins of 43, 95, and 160 kDa. Using a double immunoprecipitation protocol, the transcription factor c-Jun was also found to increase in immunoreactive phosphotyrosine in response to IGF-1. A similar pattern of tyrosyl phosphorylation of nuclear proteins was observed in the epidermoid carcinoma cell line CaSki. These data suggest that tyrosyl phosphorylation of nuclear proteins may be a step in the transduction of mitogenic signals.
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PMID:Insulin-like growth factor-1 induces tyrosyl phosphorylation of nuclear proteins. 166 5

Although the p38 mitogen-activated protein kinase (MAPK) has been implicated in signal transduction events, its role in regulating the Mr 92,000 type IV collagenase matrix metalloprotease-9 (MMP-9) and in vitro invasiveness in cancer has not yet been determined. We made the surprising observation that, in a human squamous cell carcinoma cell line (UM-SCC-1), phorbol ester-enhanced MMP-9 secretion and in vitro invasiveness were associated with a strong activation of the p38 MAPK and its downstream target, MAPK-activated protein kinase-2. To determine the role of p38 activation in these events, we investigated the effect of SB 203580, a novel specific p38 inhibitor, on protease expression and in vitro invasion of these cells. We found that inhibition of p38 by SB 203580 resulted in the almost complete reduction of phorbol myristate acetate-induced MMP-9 secretion but not of urokinase-type plasminogen activator secretion. In contrast, the activation of a transiently transfected wild-type MMP-9 promoter by MEKK-1, a specific c-Jun NH2-terminal kinase activator, was only marginally inhibited by the compound, arguing for the specificity of SB 203580. Moreover, phorbol myristate acetate-enhanced in vitro invasion was completely blocked by SB 203580, whereas p38 inhibition had little effect on growth. These findings suggest that activation of p38 may contribute to a more invasive phenotype in vitro, possibly via the expression of MMP-9, and that targeting of p38 using SB 203580 may provide a novel means of controlling invasion of cancers in which this MAPK is activated.
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PMID:Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. 951 96

The effect of transient transfection with expression vector of c-Fos on the expression of 12-lipoxygenase in human epidermoid carcinoma A431 cells was studied. Overexpression of c-Fos increased the expression of 12-lipoxygenase mRNA and enzyme activity, and also activated the promoter activity of 12-lipoxygenase gene in a dose-dependent manner. Co-transfection with c-Fos and c-Jun expression vectors in cells synergistically increased the promoter activity of 12-lipoxygenase. With the aid of additional 5'-deletion and site-directed mutagenesis, the downstream and middle Sp1 sites residing at -123 to -114 bp and -158 to -150 bp were found to be critical for the c-Fos response of activating the transcription of human 12-lipoxygenase gene. Furthermore, the specific role of Sp1 in c-Fos response was confirmed by using the reporter plasmid driven by SV40 early promoter. These results indicate that the requirement of Sp1-binding sites in the promoter region of 12-lipoxygenase gene for c-Fos response is similar to that previously observed in EGF response.
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PMID:Overexpression of c-Fos enhances the transcription of human arachidonate 12-lipoxygenase in A431 cells. 1044 14

The role of mitogen-activated protein kinase signaling and the transcription factor c-Jun in epidermal growth factor (EGF)-induced expression of 12-lipoxygenase in human epidermoid carcinoma A431 cells was studied. EGF increased the activation of extracellular signal-regulated kinase (ERK) and c-Jun amino terminal kinase (JNK) in a time-dependent manner. Treatment of the cells with an mitogen-activated protein kinase kinase inhibitor, PD098059 (30 microM), inhibited the EGF- and pSV2ras-induced expression of 12-lipoxygenase mRNA. Transfection of the cells with Ras, ERK2, Rac, JNK dominant negative mutants pMMrasDN, K52R ERK2, RacN17, and mJNK all inhibited the EGF-induced promoter activation of the 12-lipoxygenase gene. EGF induced the expression of c-Jun and the activity of transcription factor activator protein 1 in cells, and these effects were blocked by the treatment with K52R ERK2 and mJNK. Overexpression of c-Jun increased the expression of 12-lipoxygenase mRNA and enzyme activity. Furthermore, the Sp1-binding sites in the promoter region of the 12-lipoxygenase gene were requisite for c-Jun response, which was similar to that previously observed in EGF response. The results indicate that the EGF-induced expression of 12-lipoxygenase in A431 cells was mediated through the Ras-ERK and Ras-Rac-JNK signal pathways. Subsequent induction of c-Jun led by ERK and JNK activation was essential for this EGF response.
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PMID:Essential role of mitogen-activated protein kinase pathway and c-Jun induction in epidermal growth factor-induced gene expression of human 12-lipoxygenase. 1061 90

