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)

Adrenomedullin is a secreted peptide hormone with multiple functions. Although a number of reports have indicated that adrenomedullin may be involved in tumor progression, its mechanism of action remains obscure. In this study, we have analysed the signal transduction pathway activated by adrenomedullin in human glioma cells. Our results revealed that adrenomedullin induced the phosphorylation of both c-Jun and JNK in glioblastoma cells. Silencing JNK expression with siRNA reversed the phosphorylation of c-Jun induced by adrenomedullin, indicating that JNK is responsible of c-Jun activation. In addition, electrophoretic mobility-shift assays showed that the increase in phosphorylation of c-Jun was associated with increased AP-1 DNA binding activity. Supershift assays and co-immunoprecipitation demonstrated that c-Jun and JunD are part of the AP-1 complex, indicating that activated c-Jun is dimerized with JunD in response to adrenomedullin. Furthermore, adrenomedullin was shown to promote cell transit beyond cell cycle phases with a concomittant increase in cyclin D1 protein level, suggesting that adrenomedullin effects cell proliferation through up-regulation of cyclin D1. The inhibition of JNK activation or the suppression of c-Jun or JunD expression with siRNA impaired the effects of adrenomedullin on cell proliferation and on cyclin D1. Taken together, these data demonstrate that activation of cJun/JNK pathway is involved in the growth regulatory activity of adrenomedullin in glioblastoma cells.
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PMID:Adrenomedullin promotes cell cycle transit and up-regulates cyclin D1 protein level in human glioblastoma cells through the activation of c-Jun/JNK/AP-1 signal transduction pathway. 1916 30

Proteasome inhibitor, which inhibits NF-kappaB activation, has been reported to activate c-Jun N-terminal kinase (JNK)-c-Jun pathway. In this study, we investigated the effects of proteasome inhibitor on the human cytomegalovirus (HCMV) major immediate early (MIE) gene expression in human central nervous system (CNS)-derived cell lines. Treatment of HCMV-infected 118MGC glioma and U373-MG astrocytoma cells with three proteasome inhibitors, MG132, clasto-lactacystin beta-lactone, and epoxomicin, suppressed MIE protein expression. In contrast, in HCMV-infected IMR-32 neuroblastoma cells, the proteasome inhibitors increased MIE protein expression, even in the presence of NF-kappaB inhibitor SN-50. A luciferase reporter assay demonstrated that MG132 markedly elevated the MIE promoter/enhancer (MIEP) activity in IMR-32 cells, but down-regulated it in 118MGC and U373-MG cells. Mutation in five cAMP response elements (CREs) within the MIEP resulted in a loss of the ability to respond to MG132 in IMR-32 cells. Moreover, Western blotting analysis revealed that MG132 induced c-Jun phosphorylation in all three CNS-derived cell lines, whereas a high level of activating transcription factor-2 (ATF-2) phosphorylation was observed only in IMR-32 cells. Finally, MG132-induced MIE protein expression was suppressed by JNK inhibitor that reduced the phosphorylation levels of both c-Jun and ATF-2. Taken together, these results suggest that the proteasome inhibitors activate CRE binding proteins consisting of c-Jun and ATF-2 through activating the JNK-c-Jun pathway, thereby inducing MIE protein synthesis in IMR-32 cells under the condition where NF-kappaB activity is inhibited.
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PMID:Proteasome inhibitor differentially regulates expression of the major immediate early genes of human cytomegalovirus in human central nervous system-derived cell lines. 1920 84

