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)

Neutral matrix metalloproteinases (MMPs) are responsible for the pathological features of rheumatoid arthritis (RA) such as degradation of cartilage. We herein show the up-regulation of MMP-1 (interstitial collagenase) and MMP-3 (stromelysin) mRNAs of cultured synovial fibroblasts retrieved from rheumatoid arthritis (RA) patients in response to macrophage migration inhibitory factor (MIF). The elevation of MMP-1 and MMP-3 mRNA was dose-dependent and started at 6 h post-stimulation by MIF, reached the maximum level at 24 h, and was sustained at least up to 36 h. Interleukin (IL)-1beta mRNA was also up-regulated by MIF. These events were preceded by up-regulation of c-jun and c-fos mRNA. Tissue inhibitor of metalloproteinase (TIMP)-1, a common inhibitor of these proteases, was slightly up-regulated by MIF. Similarly, mRNA up-regulation of MMP-1 and MMP-3 was observed in the synovial fibroblasts of patients with osteoarthritis. However, their expression levels were much lower than those of RA synovial fibroblasts. The mRNA up-regulation by MIF was inhibited by the tyrosine kinase inhibitors genestein and herbimycin A, as well as the protein kinase C inhibitors staurosporine and H-7. On the other hand, the inhibition was not seen after the addition of the cyclic AMP-dependent kinase inhibitor, H-8. The mRNA up-regulation of MMPs was also inhibited by curcumin, an inhibitor of transcription factor AP-1, whereas interleukin-1 receptor antagonist, an IL-1 receptor antagonist, failed to inhibit the mRNA up-regulation. Considering these results, it is suggested that 1) MIF plays an important role in the tissue destruction of rheumatoid joints via induction of the proteinases, and 2) MIF up-regulates MMP-1 and MMP-3 via tyrosine kinase-, protein kinase C-, and AP-1- dependent pathways, bypassing IL-1beta signal transduction.
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PMID:Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis. 1061 37

Abnormal mechanical loading of joints may induce degeneration of articular cartilage. Shear stress is one mode of mechanical loading that may regulate chondrocyte metabolism. We investigated the mechanism by which shear stress induces the gene encoding matrix metalloproteinase-9, a mediator of the progressive degradation of articular cartilage in osteoarthritis. In vitro experiments using passaged rabbit chondrocytes in monolayer culture subjected to a shear stress of 16 dyn/cm2 (1.6 Pa) in a flow channel showed increased expression of the matrix metalloproteinase-9 gene. The induction of matrix metalloproteinase-9 appeared to depend on a region in the 5' promoter of the gene that contains a 12-0-tetradecanoylphorbol 13-acetate-responsive element. Transfection experiments using a construct containing a luciferase reporter driven by a 12-0-tetradecanoylphorbol 13-acetate-responsive element indicated that shear stress activated a 12-0-tetradecanoylphorbol 13-acetate-responsive element-mediated transcription in chondrocytes. Similar experiments showed that shear stress induced a matrix metalloproteinase-9 promoter construct (matrix metalloproteinase-9-luciferase). Shear stress activated c-Jun NH2-terminal kinase, extracellular signal-regulated kinase, and p38. Transfection of matrix metalloproteinase-9-luciferase together with the dominant negative mutant of c-Jun NH2-terminal kinase, but not with that of extracellular signal-regulated kinase or p38, attenuated the shear-induced matrix metalloproteinase-9 promoter activity. In addition, transfection of constructs encoding dominant negative mutants of Ras, Rac, and Cdc42 attenuated the induction of c-Jun transcriptional activity by shear stress. Thus. shear stimulation of chondrocytes stimulates Ras, Rac, and Cdc42, which subsequently activate c-Jun NH2-terminal kinase to induce a 12-0-tetradecanoylphorbol 13-acetate-responsive element-mediated expression of matrix metalloproteinase-9.
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PMID:Biomechanical regulation of matrix metalloproteinase-9 in cultured chondrocytes. 1119 49

