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 gastrin and glycine-extended progastrin processing intermediates (G-Gly) exert growth-promoting effects on AR4-2J cells (derived from rat pancreas) via interaction with distinct receptors. In this study we sought to investigate the mechanisms by which gastrin and G-Gly stimulate cell proliferation. While gastrin increased [Ca2+]i in AR4-2J cells, G-Gly had no effect. Similarly, G-Gly had no effect either on basal and 10(-7) M vasoactive intestinal polypeptide-stimulated cAMP generation, although gastrin is known to inhibit cAMP generation. Gastrin dose dependently stimulated AR4-2J cell mRNA content of both c-fos and c-jun, two genes known to function in regulating cell proliferation, but G-Gly had no effect. Gastrin also induced the expression of luciferase in AR4-2J cells transfected with a construct consisting of a luciferase reporter gene coupled to the serum response element of the c-fos gene promoter. In similar fashion, gastrin stimulated the activity of mitogen-activated protein kinase, an enzyme known to mediate the induction of the c-fos serum response element in response to growth factor stimulation. Although G-Gly had none of these effects of gastrin in AR4-2J cells, it stimulated activity of c-Jun amino-terminal kinase, an enzyme known to phosphorylate and transcriptionally activate c-Jun. These data support the notion that gastrin stimulates cell proliferation by inducing c-fos and c-jun gene expression, while G-Gly acts by post-translationally regulating early gene transcriptional activation. Our studies represent a novel model in which both the precursor and the product of a key processing reaction, peptide alpha-amidation, act cooperatively to stimulate cell proliferation via distinct receptors linked to different signal transduction pathways.
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PMID:Gastrin and glycine-extended progastrin processing intermediates induce different programs of early gene activation. 749 34

Activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappa B) represent mammalian transcription factors which bind to distinct enhancer motifs. The specific mu-receptor opioid agonist, Tyr, D-Ala2, Gly, N-Me-Phe4, Gly-ol5 (DAMGO), was found to increase AP-1 and NF-kappa B activity in primary cultures of neurons from rat cerebral cortex. Acute (2 h, 4 h) and long-term (72 h) treatment with DAMGO time-dependently increased the DNA-binding activity of both AP-1 and NF-kappa B and the stimulation could be abolished or inhibited by concurrent incubation with naloxone. However, acute naloxone-precipitated withdrawal did not significantly change AP-1 or NF-kappa B activity. These results indicate a mu-opioid receptor-related co-induction of AP-1 and NF-kappa B transcription factors in cultured cortical neurons.
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PMID:A mu-receptor opioid agonist induces AP-1 and NF-kappa B transcription factor activity in primary cultures of rat cortical neurons. 884 97

Although the frequency of activated Ki-ras genes is high in human colorectal tumors, much less is known of activated Ki-ras-mediated signaling pathways. Using gene targeting, we examined HCT116 cells that contain the Gly-13-->Asp mutation of Ki-ras and activated Ki-ras-disrupted clones derived from HCT116. 12-O-Tetradecanoylphorbol-13-acetate (TPA) induced immediate early genes, such as c-Jun, c-Fos, and Egr-1 in activated Ki-ras-disrupted clones, whereas c-Jun induction was rare in HCT116. TPA induced both phosphorylation of stress-activated protein kinase kinase 1 (SEK1) and c-Jun NH2-terminal kinase (JNK) in the activated Ki-ras-disrupted clones but not in HCT116. On the other hand, TPA-induced mitogen-activated protein kinase kinase 1/2 (MEK1/2)-extracellular signal-regulated kinase (ERK) activation was equally induced between HCT116 and the Ki-ras-disrupted clones. Furthermore, TPA-induced SEK1-JNK activation was observed in a DLD-1-derived activated Ki-ras-disrupted clone but not in DLD-1. The TPA-induced SEK1-JNK activation in these disrupted clones was completely inhibited by the protein kinase C (PKC) inhibitor, GF109203X (1 microM), but not by another PKC inhibitor, H7 (50 microM), whereas TPA-induced MEK1/2-ERK activation was partially and completely inhibited by GF109203X (1 microM) and H7 (50 microM), respectively. A phosphoinositol 3-kinase inhibitor, LY294002, did not inhibit the TPA-induced SEK1-JNK activation. Taken together, these results suggest that activated Ki-Ras-mediated signals are involved in the SEK1-JNK pathway through a PKC isotype that is distinct from that involved in MEK1/2-ERK activation in human colon cancer cells and independent of phosphoinositol 3-kinase activation, and the imbalance between ERK and JNK activity caused by activated Ki-Ras may play critical roles in human colorectal tumorigenesis.
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PMID:Activated Ki-Ras suppresses 12-O-tetradecanoylphorbol-13-acetate-induced activation of the c-Jun NH2-terminal kinase pathway in human colon cancer cells. 1034 56