Hypoxia and necrosis are fundamental features of glioblastoma (GBM) and their emergence is critical for the rapid biological progression of this fatal tumor; yet, underlying mechanisms are poorly understood. We have suggested that vaso-occlusion following intravascular thrombosis could initiate or propagate hypoxia and necrosis in GBM. Tissue factor (TF), the main cellular initiator of coagulation, is overexpressed in GBMs and likely favors a thrombotic microenvironment. Epidermal growth factor receptor (EGFR) amplification and PTEN loss are two common genetic alterations seen in GBM but not in lower-grade astrocytomas that could be responsible for TF up-regulation. The most frequent EGFR mutation in GBM involves deletion of exons 2 to 7, resulting in the expression of a constitutively active receptor, EGFRvIII. Here, we show that overexpression of EGFR or EGFRvIII in human glioma cells causes increased basal TF expression and that stimulation of EGFR by its ligand, EGF, leads to a marked dose-dependent up-regulation of TF. In all cases, increased TF expression led to accelerated plasma coagulation in vitro. EGFR-mediated TF expression depended most strongly on activator protein-1 (AP-1) transcriptional activity and was associated with c-Jun NH(2)-terminal kinase (JNK) and JunD activation. Restoration of PTEN expression in PTEN-deficient GBM cells diminished EGFR-induced TF expression by inhibiting JunD/AP-1 transcriptional activity. PTEN mediated this effect by antagonizing phosphatidylinositol 3-kinase activity, which in turn attenuated both Akt and JNK activities. These mechanisms are likely at work in vivo, as EGFR expression was highly correlated with TF expression in human high-grade astrocytoma specimens.
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PMID:Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity. 1927 85

Malignant gliomas are common and aggressive brain tumors in adults. The rapid proliferation and diffuse brain migration are main obstacles to successful treatment. Here we show that pentobarbital, a central depressant introduced clinically a century ago, is capable of suppressing proliferation and migration of C6 malignant glioma cells in a concentration-dependent manner. Pentobarbital also leads to a G1 phase cell cycle arrest accompanied by suppressed G1 cell cycle regulatory proteins Cyclin D1, Cyclin D3, CDK2 and phosphorylated Rb. In addition, noticeable morphological changes and interrupted alpha-tubulin microtubule assembly are induced by pentobarbital exposure. Intracellular signal pathways involved in the effect of pentobarbital is concerned with inactivation of ERK, c-Jun and Akt. Together, these findings suggest anti-proliferation and anti-migration effects of pentobarbital on malignant gliomas, most likely by arresting cell cycle and interfering microtubule. ERK, c-Jun MAPK and PI3K/Akt are possible signaling pathways involved.
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PMID:Anesthetic pentobarbital inhibits proliferation and migration of malignant glioma cells. 1934 66

Penta-acetyl geniposide [(Ac)(5)GP], an acetylated geniposide product from Gardenia fructus, has been known to have hepatoprotective properties and recent studies have revealed its anti-proliferative and apoptotic effect on C6 glioma cells. In this study, we first report the anti-metastastic effect of (Ac)(5)GP in the rat neuroblastoma line: C6 glioma cells. First (Ac)(5)GP exhibited an inhibitory effect on abilities of adhesion and motility by cell-matrix adhesion assay, wound healing assay and Boyden chamber assay. Second, the decreasing activity of matrix metalloproteinase-2 (MMP-2) was noted by gelatin zymography assay. Further analysis with semi-quantitative RT-PCR showed the mRNA levels of MMP-2 and membrane type I matrix metalloproteinase (MT1-MMP) were significantly reduced, while the tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) was elevated by (Ac)(5)GP treatment. Further (Ac)(5)GP also exerted an inhibitory effect on phosphoinositide 3-kinase (PI3K) protein expression, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and inhibition of activation of transcription factor nuclear factor kappa B (NF-kappaB), c-Fos, c-Jun. These findings proved (Ac)(5)GP is highly likely to be a inhibiting cancer migration agent to be further developed in the future.
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PMID:Inhibitory effect of penta-acetyl geniposide on C6 glioma cells metastasis by inhibiting matrix metalloproteinase-2 expression involved in both the PI3K and ERK signaling pathways. 1946 79

