Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Changes in the components of the Jun N-terminal kinase (JNK) signalling pathway were investigated in human A549 lung carcinoma cells treated with sodium dichromate. Sodium dichromate (100 microM, 0-6h) failed to activate nuclear factor kappa B (NF-kappaB) as determined by a lack of nuclear translocation of p65 but resulted in Jun N-terminal kinase activation as assessed by phospho-Jun N-terminal kinase Western blotting in a dose-dependent (>25 microM) and time-dependent (>1h) manner. In addition, c-Jun, a downstream target of Jun N-terminal kinase signalling was also activated with a similar dose- and time-dependency at the level of both protein expression and degree of phosphorylation. In contrast, sodium dichromate treatment had no effect on levels of phospho-p38. Immunoprecipitation demonstrated that apoptosis signal regulating kinase-1 (ASK-1), an upstream activator of Jun N-terminal kinase was dissociated from its inhibitory partner thioredoxin (Trx) in response to sodium dichromate (100 microM, 4h) treatment. This treatment was also associated with a transient (2h) increase in cytosolic levels of thioredoxin but no nuclear translocation of thioredoxin was observed. In conclusion, sodium dichromate had a stimulatory effect on the Jun N-terminal kinase signalling pathway in A549 cells, resulting in activation of downstream effector molecules. We hypothesise that dissociation of apoptosis signal regulating kinase-1 from thioredoxin may be at least partially responsible for Jun N-terminal kinase activation.
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PMID:Activation of c-Jun N-terminal kinase in A549 lung carcinoma cells by sodium dichromate: role of dissociation of apoptosis signal regulating kinase-1 from its physiological inhibitor thioredoxin. 1500 21

Proteasome inhibition has become a target for antitumour and anti-inflammatory therapy. The present study investigated the influence of cysteine proteinase and proteasome inhibitors on chemokine production in lung epithelial cells and monocytic cells. The lung carcinoma cell lines A549, SK-MES, NCI-H727, virus-transformed bronchial epithelial cell line BEAS-2B, primary lung epithelial cells, and the acute monocytic leukaemia cell lines Mono-Mac-6 and THP-1 were incubated with proteasome (N-acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN), beta-lactone) or cysteine proteinase inhibitor (L-trans-Epoxysuccinyl-Leu-3-methylbutylamide-ethyl ester) and the influence on chemokine production (interleukin-8: IL-8, monocyte chemoattractant protein-1, RANTES) was quantified at protein and mRNA levels. Inhibition of proteasome activity by ALLN and beta-lactone resulted in significantly increased IL-8 secretion (5- to 22-fold). Cysteine proteinase inhibitors did not influence chemokine production. The simultaneous rise in IL-8 mRNA was caused by an increased half-life of mRNA and increased RNA synthesis. Moreover, analysis of transcription factor activation revealed induction of activator protein-1 (c-Jun) activity by proteasome inhibition, whereas nuclear factor-kappaB (p50 and p65) was not activated. The significant increase in IL-8 production after proteasome inhibition was also observed in primary lung epithelial cells and in monocytic cells. In addition, the secreted IL-8 was biologically active as shown by the neutrophil chemotaxis assay. In conclusion, it was shown that proteasome inhibitors stimulate interleukin-8 secretion in lung epithelial cells and monocytic cells, thus recruiting neutrophils.
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PMID:Proteasome inhibitors modulate chemokine production in lung epithelial and monocytic cells. 1529 3

The cytoprotective function of p53 recently has been exploited as a therapeutic advantage for cancer prevention; agents activating the prosurvival activity of p53 are shown to prevent UV-induced damages. To explore the mechanisms of p53-mediated protection from UV-induced apoptosis, we have established stable clones of H1299 lung carcinoma cells expressing a temperature-sensitive p53 mutant, tsp53(V143A). At the permissive temperature of 32 degrees C, the tsp53(V143A)-expressing cells were arrested in G(1) phase without the occurrence of apoptosis; consistent with this is the preferential induction of genes related to growth arrest and DNA damage repair. Previous expression of functional tsp53(V143A) for > or =18 hours inhibited the release of proapoptotic molecules from mitochondria and protected the cells from UV-induced apoptosis; moreover, it suppressed the activation of c-Jun NH(2)-terminal kinase (JNK) signaling and relieved the effect of UV on p53 target gene activation. p53 associated with JNK and inhibited its kinase activity. Using the p53-null H1299 cells, we showed that inhibition of JNK blocked the UV-elicited mitochondrial death signaling and caspase activation. Our results suggest that the ability of p53 to bind and inactivate JNK, together with the activation of the p53 target genes related to cell cycle arrest and DNA damage repair, is responsible for its protection of cells against UV-induced apoptosis.
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PMID:The prosurvival activity of p53 protects cells from UV-induced apoptosis by inhibiting c-Jun NH2-terminal kinase activity and mitochondrial death signaling. 1557 85