Platelets are an interesting model for studying the relationship betwen adhesion and mitogen-activated protein (MAP) kinase activation. We have recently shown that in platelets, ERK2 was activated by thrombin and downregulated by alpha(IIb)beta(3) integrin engagement. Here we focused our attention on the c-Jun NH2-terminal kinases (JNKs) and their activation in conditions of platelet aggregation. We found that JNK1 was present in human platelets and was activated after thrombin induction. JNK1 phosphorylation was detected with low concentrations of thrombin (0. 02 U/mL) and after 1 minute of thrombin-induced platelet aggregation. JNK1 activation was increased (fivefold) when fibrinogen binding to alpha(IIb)beta(3) integrin was inhibited by the Arg-Gly-Asp-Ser (RGDS) peptide or (Fab')(2) fragments of a monoclonal antibody specific for alpha(IIb)beta(3), demonstrating that, like ERK2, alpha(IIb)beta(3) integrin engagement negatively regulates JNK1 activation. Comparison of JNK1 activation by thrombin in stirred and unstirred platelets in the presence of RGDS peptide showed a positive regulation by stirring itself, independently of alpha(IIb)beta(3) integrin engagement, which was confirmed in a thrombasthenic patient lacking platelet alpha(IIb)beta(3). The same positive regulation by stirring was found for ERK2. These results suggest that MAP kinases (JNK1 and ERK2) are activated positively by thrombin and stirring. In conclusion, we found that JNK1 is present in platelets and can be activated after thrombin induction. Moreover, this is the first report showing that two different MAP kinases (ERK2 and JNK1) are regulated negatively by alpha(IIb)beta(3) engagement and positively by mechanical forces in platelets.
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PMID:Regulation of c-jun-NH2 terminal kinase and extracellular-signal regulated kinase in human platelets. 1057 94

The 29-kDa amino-terminal fibronectin fragment (FN-f) has a potent chondrolytic effect and is thought to be involved in cartilage degradation in arthritis. However, little is known about signal transduction pathways that are activated by FN-f. Here we demonstrated that FN-f induced nitric oxide (NO) production from human articular chondrocytes. Expression of inducible nitric-oxide synthase (iNOS) mRNA and NO production were observed at 6 and 48 h after FN-f treatment, respectively. Interleukin-1beta (IL-1beta) mRNA up-regulation was stimulated by FN-f in human chondrocytes. To address the possibility that FN-f-induced NO release is mediated by IL-1beta production, the effect of IL-1 receptor antagonist (IL-1ra) was determined. IL-1ra partially inhibited FN-f-induced NO release although it almost completely inhibited IL-1beta-induced NO release. Tyrosine phosphorylation of focal adhesion kinase was induced transiently by FN-f treatment. Blocking antibodies to alpha(5) or beta(1) integrin and Arg-Gly-Asp-containing peptides did not inhibit FN-f-induced NO production. PP2, a Src family kinase inhibitor, or cytochalasin D, which selectively disrupts the network of actin filaments, inhibited both FAK phosphorylation and NO production induced by FN-f, but the phosphatidylinositol 3-kinase inhibitor wortmannin had no effect. Analysis of mitogen-activated protein kinases (MAPK) showed activation of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase, and p38 MAPK. High concentrations of SB203580, which inhibit both JNK and p38 MAPK, and PD98059 a selective inhibitor of MEK1/2 that blocks ERK activation, inhibited FN-f induced NO production. These data suggest that focal adhesion kinase and MAPK mediate FN-f induced activation of human articular chondrocytes.
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PMID:Focal adhesion kinase and mitogen-activated protein kinases are involved in chondrocyte activation by the 29-kDa amino-terminal fibronectin fragment. 1167 48

