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)

One of the characteristic responses of HT29 human colon adenocarcinoma cells to hypoxic stress is the induction of c-jun expression and binding to the activator-protein 1 (AP-1) element. To study the mechanism of c-jun activation during hypoxia, inhibitors of signaling pathways leading to the activation of AP-1 transcription factor were used. One of them, the benzoquinone ansamycin geldanamycin (GA) Mr-90,000 heat-shock protein (hsp90)-binding antibiotic, is known to disrupt signaling pathways by inducing destabilization of the enzyme complexes and degradation of signaling intermediates involving the proteasome. In our experiments, GA inhibited both basal and hypoxia-induced c-jun expression (IC50 = 75 nM). GA also abolished the hypoxia-induced increase in c-Jun NH2-terminal kinase (JNK1) catalytic activity and demonstrated an inhibitory effect on stress-activated protein kinase/ERK kinase-1 (SEK1); other participants in the mitogen-activated protein kinase and p38 signal transduction pathways were not affected to the same degree. GA treatment led to a decrease in the nuclear content of c-Jun but not that of c-Fos or of activating transcription factor 2. Functional consequences of these effects were suggested by the inhibition of AP-1 binding in hypoxic HT29 cells in the presence of GA. Pretreatment with the proteasome inhibitor lactacystin before the addition of GA resulted in the elevation of overall c-jun level, but it was unable to restore the hypoxia-induced c-jun expression. Our results demonstrate that GA acts as a highly potent inhibitor of hypoxia-induced c-jun expression, affecting the activation of JNK and of the AP-1 transcription factor. However, the effect of GA cannot be attributed solely to the inhibition of signaling through JNK, and additional mechanisms remain to be identified.
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PMID:Effects of geldanamycin on signaling through activator-protein 1 in hypoxic HT29 human colon adenocarcinoma cells. 1046 87

The ubiquitin-proteasome system has been regarded as being important in the progression of neurodegenerative diseases, although its exact role remains uncertain. This in vitro study using PC12h cell cultures examined whether interference with the ubiquitin-proteasome system by proteasome inhibitors induces the neuropathological features of neurodegenerative diseases. Perikaryal accumulation of phosphorylated neurofilaments and an increase in c-Jun as well as phosphorylated form of c-Jun and apoptosis-specific protein were induced by the proteasome inhibitors lactacystin and N-carbobenzoxy-leucyl-leucyl-leucinal. These changes were not observed when only calpain was inhibited. The present study therefore suggests the possibility that a perturbation of the ubiquitin-proteasome system may be one of the causes that result in the development of neuropathological features. Additionally, activity assays showed that the proteasome inhibitor caused an increase in the activity of c-Jun N-terminal kinase (JNK/SAPK), which can phosphorylate neurofilaments and c-Jun, suggesting the possible involvement of JNK in phosphorylation of these proteins.
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PMID:Accumulation of phosphorylated neurofilaments and increase in apoptosis-specific protein and phosphorylated c-Jun induced by proteasome inhibitors. 1100 89