c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family, and its function is critical for signal transduction in tumor and endothelial cells. JNK is a serine/threonine protein kinase that phosphorylates c-Jun, a component of the activator protein-1 transcription factor complex. We hypothesize that inhibiting JNK will lead to the inhibition of tumor growth; therefore, we evaluated the efficacy of the recently described JNK inhibitor SP600125 [anthra[1,9-cd] pyrazol-6 (2H)-one]. SP600125 is an anthrapyrazole that is a reversible, ATP-competitive inhibitor of JNK1/2. SP600125 exhibited broad-based antiproliferative activity in human endothelial and tumor cell lines. SP600125 affects proliferation by arresting cells in the G2/M phase of the cell cycle. SP600125 also acts to inhibit endothelial cell migration. In cell lines, a correlation of cell growth inhibition with reduced JNK activity was observed. The systemic administration of SP600125 resulted in the inhibition of DU145 human prostate carcinoma xenografts and murine Lewis lung carcinoma. SP600125 also enhanced the potency of cyclophosphamide in the inhibition of Lewis lung tumor growth. These data indicate the therapeutic antitumor potential of small molecule inhibitors that act to block the cellular activity of JNK.
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PMID:Inhibition of tumor growth, angiogenesis, and tumor cell proliferation by a small molecule inhibitor of c-Jun N-terminal kinase. 1562 22

Tumor cell expression of COX-2 has been implicated in the progression of murine and human lung cancer. Inhibition of COX-2 by nonsteroidal antiinflammatory drugs reduces the risk of cancer development in humans and suppresses tumor growth in animal models. However, the underlying mechanisms for this beneficial effect are not fully understood. Here we explore the potential link between the anticancer effects of COX-2 inhibitors and the expression of the integrin alpha5beta1. Expression of this integrin in carcinoma cells is associated with invasiveness and malignant progression. This, together with our studies showing that fibronectin, the ligand of alpha5beta1, stimulates the growth of human lung carcinoma cells, and that this effect is mediated through alpha5beta1-dependent signals, has prompted us to examine the effects of COX-2 inhibitors on alpha5beta1 expression in human non small cell lung carcinoma (NSCLC) cells. We found that the selective COX-2 inhibitors NS398 and Nimesulide decreased mRNA expression and protein production of the integrin alpha5 subunit. This effect was associated with inhibition of NSCLC cell adhesion to fibronectin. The COX-2 inhibitors triggered the phosphorylation of extracellular signal-regulated kinase (Erk) in a time-dependent manner, and the inhibitor of Mek-1/Erk PD98095 prevented their inhibitory effects on integrin alpha5 expression. Transient transfection assays showed that the COX-2 inhibitors affected integrin alpha5 gene transcription by acting between -92 to -41 bp of the human integrin alpha5 gene promoter. Gel mobility shift assays showed that the COX-2 inhibitors increased Sp1 DNA binding, but decreased that of AP-1. These effects were accompanied by an increase in Sp1 protein and a decrease in c-Jun protein expression, as well as inhibition of SAPK/JNK phosphorylation. The Sp1 inhibitor, Mithramycin A, also blocked the inhibitory effect of the COX-2 inhibitors on alpha5 expression and promoter activity. Overall, these findings suggest that COX-2 inhibitors suppress alpha5beta1 integrin expression in NSCLC through effects on integrin alpha5 gene transcription mediated by Erk activation, increased Sp1, decreased AP-1 DNA binding and inactivation of SAPK/JNK signals. Our observations unveil a new mechanism of action against NSCLC for COX-2 inhibitors that relates to regulation of integrin alpha5 gene expression and, consequently, recognition of extracellular matrices (i.e., fibronectin) by tumor cells. (c) 2005 Wiley-Liss, Inc.
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PMID:COX-2 inhibitors suppress integrin alpha5 expression in human lung carcinoma cells through activation of Erk: involvement of Sp1 and AP-1 sites. 2625 13