The apoptotic cell death of Jurkat cells due to Cd(2+) toxicity was studied by fluorescence microscopic observation and DNA fragmentation assaying. It was suggested that the apoptotic response to Cd(2+) was less clear than that to a typical apoptosis inducer, ultraviolet light (254 nm). Examination of MAP kinase phosphorylation (p38, JNKs, and c-Jun) due to Cd(2+) toxicity indicated that the phosphorylation was very slowly activated (4 h after stimulation), while UV light could activate the phosphorylation immediately. Therefore, it was suggested that Cd(2+) may not be a typical apoptosis inducer. Antioxidants [glutathione (GSH) and N-acetylcysteine (NAC)] could detoxify Cd(2+), indicating that the toxicity is a kind of oxidative stress. The detoxification effect of antioxidants showed cooperation with Bcl-2, suggesting that Cd(2+)-treatment causes diversified toxic signals including oxidative stress. On the addition of a plant-specific peptide, phytochelatin [PC(7), (gammaGlu-Cys)(7)-Gly], to the medium, the detoxification of Cd(2+) and cooperation with Bcl-2 were more intense than in the cases of GSH and NAC. Using an appropriate vector, a PC synthase gene was transferred from Arabidopsis thaliana to the Jurkat cell. The transfectant exhibited resistance to Cd(2+) and production of plant-specific PC (PC(2-6)).
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PMID:Cellular toxicity of cadmium ions and their detoxification by heavy metal-specific plant peptides, phytochelatins, expressed in Mammalian cells. 1182 Sep 37

We previously found that human chymase cleaves big endothelins (ETs) at the Tyr(31)-Gly(32) bond and produces 31-amino acid ETs (1-31), without any further degradation products. In the present study, we investigated the effects of various antioxidants on the ET-1 (1-31)-induced change in intracellular signaling and proliferation of cultured rat aortic smooth muscle cells (RASMC). ET-1 (1-31) stimulated rapid and significant activation of the mitogen-activated protein (MAP) kinase family, i.e. extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK, in RASMC to an extent similar to that of ET-1. All of the antioxidants examined, i.e. N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), and L-(+)-ascorbic acid (ascorbic acid), inhibited both ET-1 (1-31)- and ET-1-induced JNK and p38 MAPK activation but not ERK1/2 activation. Electron paramagnetic resonance (EPR) spectroscopy measurements revealed that NAC, DPI, and ascorbic acid inhibited xanthine oxidase-induced superoxide (O(2)(.-)) generation in a cell-free system. ET-1 (1-31) in addition to ET-1 increased the generation of cellular reactive oxygen species (ROS) in RASMC. ET-1 (1-31)- and ET-1-induced cellular ROS generation was inhibited similarly by NAC, DPI, and ascorbic acid in RASMC. Gel-mobility shift analysis showed that ET-1 (1-31) and ET-1 caused an increase in activator protein-1 (AP-1)-DNA binding activity in RASMC that was inhibited by the above three antioxidants. ET-1 (1-31) increased [3H]thymidine incorporation into cells to an extent similar to that of ET-1. This ET-1 (1-31)-induced increase in [3H]thymidine incorporation was also inhibited by NAC and DPI, but not by ascorbic acid. These results suggest that antioxidants inhibit ET-1 (1-31)-induced RASMC proliferation by inhibiting ROS generation within the cells. The underlying mechanisms of the inhibition of cellular proliferation by antioxidants may be explained, in part, by the inhibition of JNK activation and the resultant inhibition of AP-1-DNA binding.
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PMID:Antioxidants inhibit endothelin-1 (1-31)-induced proliferation of vascular smooth muscle cells via the inhibition of mitogen-activated protein (MAP) kinase and activator protein-1 (AP-1). 1241 65

