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 studied the effects of bile acids on inducibility of the transcription factor AP-1 in human colon carcinoma LoVo cells. Firstly, cells were treated with chenodeoxycholic acid and the nuclear extracts from those cells were processed by electrophoretic mobility shift assays to analyze nuclear AP-1 DNA-binding activity. We demonstrated that chenodeoxycholic acid induced AP-1 DNA-binding activity in a dose- and time-dependent fashion. Antibody supershift experiments clearly revealed that the majority of protein components in induced AP-1 DNA-binding activity were the products of oncogenes c-fos and c-jun. On the other hand, DNA-binding activity in the nuclear extracts for either NF kappa B, Sp1, or ATF/CREB was not affected by bile acids, suggesting that the effect of bile acids was rather specific for AP-1. Transient transfection experiments supported this notion: expression of the AP-1-luciferase reporter construct was induced by bile acids in a dose-dependent manner, and expression of either reporter construct for NF kappa B, Sp1, or ATF/CREB was not influenced by treatment of the cells with bile acids. We also demonstrated that those bile acids efficiently activated AP-1-dependent promoter in DLD-1 cells, which (as well as LoVo cells), are derived from colon adenocarcinoma, but not in COLO320DM cells which are from colon carcinoid tumor. Thus, we may indicate that bile acids exclusively induce nuclear AP-1 activity in colon adenocarcinoma cells.
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PMID:Induction of the transcription factor AP-1 in cultured human colon adenocarcinoma cells following exposure to bile acids. 863 Nov 27

1. Protein phosphorylation is involved in the induction of nitric oxide synthase II (NOS II, iNOS) in several types of animal cells. Here we have investigated the possible involvement of major protein kinases in the induction of NOS II expression in human DLD-1 cells. 2. In DLD-1 cells, interferon--gamma alone induced a submaximal NOS II expression; a cytokine mixture consisting of interferon-gamma, tumour necrosis factor-alpha and interleukin-1beta produced maximal NOS II induction. 3. Activators of protein kinase A (forskolin, 8-dibutyryl-cyclic AMP), of protein kinase C (tetradecanoylphorbol-13-acetate), and of protein kinase G (8-bromo cyclic GMP) did not induce NOS II mRNA by themselves, nor did they alter NOS II mRNA induction in response to cytokines. 4. Inhibitors of protein kinase A (compound H89), of protein kinase C (bisindolylmaleimide, chelerythrine or staurosporine), of phosphatidylinositol 3-kinase (wortmannin), of p38 mitogen-activated protein kinase (compound SB 203580) and of extracellular signal-regulated kinase (compound PD 98059) also had no influence on basal or cytokine-induced NOS II mRNA expression. 5. Immunoprecipitation kinase assays showed no activation of extracellular signal-regulated kinase or p38 mitogen-activated protein kinase in cytokine-incubated DLD-1 cells. The c-Jun NH2-terminal kinase was activated by cytokines, but the most efficacious cytokine was tumour necrosis factor-alpha which did not induce NOS II by itself. 6. In contrast, the protein tyrosine kinase inhibitor tyrphostin B42 (a specific inhibitor of interferon-gamma-activated janus kinase 2) and the protein tyrosine kinase inhibitor tyrphostin A25 both reduced CM-induced NOS II mRNA expression in a concentration-dependent manner. 7. These results suggest that activation of NOS II expression in DLD-1 cells is independent of the activities of protein kinases A, C and G, phosphatidylinositol 3-kinase, extracellular signal regulated kinase and p38 mitogen-activated protein kinase, but seems to require protein tyrosine kinase activity, especially the interferon-gamma-activated janus kinase 2.
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PMID:Involvement of protein kinases in the induction of NO synthase II in human DLD-1 cells. 960 80