Proteasome inhibitors, the well-known inhibitors of NF-kappaB, are recently considered therapeutic agents for inflammation. However, the anti-inflammatory properties of these agents have not been fully evaluated. In this report we describe a novel effect of proteasome inhibitors on the expression of monocyte chemoattractant protein 1 (MCP-1) in mesangial cells. We found that proteasome inhibitor MG132 dose-dependently induced expression of MCP-1 at the transcriptional level. The stimulatory effect was similarly observed with other proteasome inhibitors (proteasome inhibitor 1 and lactacystin) and in other cell types (NRK fibroblasts). The 5'-flanking region of the MCP-1 gene contains multiple AP-1 sites. To explore the mechanisms involved, we examined the effects of proteasome inhibition on the AP-1 pathway. Northern blot analysis showed that MG132 rapidly induced the expression of c-jun, but not c-fos. Immunoblot analysis showed that MG132 prevented degradation of c-Jun protein. Kinase assay revealed that c-Jun N-terminal kinase (JNK) was rapidly activated by MG132. Consistent with these results, a reporter assay showed that AP-1 activity was up-regulated after treatment with MG132. Curcumin, a pharmacological inhibitor of the JNK-AP-1 pathway, abrogated the induction of MCP-1 by MG132. Similarly, stable transfection with a dominant-negative mutant of c-Jun attenuated both MG132-induced activation of AP-1 and expression of MCP-1. The transcriptional activation by proteasome inhibitors was observed not only in MCP-1, but also in other AP-1-dependent genes, including stromelysin and mitogen-activated protein kinase phosphatase 1. These data revealed that proteasome inhibition triggered the expression of MCP-1 and other genes via the multistep induction of the JNK-c-Jun/AP-1 pathway.
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PMID:Unexpected transcriptional induction of monocyte chemoattractant protein 1 by proteasome inhibition: involvement of the c-Jun N-terminal kinase-activator protein 1 pathway. 1146 28

The role of c-Jun NH2-terminal kinase (JNK) signaling cascade in the stress-inducible phosphorylation of heat shock factor 1 (HSF1) was investigated using known agonists and antagonists of JNK. We showed that treatment of HeLa cells with MG132, a proteasome inhibitor and known INK activator, caused the transcriptional activation domain of HSF1 to be targeted and phosphorylated by JNK2 in vivo. Dose-response and time course studies of the effects of heat shock and anisomycin treatment showed a close correlation of the activation of JNK and hyperphosphorylation of HSF1. SB203580 inhibited INK at the 100 microM concentration and significantly reduced the amount of hyperphosphorylated HSF1 upon heat shock or anisomycin treatment. SB203580 and dominant-negative JNK suppress hsp70 promoter-driven reporter gene expression selectively at 45 degrees C but not at 42 degrees C heat stress, suggesting that JNK would be preferentially associated with the protective heat shock response against severe heat stress. The possibility that JNK-mediated phosphorylation of HSF1 may selectively stabilize the HSF1 protein and confers protection to cells under conditions of severe stress is discussed.
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PMID:JNK phosphorylates the HSF1 transcriptional activation domain: role of JNK in the regulation of the heat shock response. 1152 57

GL331 is a novel podophyllotoxin-derived compound. In this study, GL331 induced human lung adenocarcinoma cell line CL1-5 growth arrest before death during the initial 24-h incubation period. We found that GL331 had no inhibitory effect on the expression of cyclins E, A, B1, CDK 4, and CDK 2; instead, its cell growth-inhibitory effect was partly attributable to an early down-regulation of cyclin D1 expression and in turn the reduction of retinoblastoma protein phosphorylation. GL331 enhanced the proteolysis of cyclin D1, and a proteasome inhibitor was able to block GL331-caused cyclin D1 reduction, suggesting that GL331-stimulated cyclin D1 degradation was through proteasomal processes. Additionally, GL331 reduced cellular cyclin D1 mRNA level down to 45% of control in 4 h and further to around 20% in 12 h. However, GL331 did not accelerate the disappearance of cyclin D1 mRNA under the condition of transcription blockage induced by actinomycin D. It was reported that a certain region in the 3'-untranslated region (UTR) of cyclin D1 mRNA mediated the mRNA degradation upon extracellular stresses. Herein, transient transfection studies demonstrated that the 3'-UTR insertion did not confer the susceptibility of luciferase reporter gene to the GL331 treatment. Together, these data suggested that GL331 did not decrease the stability of cyclin D1 mRNA. On the other hand, we found that GL331 specifically inhibited the cyclin D1 promoter-driven luciferase reporter activity. Western blot analyses showed that GL331 decreased the level of phosphorylated extracellular signal-regulated kinase (Erk), with no effect on p38 or c-Jun NH(2)-terminal kinase. Furthermore, GL331's inhibition of cyclin D1 promoter was attenuated by ectopic Erk-2 overexpression. These data suggested that GL331 inhibited cyclin D1 gene transcription via the Erk signaling pathway. In summary, we report that GL331 induced an early decline of cyclin D1 expression by dual mechanisms: 1) enhancement of protein turnover and 2) repression of Erk-mediated gene transcription.
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PMID:GL331 induces down-regulation of cyclin D1 expression via enhanced proteolysis and repressed transcription. 1156 39