When characterizing the 5' flanking region of the c-Jun NH2-terminal kinase 3 ( JNK3) gene at 4q21-22, where frequent allelic losses and loss of expression had been detected in patients with brain tumors and hepatocellular carcinomas, we discovered that the Fas-associated phosphatase-1 ( FAP-1) gene was located only 633 bp upstream from JNK3 in a head-to-head orientation. A short G/C-rich region between the cap sites of the two genes suggested that they might share a bidirectional promoter region that appeared to contain multiple cis elements, including Sp1, AP-1, AP-2, GATA-1, a GC box, and a CCAAT box. The FAP-1 gene, consisting of 48 exons, initiates transcription within exon 2 and terminates in exon 48. Exons 2-5, 21-23, 25-28, 29-30, 33-34, and 34-36 encode six Gly-Leu-Gly-Phe repeat domains, and exons 12-17 and 44-88 encode the membrane-binding and catalytic domains, respectively. Seven polymorphisms were identified within functional domains or the putative promoter region, including two with amino acid substitutions, Leu1419Pro and Ile1522Met.
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PMID:Head-to-head juxtaposition of Fas-associated phosphatase-1 (FAP-1) and c-Jun NH2-terminal kinase 3 (JNK3) genes: genomic structure and seven polymorphisms of the FAP-1 gene. 1243 99

Glycine-extended gastrin (G-Gly) is produced by colon cancers and has growth promoting and anti-apoptotic effects in the colonic epithelium. We have examined the anti-apoptotic effects of G-Gly and the signal transduction pathways involved. G-Gly stimulated HT-29 cell proliferation in a concentration dependent manner and inhibited serum-starvation and celecoxib-induced apoptosis. Inhibition of signalling via c-Jun NH2-terminal kinase (JNK) with SP600125 or PI3-kinase/Akt with LY294002 abolished the effects of G-Gly. G-Gly significantly increased phosphorylation of both JNK and Akt. The JAK2 inhibitor AG490 abolished the anti-apoptotic effect of G-Gly and inhibited phosphorylation of Akt but not of JNK. G-Gly stimulated tyrosine phosphorylation of JAK2. G-Gly-increased activation of AP-1 was JNK-dependant and activation of STAT3 was JAK2-dependant. We conclude that G-Gly promotes growth and inhibits apoptosis in colon cancer cells. These effects are mediated via the JAK2, PI3-kinase/Akt and JNK pathways. Activation of JAK2 is upstream of Akt but not of JNK.
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PMID:Glycine-extended gastrin inhibits apoptosis in colon cancer cells via separate activation of Akt and JNK pathways. 1644 4

Compound CU201 [SUIM-(d-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-d-Igl-Oic-Arg)(2), where SUIM=suberimidyl; Hyp=trans-4-hydroxyproline; Igl=alpha-(2-indanyl)-glycine; Oic=octahydroindole-2-carboxylic acid], is a dimeric analog of the potent bradykinin antagonist peptide B9430. It blocks the G(alphaq,11) signal of the heterotrimeric G proteins, stimulates c-Jun kinases, and induces apoptosis in lung cancer cells with neuroendocrine features. CU201 shows potent inhibition for small-cell lung cancer cells in vitro (ED(50)=0.15microM), as well as for small-cell lung cancer SHP-77 tumor growth in vivo. An HPLC method was developed, as part of a study supported by the National Cancer Institute's (NCI's) Rapid Access to Interventional Development (RAID) program, to assess the purity and stability of CU201. Impurities and degradation products were characterized by LC/MS. The identity of a major impurity, with 1 mass unit different from CU201, was confirmed by high resolution LC/MS and the investigation of model compounds. Susceptible linkages in the peptide chains were revealed by the degradation study.
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PMID:LC/MS characterization of impurities and degradation products of a potent antitumor peptidic dimer, CU201. 1989 31


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