1. In human epithelial-like DLD-I cells, nitric oxide synthase (NOS) II expression was induced by interferon-gamma (100 u ml(-1)) alone and, to a larger extent, by a cytokine mixture (CM) consisting of interferon-gamma, interleukin-1beta (50 u ml(-1)) and tumor necrosis factor-alpha (10 ng ml(-1)). 2. CM-induced NOS II expression was inhibited by tyrphostin B42 (mRNA down to 1%; nitrite production down to 0.5% at 300 microM) and tyrphostin A25 (mRNA down to 24%, nitrite production down to 1% at 200 microM), suggesting the involvement of janus kinase 2 (JAK-2). Tyrphostin B42 also blocked the CM-induced JAK-2 phosphorylation (kinase assay) and reduced the CM-stimulated STAT1alpha binding activity (gel shift analysis). 3. CM reduced the nuclear binding activity of transcription factor AP-1. A heterogenous group of compounds, that stimulated the expression of c-fos/c-jun, enhanced the nuclear binding activity of AP-1. This group includes the protein phosphatase inhibitors calyculin A, okadaic acid, and phenylarsine oxide, as well as the inhibitor of translation anisomycin. All of these compounds reduced CM-induced NOS II mRNA expression (to 9% at 50 nM calyculin A; to 28% at 500 nM okadaic acid; to 18% at 10 microM phenylarsine oxide; and to 19% at 100 ng ml(-1) anisomycin) without changing NOS II mRNA stability. In cotransfection experiments, overexpression of c-Jun and c-Fos reduced promoter activity of a 7 kb DNA fragment of the 5'-flanking sequence of the human NOS II gene to 63%. 4. Nuclear extracts from resting DLD-1 cells showed significant binding activity for transcription factor NF-kappaB, which was only slightly enhanced by CM. The NF-kappaB inhibitors dexamethasone (1 microM), 3,4-dichloroisocoumarin (50 microM), panepoxydone (5 microg ml(-1)) and pyrrolidine dithiocarbamate (100 microM) produced no inhibition of CM-induced NOS II induction. 5. We conclude that in human DLD-1 cells, the interferon-gamma-JAK-2-STAT1alpha pathway is important for NOS II induction. AP-1 (that is downregulated by CM) seems to be a negative regulator of NOS II expression. NF-kappaB, which is probably important for basal activity of the human NOS II promoter, is unlikely to function as a major effector of CM in DLD-1 cells.
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PMID:Cytokine induction of NO synthase II in human DLD-1 cells: roles of the JAK-STAT, AP-1 and NF-kappaB-signaling pathways. 977 60

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

The protease inhibitor ritonavir is an integral part of current antiretroviral therapy targeting human immunodeficiency virus. Recent studies demonstrate that ritonavir induces apoptotic cell death with high efficiency in lymphoblastoid cell lines. Moreover, ritonavir can suppress activation of the transcription factor nuclear factor-kappaB and is an inhibitor of interleukin-1beta and tumor necrosis factor-alpha production in peripheral blood mononuclear cells. Thus, ritonavir appears to have anti-inflammatory properties. In the present study, we investigated in DLD-1 colon carcinoma cell effects of ritonavir on apoptotic cell death and expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme that may be critically involved in the modulation of colonic inflammation. Compared to unstimulated control, ritonavir resulted in a moderate increase in the rate of apoptotic cell death as observed after 20 h of incubation. Notably, ritonavir potently synergized with the short-chain fatty acid butyrate for induction of caspase-3-dependent apoptosis in DLD-1 cells. Ritonavir enhanced mRNA and protein expression of HO-1 in DLD-1 cells. Ritonavir-induced HO-1 protein was suppressed by SB203580 or SB202190 and preceded by immediate upregulation of cellular c-Fos and c-Jun protein levels. This process was associated with induction of activator protein-1 as detected by electrophoretic mobility shift analysis. The present data suggest that ritonavir has the potential to curb colon carcinogenesis by reducing cell growth via mechanisms that include apoptosis and by simultaneously modulating colonic inflammation via induction of anti-inflammatory HO-1.
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PMID:The HIV protease inhibitor ritonavir synergizes with butyrate for induction of apoptotic cell death and mediates expression of heme oxygenase-1 in DLD-1 colon carcinoma cells. 1550 50