Stratified epithelia of the oral cavity are continually exposed to bacterial challenge that is initially resisted by neutrophils and epithelial factors, including antimicrobial peptides of the beta-defensin family. Previous work has shown that multiple signaling pathways are involved in human beta-defensin (hBD)-2 mRNA regulation in human gingival epithelial cells stimulated with a periodontal bacterium, Fusobacterium nucleatum, and other stimulants. The goal of this study was to further characterize these pathways. The role of NF-kappaB in hBD-2 regulation was investigated initially due to its importance in inflammation and infection. Nuclear translocation of p65 and NF-kappaB activation was seen in human gingival epithelial cells stimulated with F. nucleatum cell wall extract, indicating possible involvement of NF-kappaB in hBD-2 regulation. However, hBD-2 induction by F. nucleatum was not blocked by pretreatment with two NF-kappaB inhibitors, pyrrolidine dithiocarbamate and the proteasome inhibitor, MG132. To investigate alternative modes of hBD-2 regulation, we explored involvement of mitogen-activated protein kinase pathways. F. nucleatum activated p38 and c-Jun NH(2)-terminal kinase (JNK) pathways, whereas it had little effect on p44/42. Furthermore, inhibition of p38 and JNK partially blocked hBD-2 mRNA induction by F. nucleatum, and the combination of two inhibitors completely blocked expression. Our results suggest that NF-kappaB is neither essential nor sufficient for hBD-2 induction, and that hBD-2 regulation by F. nucleatum is via p38 and JNK, while phorbol ester induces hBD-2 via the p44/42 extracellular signal-regulated kinase pathway. Studies of hBD-2 regulation provide insight into how its expression may be enhanced to control infection locally within the mucosa and thereby reduce microbial invasion into the underlying tissue.
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PMID:Regulation of human beta-defensin-2 in gingival epithelial cells: the involvement of mitogen-activated protein kinase pathways, but not the NF-kappaB transcription factor family. 1175 76

1: Prostaglandin H synthase-2 (PGHS-2), is an inducible enzyme involved in various inflammatory responses. We established here that interleukin-1beta (IL-1beta) but not tumour necrosis factor-alpha (TNF-alpha) increased its expression in human pulmonary microvascular endothelial cells (HPMEC). However, associated with IL-1beta, TNF-alpha greatly potentiated this enzyme induction. 2: Although unable to induce PGHS-2 expression by itself, TNF-alpha promoted a similar transcription nuclear factor-kappaB (NF-kappaB) activation to IL-1beta. This effect was more pronounced when cells were co-exposed to both cytokines. HPMEC pre-treatment with MG-132, a proteasome inhibitor, prevented NF-kappaB activation as well as more distal signalling response, indicating that NF-kappaB activation is required but not sufficient for PGHS-2 expression. 3: Both IL-1beta and TNF-alpha failed to activate c-Jun NH2-terminal kinase (JNK). In addition, PD98059, a p42/44 mitogen-activated protein kinase (MAPK) phosphorylation inhibitor, did not decrease PGHS-2 expression. However, SB 203580, a p38 MAPK inhibitor, suppressed PGHS-2 induction by IL-1beta alone or combined with TNF-alpha, demonstrating that p38 MAPK but not p42/44 MAPK or JNK cascades are required for PGHS-2 up-regulation. 4: Finally, TNF-alpha, unlike IL-1beta, was unable to promote p38 MAPK phosphorylation, indicating that the failure of TNF-alpha to induce PGHS-2 expression is linked, at least in part, to its inability to activate p38 MAPK signalling pathway. Altogether, these data enhanced our understanding of PGHS-2 regulation in HPMEC and emphasize the heterogeneity of cellular responses to proinflammatory cytokines.
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PMID:TNF-alpha, inefficient by itself, potentiates IL-1beta-induced PGHS-2 expression in human pulmonary microvascular endothelial cells: requirement of NF-kappaB and p38 MAPK pathways. 1214