The functional role of the interaction between c-Jun and simian virus 40 promoter factor 1 (Sp1) in epidermal growth factor (EGF)-induced expression of 12(S)-lipoxygenase gene in human epidermoid carcinoma A431 cells was studied. Coimmunoprecipitation experiments indicated that EGF stimulated interaction between c-Jun and Sp1 in a time-dependent manner. Overexpression of Ha-ras and c-Jun also enhanced the amount of c-Jun binding to Sp1. In addition, the c-Jun dominant negative mutant TAM-67 not only inhibited the coimmunoprecipitated c-Jun binding to Sp1 in a dose-dependent manner in cells overexpressing c-Jun but also reduced promoter activity of the 12(S)-lipoxygenase gene induced by c-Jun overexpression. Treatment of cells with EGF increased the interaction between the Sp1 oligonucleotide and nuclear c-Jun/Sp1 in a time-dependent manner. Furthermore, EGF activated the chimeric promoter consisting of 10 tandem GAL4-binding sites, which replaced the three Sp1-binding sites in the 12(S)lipoxygenase promoter only when coexpressed with GAL4-c-Jun () fusion proteins. These results indicate that the direct interaction between c-Jun and Sp1 induced by EGF cooperatively activated expression of the 12(S)-lipoxygenase gene, and that Sp1 may serve at least in part as a carrier bringing c-Jun to the promoter, thus transactivating the transcriptional activity of 12(S)-lipoxygenase gene.
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PMID:Functional interaction between c-Jun and promoter factor Sp1 in epidermal growth factor-induced gene expression of human 12(S)-lipoxygenase. 1097 89

Collagenase-1 [matrix metalloproteinase (MMP)-1] is expressed by stromal fibroblasts of various invasive malignant tumors. Here, we have examined the molecular mechanisms of tumor-induced expression of MMP-1 by stromal fibroblasts. Treatment of fibroblasts with conditioned media of tumor cells derived from squamous cell carcinomas (SCCs) of the oral cavity and larynx resulted in activation of fibroblast MMP-1 expression at the transcriptional level. The induction of MMP-1 expression correlates with activation of c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase and phosphorylation of c-Jun and activating transcription factor-2 (ATF-2) and is dependent on the activity of p38 mitogen-activated protein kinase. Furthermore, using fibroblasts derived from JNK2-/- mice, we show that JNK2 is required for induction of fibroblast collagenase-3 expression in response to conditioned SCC tumor cell medium. Together, these results provide evidence that stress-activated p38 and JNK pathways play a crucial role in paracrine regulation of collagenolytic capacity of stromal fibroblasts in SCCs and suggest JNK2 as a novel target for inhibition of MMP-1 expression and tumor invasion.
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PMID:Activation of fibroblast collagenase-1 expression by tumor cells of squamous cell carcinomas is mediated by p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase-2. 1115 25

The functional role of mitogen-activated protein kinase (MAPK) signaling and c-Jun induction in phorbol 12-myristate 13-acetate (PMA)-induced human 12(S)-lipoxygenase gene expression was studied in human epidermoid carcinoma A431 cells. Among the family of MAPK, PMA only increased the activity of extracellular signal-regulated kinase (ERK). Treatment of cells with PD98059, which is an inhibitor of mitogen-activated protein kinase kinase (MEK), decreased the PMA-induced expression of 12(S)-lipoxygenase. Transfection of cells with Ras, Raf and ERK2 dominant negative mutants inhibited the PMA-induced promoter activation of the 12(S)-lipoxygenase gene in all cases. PMA-induced expression of c-Jun was inhibited by pretreatment with PD98059. Following treatment with PMA, the interaction between c-Jun and simian virus 40 promoter factor 1 (Sp1) in cells increased with time. Enhancement of binding between the c-Jun-Sp1 complex and the Sp1 oligonucleotide was observed in cells treated with PMA, suggesting the possible interaction of c-Jun-Sp1 with GC-rich binding sites in the gene promoter. These results indicate that PMA treatment induced ERK activation mainly through the Raf-MEK-ERK signaling pathway following induction of c-Jun expression, and the formation of the c-Jun-Sp1 complex. Finally, PMA activated the promoter activity of the 12(S)-lipoxygenase gene in cells overexpressing protein kinase C (PKC)delta but not PKCalpha, indicating that PKCdelta played the functional role in mediating the gene activation of 12(S)-lipoxygenase induced by PMA.
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PMID:Functional role of extracellular signal-regulated kinase activation and c-Jun induction in phorbol ester-induced promoter activation of human 12(S)-lipoxygenase gene. 1191 83