PRIMA-1 (p53 reactivation and induction of massive apoptosis) is a chemical compound that was originally identified as a selective mutant p53-dependent growth suppressor by screening a library of low-molecular-weight compounds. However, its mechanism of action is unknown. In this study, we examined toxicity of PRIMA-1 to three premalignant human colorectal adenoma cell lines (RG/C2, BR/C1, and AA/C1) and four colorectal carcinoma cell lines (DLD-1, SW480, LOVO, and HCT116) and its mechanism of action. It selectively induced apoptosis only in the mutant p53 premalignant and malignant colon cell lines, but was not toxic to the wild-type p53 premalignant and malignant colon cell lines. Using stable transfectants of temperature-sensitive p53 mutant Ala(143) in null p53 H1299 lung cancer cells, we found that PRIMA-1 induced significantly more apoptosis in cells with mutant p53 conformation (37 degrees C) than the wild-type p53 conformation (32.5 degrees C). Cell cycle analysis indicated that its inhibition of cell growth was correlated with induction of G(2) arrest. Western blot analysis showed PRIMA-1 increased p21 and GADD45 expression selectively in the mutant p53 cells. However, Fas, Bcl-2 family proteins, and caspases were not involved in PRIMA-1-induced cell death. The c-Jun-NH(2)-kinase (JNK) inhibitor SP 600125, but not p38 mitogen-activated protein kinase inhibitor SB 203580 or extracellular signal-regulated kinase inhibitor PD 98059, blocked PRIMA-1-induced apoptosis. Transfection with a dominant-negative phosphorylation mutant JNK, but not a dominant-negative p38 or wild-type JNK, inhibited PRIMA-1-induced cell death, suggesting that the JNK pathway plays an important role in PRIMA-1-induced apoptosis. PRIMA-1 is a highly selective small molecule toxic to p53 mutant cells and may serve as a prototype for the development of new p53-targeting agents for therapy of premalignant and malignant cells.
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PMID:Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway. 1595 47

Development of new therapeutic agents for colon cancer is highly desirable. To this end, we screened a chemical library for new anticancer agents and identified a synthetic compound, 5-(2,4-dihydroxybenzylidene)-2-(phenylimino)-1,3-thiazolidin (DBPT), which kills cancer cells more effectively than it kills normal human fibroblasts. The molecular mechanism of the antitumor action of DBPT was further analyzed in three human colorectal cancer cell lines. DBPT effectively inhibited the growth of colorectal cancer cells, independent of p53 and P-glycoprotein status, whereas normal fibroblasts were unaffected at the same IC50. Over time, DLD-1 cancer cells treated with DBPT underwent apoptosis. The general caspase inhibitor benzyloxycarbonyl-valine-alanine-aspartate-fluoromethylketone partially blocked DBPT-induced apoptosis in a dose-dependent manner. DBPT-induced apoptosis, including cytochrome c release and caspase activation, was abrogated when c-Jun NH2-terminal kinase (JNK) activation was blocked with either a specific JNK inhibitor or a dominant-negative JNK1 gene. However, constitutive JNK activation alone did not replicate the effects of DBPT in DLD-1 cells, and excessive JNK activation by adenovirus encoding MKK7 had little influence on DBPT-induced apoptosis. Our results suggested that DBPT induces apoptosis in colorectal cancer cell lines through caspase-dependent and caspase-independent pathways and that JNK activation was crucial for DBPT-induced apoptosis. DBPT and its analogues might be useful as anticancer agents.
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PMID:Identification of a novel synthetic thiazolidin compound capable of inducing c-Jun NH2-terminal kinase-dependent apoptosis in human colon cancer cells. 1602 41