We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH(2)-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.
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PMID:Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. 1239

In this study, we examined the effects of isoform-specific functional inhibitors of lysophosphatidic acid acyltransferase (LPAAT), which converts lysophosphatidic acid to phosphatidic acid, on multiple myeloma (MM) cell growth and survival. The LPAAT-beta inhibitors CT-32176, CT-32458, and CT-32615 induced >95% growth inhibition (P < 0.01) in MM.1S, U266, and RPMI8226 MM cell lines, as well as MM cells from patients (IC(50), 50-200 nM). We further characterized this LPAAT-beta inhibitory effect using CT-32615, the most potent inhibitor of MM cell growth. CT-32615 triggered apoptosis in MM cells via caspase-8, caspase-3, caspase-7, and poly (ADP-ribose) polymerase cleavage. Neither interleukin 6 nor insulin-like growth factor I inhibited CT-32615-induced apoptosis. Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-beta inhibitors. CT-32615-induced apoptosis was associated with phosphorylation of p53 and c-Jun NH(2)-terminal kinase (JNK); conversely, JNK inhibitor SP600125 and dominant-negative JNK inhibited CT-32615-induced apoptosis. Importantly, CT-32615 inhibited tumor necrosis factor-alpha-triggered nuclear factor-kappaB activation but did not affect either tumor necrosis factor-alpha-induced p38 mitogen-activated protein kinase phosphorylation or interleukin 6-triggered signal transducers and activators of transcription 3 phosphorylation. Finally, although binding of MM cells to bone marrow stromal cells augments MM cell growth and protects against dexamethasone-induced apoptosis, CT-32615 induced apoptosis even of adherent MM cells. Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM.
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PMID:Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. 1467 6

c-Jun is an immediate-early gene whose degradation by the proteasome pathway is required for an efficient transactivation. In this report, we demonstrated that the c-Jun coactivator, nascent polypeptide associated complex and coactivator alpha (alphaNAC) was also a target for degradation by the 26S proteasome. The proteasome inhibitor lactacystin increased the metabolic stability of alphaNAC in vivo, and lactacystin, MG-132, or epoxomicin treatment of cells induced nuclear translocation of alphaNAC. We have shown that the ubiquitous kinase glycogen synthase kinase 3beta (GSK3beta) directly phosphorylated alphaNAC in vitro and in vivo. Inhibition of the endogenous GSKappa3beta activity resulted in the stabilization of this coactivator in vivo. We identified the phosphoacceptor site in the C-terminal end of the coactivator, on position threonine 159. We demonstrated that the inhibition of GSK3beta activity by treatment of cells with the inhibitor 5-iodo-indirubin-3'-monoxime, as well as with a dominant-negative GSK3beta mutant, induced the accumulation of alphaNAC in the nuclei of cells. Mutation of the GSK3beta phosphoacceptor site on alphaNAC induced a significant increase of its coactivation potency. We conclude that GSK3beta-dependent phosphorylation of alphaNAC was the signal that directed the protein to the proteasome. The accumulation of alphaNAC caused by the inhibition of the proteasome pathway or the activity of GSK3beta contributes to its nuclear translocation and impacts on its coactivating function.
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PMID:GSK3 beta-dependent phosphorylation of the alpha NAC coactivator regulates its nuclear translocation and proteasome-mediated degradation. 1500 26


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