Activation of mitogen activated protein kinases (MAPK) is a critical event in pro-inflammatory cytokine-induced signaling cascade in synoviocytes and chondrocytes that lead to the production of several mediators of cartilage damage in an arthritic joint. Green tea (Camellia sinensis) is a widely consumed beverage and we earlier showed that polyphenols present in green tea (GTP) inhibit the development of inflammation and cartilage damage in an animal model of arthritis. In this study we evaluated the role of epigallocatechin-3-gallate (EGCG), a green tea polyphenol which mimics its anti-inflammatory effects, in modulating the IL-1beta-induced activation of MAPK's in human chondrocytes. We discovered that EGCG inhibited the IL-1beta-induced phosphorylation of c-Jun N-terminal kinase (JNK) isoforms, accumulation of phospho-c-Jun and DNA binding activity of AP-1 in osteoarthritis (OA) chondrocytes. Also IL-1beta, but not EGCG, induced the expression of JNK p46 without modulating the expression of JNK p54 in OA chondrocytes. In immunecomplex kinase assays, EGCG completely blocked the substrate phosphorylating activity of JNK but not of p38-MAPK. EGCG had no inhibitory effect on the activation of extracellular signal-regulated kinase p44/p42 (ERKp44/p42) or p38-MAPK in OA chondrocytes. EGCG or IL-1beta did not alter the total non-phosphorylated levels of either p38-MAPK or ERKp44/p42 in OA chondrocytes. These are novel findings and indicate that EGCG may be of potential benefit in inhibiting IL-1beta-induced catabolic effects in OA chondrocytes that are dependent on JNK activity.
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PMID:Epigallocatechin-3-gallate selectively inhibits interleukin-1beta-induced activation of mitogen activated protein kinase subgroup c-Jun N-terminal kinase in human osteoarthritis chondrocytes. 1250 86

Cytokine-mediated induction and overexpression of matrix metalloproteinases (MMPs) is recognized as an important factor in the pathogenesis of arthritis. Interleukin (IL)-1 beta is a proinflammatory cytokine that is known to superinduce the expression and production of MMP-13 in many cell types. Phenyl N-tert-butylnitrone (PBN), a spin trap agent, inhibited the IL-1 beta-induced expression of MMP-13 in human osteoarthritis (OA) chondrocytes. Down-regulation of MMP-13 expression correlated with the inhibition of mitogen-activated protein kinase (MAPK) subgroups c-Jun NH2-terminal kinase (JNK) and p38-MAPK activation, accumulation of phospho-c-jun, and the DNA binding activity of activating protein-1 (AP-1). Results of in vitro kinase assays showed that exogenously added PBN completely blocked the c-Jun phosphorylating activity of JNK. Interestingly, using in vitro kinase assay, we also found that chondrocyte p38-MAPK phosphorylate c-Jun and that PBN was not very effective in inhibiting c-Jun phosphorylating activity of p38-MAPK. In addition, PBN did not block the ATF-2 phosphorylating activity of p38-MAPK and Elk-1 phosphorylating activity of extracellular regulated kinase p44/p42 in vitro, indicating that PBN may act selectively to inhibit the phosphorylation of c-Jun in OA chondrocytes. Together, our results for the first time demonstrate that PBN suppresses the IL-1 beta-stimulated expression of MMP-13 in OA chondrocytes and that this was achieved by inhibiting the activation of JNK and AP-1. These results suggest that use of PBN or compounds derived from it may be of potential benefit in inhibiting signaling events associated with cartilage degradation in arthritis.
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PMID:Phenyl N-tert-butylnitrone down-regulates interleukin-1 beta-stimulated matrix metalloproteinase-13 gene expression in human chondrocytes: suppression of c-Jun NH2-terminal kinase, p38-mitogen-activated protein kinase and activating protein-1. 1262 40