Cyclooxygenase-2 (COX-2) plays important roles in tumor development. Especially in the early-stage colorectal tumors, COX-2 expression is often observed in the tumor stroma. However, the mechanism regulating such stromal expression of COX-2 remains unknown. In the present study, we simulated the indirect interaction between epithelial cells and stromal cells in the process of colorectal tumor development using an in vitro co-culture model in which NIH3T3 fibroblasts were co-cultured with 'sparsely' or 'densely' populated intestinal epithelial cells, Intestine-407 as a model of premalignant or benign intestinal epithelial cells, and DLD-1 and Caco-2 as models of malignant epithelial cells. COX-2 expression in NIH3T3 fibroblasts was upregulated when co-cultured with the 'dense' epithelial cells regardless of their character. Interestingly, there was pericellular hypoxia in the vicinity of NIH3T3 fibroblasts when co-cultured with 'dense' epithelial cells, and the recovery of the partial pressure of oxygen level resulted in the reduction of enhanced COX-2 expression only in NIH3T3 fibroblasts co-cultured with 'dense' Intestine-407 cells. Furthermore, COX-2 expression was also reduced by the inhibition of transcription factor AP-1. Thus, pericellular hypoxia of the stromal cells caused by densely populated epithelial cells may be one of the potent COX-2 enhancers before completion of malignant transformation during intestinal tumor development.
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PMID:Hypoxia induced by benign intestinal epithelial cells is associated with cyclooxygenase-2 expression in stromal cells through AP-1-dependent pathway. 1640 21

Sweetpotato leaves (Ipomoea batatas L.) contain a high content of polyphenolics that consist of caffeic acid, chlorogenic acid, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, and 3,4,5-tri-O-caffeoylquinic acid. We investigated the suppression of the proliferation of selected human cancer cells by phenolic compounds isolated from sweetpotato leaf. The human cancer cells used in this research included a stomach cancer (Kato III), a colon cancer (DLD-1), and a promyelocytic leukemia cell (HL-60). Caffeic acid and di- and tricaffeoylquinic acids dose-dependently depressed cancer cell proliferation, and the difference in sensitivity between caffeoylquinic acid derivatives and each kind of cancer cell was observed. Specifically, 3,4,5-tri-O-caffeoylquinic acid effectively depressed the growth of three kinds of cancer cells, and caffeic acid had an exceptionally higher effect against HL-60 cells than other di- and tricaffeoylquinic acids. In attempting to clarify the mechanism of growth suppression with the addition of the apoptotic inhibitor N-ethylmaleimide, we observed that the nuclear granulation in 3,4,5-tri-O-caffeoylquinic acid-treated HL-60 cells suggested apoptosis induction. This effect was confirmed by DNA fragmentation, an increase of caspase-3 activity, and expression of c-Jun. Growth suppression of HL-60 cells by 3,4,5-tri-O-caffeoylquinic acid was determined to be the result of apoptotic death of the cells. These results indicate that 3,4,5-tri-O-caffeoylquinic acid may have potential for cancer prevention.
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PMID:Growth suppression of human cancer cells by polyphenolics from sweetpotato (Ipomoea batatas L.) leaves. 1719 31

Scaffold proteins for MAP kinase (MAPK) signalling modules play an important role in the specific and efficient signal transduction of the relevant MAPK cascades. Here, we investigated the function of the scaffolding protein c-Jun NH(2)-terminal kinase (JNK)-associated leucine zipper protein (JLP) by depleting it in cultured cells using a short hairpin RNA (shRNA) against human JLP. HeLa and DLD-1 cells stably expressing the shRNA showed a defect in cell migration. The re-expression of full-length shRNA-resistant mouse JLP rescued the impaired cell migration of the JLP-depleted HeLa cells; whereas, a C-terminal deletion mutant of mouse JLP, which failed to bind the G protein G(alpha13), showed little or no effect on the cell migration defect. Furthermore, although a constitutively active G(alpha13) enhanced the migration of control HeLa cells, the G(alpha13)-induced cell migration was significantly suppressed in the JLP-depleted HeLa cells. Taken together, these results suggest that JLP regulates cell migration through an interaction with G(alpha13).
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PMID:The scaffold protein c-Jun NH2-terminal kinase-associated leucine zipper protein regulates cell migration through interaction with the G protein G(alpha 13). 1882 71


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