Anthocyanins, present in various fruits and vegetables as natural colorant, have been well characterized to be involved in various bioactive properties and are wildly used for their antioxidant properties. Furthermore, recent studies have revealed pleiotropic anticancer and antiproliferative capabilities of anthocyanin. Berry extract contains high amounts of anthocyanins and is commonly used in diet or in some therapeutic applications. In this study, we first observed that cyanidin 3-rutinoside and cyanidin 3-glucoside (extracted from Morus alba L.) exerted a dose-dependent inhibitory effect on the migration and invasion, of highly metastatic A549 human lung carcinoma cells in absence of cytotoxicity. The results showed that cyanidin 3-glucoside and cyanidin 3-rutinoside treatments could decrease the expressions of matrix matalloprotinase-2 (MMP-2) and urokinase-plasminogen activator (u-PA) in a dose-dependent manner and enhance the expression of tissue inhibitor of matrix matalloprotinase-2 (TIMP-2) and plasminogen activator inhibitor (PAI). Further analysis with semi-quantitative RT-PCR showed that these alterations were all on the transcriptional level. Further, a treatment of cyanidin 3-rutinoside and cyanidin 3-glucoside also resulted in an inhibition on the activation of c-Jun and NF-kappaB. Together, these result suggested that anthocyanins could decrease the in vitro invasiveness of cancer cells and therefore, may be of great value in developing a potential cancer therapy.
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PMID:Mulberry anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, exhibited an inhibitory effect on the migration and invasion of a human lung cancer cell line. 1597 9

Vanadate is a transition metal widely distributed in the environment. It has been reported that vanadate associated with air pollution particles can modify DNA synthesis, causing cell growth arrest, and apoptosis. Moreover, vanadium exposure was also found to cause the synthesis of inflammatory cytokines, such as interleukin-1, tumor necrosis factor-alpha, and prostaglandin E(2). Here, we found that exposure of A549 human lung carcinoma cells to vanadate led to extracellular signal-regulated kinase, c-Jun NH(2)-terminal protein kinases (JNKs), p38 mitogen-activated protein kinase (p38) activation, and COX-2 protein expression in a dose-dependent manner. SB203580, a p38 MAPK inhibitor, but not PD098059 and SP600125, specific inhibitor of MKK1 and selective inhibitor of JNK, respectively, suppressed COX-2 expression. Furthermore, the epithelial growth factor (EGF) receptor specific inhibitor (PD153035) reduced vanadate-induced COX-2 expression. However, scavenging of vanadate-induced reactive oxygen species by catalase, a specific H(2)O(2) inhibitor, or DPI, an NADPH oxidase inhibitor, resulted in no inhibition on COX-2 expression. Together, we suggested that EGF receptor and p38 MAPK signaling pathway may be involved in vanadate-induced COX-2 protein expression in A549 human lung carcinoma cell line.
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PMID:Induction of COX-2 protein expression by vanadate in A549 human lung carcinoma cell line through EGF receptor and p38 MAPK-mediated pathway. 1630 Jul 28