Mitogen-activated protein kinases (MAPKs) consist of major three subfamilies, extracellular-signal regulated kinases (ERK MAPKs), the c-Jun N-terminal kinases/stress activated protein kinases (JNK MAPKs/SAP MAPKs), and p38 MAPKs. ERK MAPKs pathway is one of the most important pathways for cell proliferation. ERK MAPKs are located at downstream of a lot of growth factors (epidermal growth factor (EGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), etc.), the overexpressions and activation of which are frequently detected on a number of cancers including oral squamous cell carcinoma (OSCC). These data indicate that overexpression and activation of ERK MAPKs play an important role in cancer progression. On the contrary, JNK MAPKs are possible regulators of cell death induced by chemotherapeutic agents. p38 MAPKs are activated by pro-inflammatory cytokines and inflammatory drugs (non-steroidal anti-inflammatory drug), which are known to suppress cancer growth. These findings imply that each MAPKs can be molecular targets for cancer therapy in OSCC and its investigation is very important things in OSCC.
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PMID:Overexpression of extracellular-signal regulated kinases on oral squamous cell carcinoma. 1211 Mar 41

Invasive squamous cell carcinoma (SCC) cells degrade extracellular matrix (ECM) via an extracellular protease cascade that includes urokinase-type plasminogen activator (uPA), plasmin, and the metalloprotease (MMP) family of collagenases. In this study, treatment of oral SCC cells with epidermal growth factor (EGF) stimulated the cells to invade Matrigel (constructive basement membrane (BM) protein). EGF-induced cell invasion was inhibited by antibodies to uPA and by synthetic uPA inhibitors. EGF also induced increased expression of uPA and uPA receptor (uPAR) proteins and mRNA, as well as transcription factor activator protein-1 (AP-1)-DNA binding. These EGF-induced changes were inhibited by treatment with dexamethasone (DEX). DEX treatment also stimulated the production of plasminogen activator inhibitor type 1. Moreover, transfection of SCC cells with AP-1 decoy oligodeoxynucleotides (ODNs) resulted in the suppression of EGF-induced uPA and uPAR expression and Matrigel invasion. These results suggest that oral SCC cells invade Matrigel mainly through the uPA-plasmin cascade, which is mediated by the transcription factor AP-1. The uPA-uPAR interaction is essential for augmenting proteolytic activity and uPAR-mediated signaling, which ultimately induce motility and invasion. Since DEX inhibits the expression of both uPA and uPAR, it may be a useful treatment for oral SCC.
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PMID:Inhibition of epidermal growth factor-induced invasion by dexamethasone and AP-1 decoy in human squamous cell carcinoma cell lines. 1238 86

Phosphorylation of serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism. The conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1. Inhibition of Pin1 induces apoptosis and may contribute to neuronal death in Alzheimer's disease. It has been reported that Pin1 is strikingly overexpressed in a subset of human tumors. The differential display screen revealed that Pin1 increases the transcription of several target genes, including cyclin D1 and c-myc genes. Pin1 cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1. Pin1 also regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with adenomatous polyposis coli protein (APC). However, the analysis of Pin1 expression has not been demonstrated in human oral squamous cell carcinoma (OSCC). We examined the expression of Pin1 mRNA and protein in OSCC cell lines, and analyzed Pin1/cyclin D1/beta-catenin expression in OSCC clinical samples by immunohistochemical staining. We report that Pin1 is overexpressed in OSCC and its level correlates with cyclin D1 level. These results indicate that Pin1 is related to oncogenesis of OSCC.
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PMID:Pin1 is overexpressed in oral squamous cell carcinoma and its levels correlate with cyclin D1 overexpression. 1257 89


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