Previous studies have revealed that p38, a member of the family of stress-activated protein kinases (SAPKs), cooperates with the Chk1-pathway to bring about temozolomide (TMZ)-induced G2 arrest, and that the inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells to TMZ-induced cytotoxicity. c-Jun N-terminal kinase (JNK), another SAPK, has been reported to have several roles of cell survival, oncogenesis, growth, differentiation and cell death. To elucidate the functions of JNK in glioma cells treated with TMZ, we analyzed alterations in JNK and the effect of modification of JNK in U87MG human glioma cells treated with TMZ. We found that JNK was phosphorylated 1-2 days after TMZ treatment and that pretreatment (for 24 h) and post-treatment (for 72 h) with a JNK inhibitor SP600125 at a concentration of 200 nM or higher remarkably reduced clonogenicity in the TMZ-treated cells. The phosphorylation of the JNK target protein c-Jun, but not of ATF-2, was inhibited by this concentration of SP600125. Therefore JNK was proved to have a role of survival in glioma cells treated with TMZ, and c-Jun-related responses were suggested to be more important in the JNK-mediated survival of glioma cells with DNA damage. SP600125 amplified the percentage of senescence-like cells and of mitotic catastrophe cells in TMZ-treated U87MG and U87MG-E6 cells, respectively, suggesting that the enhancement of TMZ-induced cytotoxicity by a JNK inhibitor in glioma cells is induced (at least in part) by the potentiation of cell death pathways induced by TMZ alone. Further investigation based on the present data may provide a viable approach for enhancing TMZ-induced cytotoxicity in human gliomas.
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PMID:Inhibition of c-Jun N-terminal kinase enhances temozolomide-induced cytotoxicity in human glioma cells. 1951 66

S-Adenosylhomocysteine (SAH) is a risk factor for many diseases, including tumor progression and neurodegenerative disease. In this study, we examined the hypothesis that SAH may indirectly enhance the invasion of C6 glioma cells by induction of matrix metalloproteinase-2 (MMP-2) secreted from the murine microglia BV2 cells. We obtained conditioned medium (CM) by incubating BV2 cells with SAH (1-50nM) for 24 h. We found that the SAH-containing CM (SAH-BV2-CM) strongly enhanced the invasiveness of C6 glioma cells and that this effect increased with increasing concentrations of SAH in the SAH-BV2-CM. The effect of CM could be attributed to its MMP-2 activity, as a result of increased protein and messenger RNA expression of MMP-2 in BV2 cells induced by SAH. In BV2 cells treated with SAH, the binding abilities of nuclear factor-kappa B (NF-kappaB) and stimulatory protein-1 (Sp1) to the MMP-2 promoter were increased, whereas the level of NF-kappaB inhibitor was decreased. In addition, SAH significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase/serine/threonine protein kinase (or protein kinase B) (PI3K/Akt) proteins but did not affect that of c-Jun NH2-terminal kinase or p38. Pretreatment of BV2 cells with an inhibitor specific for ERK (U0126) markedly abated the expression of ERK and MMP-2. Furthermore, SAH significantly and dose dependently decreased tissue inhibitor of metalloproteinase-2 (TIMP-2) in BV2 cells. Thus, SAH may induce the invasiveness of C6 glioma cells by decreased TIMP-2 expression and increased MMP-2 expression in BV2 cells. The latter effect is likely mediated through the ERK and PI3K/Akt pathways, with increased binding activities of NF-kappaB and Sp1 to the MMP-2 gene promoter.
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PMID:S-Adenosylhomocysteine promotes the invasion of C6 glioma cells via increased secretion of matrix metalloproteinase-2 in murine microglial BV2 cells. 1977 Apr 85