Overexpression of cyclooxygenase-2 (COX-2) is frequently observed in several human cancers, including lung, colon, and head and neck. Malignancies are also associated with the dysregulation of cell cycle events and concomitant elevated activity of cyclin-dependent kinases (CDK). CDK2 is a key cell cycle regulatory protein that controls the transition of cells from G(1) to S phase. In this study, we furnish several lines of evidence that show a functional role for the CDK2 in interleukin-1beta (IL-1beta)-induced COX-2 expression in H358 human non-small cell lung carcinoma cell line by blocking CDK2 activity. First, we show that BMS-387032, a potent CDK2 inhibitor, blocks IL-1beta-induced expression as well as steady-state mRNA levels of COX-2. Second, we show that small interfering RNA that abrogates CDK2 expression also blocks IL-1beta-induced COX-2 expression. Third, results from in vitro kinase assays clearly show that IL-1beta induces CDK2 activity in H358 cells and this activity is significantly inhibited by BMS-387032. Moreover, CDK2 inhibition blocks IL-1beta-induced binding to the NF-IL6 element of the COX-2 promoter and inhibits transcription of the COX-2 gene. We also observed that BMS-387032 does not inhibit endogenous expression of COX-2 or prostaglandin synthesis in lung carcinoma cells. Finally, we provide evidence showing that IL-1beta-induced signaling events, such as p38 mitogen-activated protein kinase, phosphorylated stress-activated protein kinase/c-Jun NH(2)-terminal kinase, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase 1/2, are not inhibited by CDK2 inhibitor. Taken together, the data suggest that CDK2 activity may play an important event in the IL-1beta-induced COX-2 expression and prostaglandin E(2) synthesis and might represent a novel target for BMS-387032.
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PMID:The cyclin-dependent kinase 2 inhibitor down-regulates interleukin-1beta-mediated induction of cyclooxygenase-2 expression in human lung carcinoma cells. 1645 36

Synthetic alkyl-lysophospholipids represent a family of promising anticancer drugs that induce apoptosis in a variety of tumor cells. Here we have found a differential subcellular distribution of the alkyl-lysophospholipid edelfosine in leukemic and solid tumor cells that leads to distinct anticancer responses. Edelfosine induced rapid apoptosis in human leukemic cells, including acute T-cell leukemia Jurkat and Peer cells, but promoted a late apoptotic response, preceded by G(2)/M arrest, in human solid tumor cells such as cervix epitheloid carcinoma HeLa cells and lung carcinoma A549 cells. c-Jun amino-terminal kinase (JNK) and caspase-3 were accordingly activated at earlier times in edelfosine-treated Jurkat cells as compared with drug-treated HeLa cells. Both leukemic and solid tumor cells took up this alkyl-lysophospholipid and expressed the two putative edelfosine targets, namely cell surface Fas death receptor (also known as APO-1 or CD95) and endoplasmic reticulum CTP: phosphocholine cytidylyltransferase. However, edelfosine was mainly located to plasma membrane lipid rafts in Jurkat and Peer leukemic cells and to endoplasmic reticulum in solid tumor HeLa and A549 cells. Edelfosine induced translocation of Fas, Fas-associated death domain-containing protein, and JNK into membrane rafts in Jurkat cells, but not in HeLa cells. In contrast, edelfosine inhibited phosphatidylcholine biosynthesis in both HeLa and A549 cells, but not in Jurkat or Peer leukemic cells, before the triggering of apoptosis. These data indicate that edelfosine targets two different subcellular structures in a cell type-dependent manner, namely cell surface lipid rafts in leukemic cells and endoplasmic reticulum in solid tumor cells.
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PMID:Differential targets and subcellular localization of antitumor alkyl-lysophospholipid in leukemic versus solid tumor cells. 1654 Apr 73

Human VRK1 (vaccinia-related kinase 1) is a novel serine-threonine kinase that regulates several transcription factors, including p53, ATF2 and c-Jun; and its loss results in defects of cell proliferation. VRK1 stabilizes p53 and the accumulated p53 downregulates VRK1 forming an autoregulatory loop. Wild-type p53, but not mutant p53, was able to downregulate VRK1 in the A549 lung carcinoma cell line. VRK1 expression has been studied in human lung carcinomas. VRK1 protein level was significantly higher in squamous cell lung carcinomas than in adenocarcinomas, and inversely correlated with p16. Tumours with p53 mutations have a positive trend with those having very high levels of VRK1 protein, particularly in squamous cell lung carcinomas. These data indicate that the VRK1-p53 autoregulatory loop was not functional in a group of lung carcinomas. The accumulation of VRK1 in tumours with mutant p53 could result in stimulation of other signalling pathways that can contribute to tumour growth and progression in addition to those resulting from loss of p53 function.
Lung Cancer 2007 Dec
PMID:Alteration of the VRK1-p53 autoregulatory loop in human lung carcinomas. 1768 19


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