Fas (CD95/APO-1) is a cell surface "death receptor" that mediates apoptosis upon engagement by its ligand, FasL. Paradoxically, Fas/FasL can also promote cell invasion among non-apoptotic cells; here, we show that Fas/FasL signaling can promote tumor invasion when apoptosis is compromised. We have developed a recombinant FasL Interfering Protein (FIP) to interfere with Fas signaling in C6 glioma cells expressing both Fas receptor and its ligand. FIP administration did not affect cell viability but impaired cell motility and invasiveness of glioma cells. Blockade of Fas signaling reduced MMP-2 activity in glioma cells, that was associated with down-regulation of MAPK signaling, and AP-1 and NFkappaB-driven transcription. FIP treatment did not affect mmp-2 and mt1-mmp expression but significantly attenuated timp-2 expression and TIMP-2 amount in the culture medium. Studies with pharmacological inhibitors of JNK/c-Jun (SP600125) and NFkappaB (BAY11-7082) signaling pathways demonstrated that timp-2 expression is regulated by NFkappaB transcription factor. Our findings show that non-apoptotic Fas signaling activated in the autocrine manner or through microenvironment derived factors can regulate invasiveness of glioma cells via modulation of MMP-2 activation, likely by controlling TIMP-2 expression.
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PMID:Non-apoptotic Fas signaling regulates invasiveness of glioma cells and modulates MMP-2 activity via NFkappaB-TIMP-2 pathway. 1978 21

The expression of proenkephalin (PENK) mRNA in C6 rat glioma cells was stimulated by norepinephrine (a beta-adrenergic agonist) and markedly enhanced by the addition of dexamethasone (a glucocorticoid agonist) to the culture medium, although dexamethasone alone exhibited no significant increase in PENK mRNA. Furthermore, no induction of glucocorticoid-response-element (GRE)-binding proteins was detectable. In contrast, the stimulation of PENK mRNA expression was not observed with a protein kinase C activator, 12-tetradecanoylphorbol-13-acetate (TPA), which stimulated the expression of c-fos and c-jun mRNA and their proto-oncoproteins (c-Fos and c-Jun). In addition, an AP-1 activity was induced by TPA and an induction of a kappaB-like binding activity was found with TPA plus cycloheximide-treated cells. Together, they suggest that activation of PENK gene in C6 cells is probably mediated mainly through the, beta-adrenergic agonist-elicited cyclic AMP signal pathway, and induction of AP-1 and kappaB-like binding activities appear not to participate in gene activation. Interestingly, the Western blot data showed no increase in intracellular levels of proenkephalin between control and treated cells. However, a marked increase in immunoreactivities for proenkephalin and its derivative, [Met(5)]-enkephalin was detected in medium and a lesser elevation in cells from modulator-treated cell culture through the time course. These results indicated that there was an association between an increase in PENK mRNA expression and an elevation of proenkephalins, and subsequently, the synthesized proenkephalins were released into the medium.
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PMID:Regulation of proenkephalin expression in C6 rat glioma cells. 1991 95

Interferon (IFN)-lambdas, including INF-lambda1, -lambda2, and -lambda3, are a newly described group of cytokines distantly related to the type I IFNs and IL-10 family members. IFN-lambda1, -lambda2, and -lambda3 bind to the same receptor (known as IL28RA) to exert their antiviral, antitumor and immunomodulatory effects. Here, we identified IL28RA genes from the genome of human, chimpanzee, macaque, orangutan, mouse, horse, rat, dog, chicken, and found that only one IL28RA existed in each genome. All the identified IL28RAs are single-pass type I membrane proteins except chicken IL28RA. They belong to the type II cytokine receptor family and contain one fibronectin type-III domain. We found human IL28RA was expressed in lymphs, testes, lymphoma, teratocarcinoma, pediatric pre-B cell acute lymphoblastic leukemia, germinal center B cells, embryonic stem cells, fetal lung, and also expressed in bladder, blood and breast cancers, glioma, head and neck cancer and lung cancer tissues. Three tumor-related transcriptional factor binding sites (AP-2, c-Jun and P53) were identified within the 1.0-kb regions upstream of the transcriptional start site of human IL28RA. Meta-analysis of the prognostic value of IL28RA genes in various cancers found that the expression of IL28RA was indeed related to the cancer prognosis in certain cancers. The STAT1 binding sites in the promoter region of IL28RA implied a specific mechanism for the amplifying effects of IFN-lambdas. The LyF-1 binding sites in the promoter region of IL28RA imply that IFN-lambdas were involved in the differentiation of early B and T cells.
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PMID:Integrative genomic analyses on IL28RA, the common receptor of interferon-lambda1, -lambda2 and -lambda3. 2037 26


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