AP-1 dependent genes, e.g., matrix-metallo-proteinases, are involved in the pathogenesis of rheumatoid arthritis (RA). Therefore, the transcription factor AP-1 and its subunits, proteins of the Jun and Fos proto-oncogene families, are interesting targets for analysis in RA. In this study, we analyzed the mRNA expression of junB in synovial membrane (SM) samples and isolated synovial fibroblasts of patients with RA, osteoarthritis (OA), and normal, non-inflammatory controls. To address the suitability of real-time RT-PCR for the quantitation of Jun proto-oncogene family members, conventional RTPCR and real-time PCR were comparatively applied for junD, a gene representing a major challenge because of its high GC-content (70%, increasing the probability of secondary structures interfering with the PCR) and its sequence homology to other Jun proto-oncogenes. In addition, a comparison was performed concerning the precision, reproducibility, costs, as well as labor and time consumption of the two PCR methods. Real-time RT-PCR proved superior to conventional PCR in terms of precision (mean deviation of measured from employed concentration 58% for real-time PCR vs 225% for conventional PCR), reproducibility, as well as labor and time consumption (4 times less for real-time RT-PCR). Experimental cDNA normalization for equivalent cDNA concentrations by sample dilution was more reliable than mathematical cDNA normalization. However, real-time PCR was 3.6-fold more expensive. Applying the more reliable real-time RT-PCR for the ex vivo analysis of junB mRNA-expression, no significantly different expression of junB was observed in SM or isolated synovial fibroblasts from RA as compared to OA. Interestingly, however, junBmRNA expression was significantly lower in RA SM and borderline significantly lower in OA SM than in normal/non-inflammatory SM, with potential effects on the functional properties of the resulting AP-1 complexes. Immunohistochemical staining of the SM with JunB-specific antibodies showed comparable JunB protein expression in SFB (collagen III mRNA-positive) of RA and OA samples. Thus, real-time RT-PCR appears suitable and time-saving for the quantitation of jun proto-oncogene mRNA-expression in tissue and cell samples with high precision and reproducibility.
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PMID:[Comparison of conventional and real-time RT-PCR for the quantitation of jun protooncogene mRNA and analysis of junB mRNA expression in synovial membranes and isolated synovial fibroblasts from rheumatoid arthritis patients]. 1292 42

Celecoxib, the first US FDA-approved selective cyclooxygenase-2 (COX-2) inhibitor initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, was reported to reduce the polyp burden in patients with familial adenomatous polyposis. This specific COX-2 inhibitor also protects against experimentally induced carcinogenesis, but molecular mechanisms underlying its chemopreventive activities remain largely unresolved. In the present work, we found that celecoxib inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of COX-2 in female ICR mouse skin when applied topically 30 min prior to TPA as determined by both immunoblot and immunohistochemical analyses. In another study, celecoxib attenuated the DNA binding activity of activator protein 1 (AP-1) through suppression of c-Jun and c-Fos expression in TPA-treated mouse skin. In addition, celecoxib inhibited both the catalytic activity and phosphorylation of p38 mitogen-activated protein (MAP) kinase. In the same animal model, TPA treatment resulted in rapid activation via phosphorylation of extracellular signal-regulated protein kinase (ERK)1/2 and p38 MAP kinase, which are upstream of AP-1 in mouse skin. In order to clarify the roles of p38 and ERK in TPA-induced AP-1 activation, we utilized the pharmacologic inhibitors of these enzymes. The p38 inhibitor SB203580 blocked TPA-mediated AP-1 activation, while the MEK1/2 inhibitor U0126 was not inhibitory despite suppression of c-Fos expression in mouse skin. Furthermore, SB203580 markedly inhibited COX-2 expression induced by TPA. Taken together, these findings suggest that celecoxib down-regulates COX-2 by blocking activation of p38 MAP kinase and AP-1, which may represent molecular mechanisms underlying antitumor promoting effects of this drug on mouse skin tumorigenesis.
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PMID:Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin. 1472 83

The mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK) is a critical regulator of collagenase-1 production in rheumatoid arthritis (RA). The MAPKs are regulated by upstream kinases, including MAPK kinases (MAPKKs) and MAPK kinase kinases (MAP3Ks). The present study was designed to evaluate the expression and regulation of the JNK pathway by MAP3K in arthritis. RT-PCR studies of MAP3K gene expression in RA and osteoarthritis synovial tissue demonstrated mitogen-activated protein kinase/ERK kinase kinase (MEKK) 1, MEKK2, apoptosis-signal regulating kinase-1, TGF-beta activated kinase 1 (TAK1) gene expression while only trace amounts of MEKK3, MEKK4, and MLK3 mRNA were detected. Western blot analysis demonstrated immunoreactive MEKK2, TAK1, and trace amounts of MEKK3 but not MEKK1 or apoptosis-signal regulating kinase-1. Analysis of MAP3K mRNA in cultured fibroblast-like synoviocytes (FLS) showed that all of the MAP3Ks examined were expressed. Western blot analysis of FLS demonstrated that MEKK1, MEKK2, and TAK1 were readily detectable and were subsequently the focus of functional studies. In vitro kinase assays using MEKK2 immunoprecipitates demonstrated that IL-1 increased MEKK2-mediated phosphorylation of the key MAPKKs that activate JNK (MAPK kinase (MKK)4 and MKK7). Furthermore, MEKK2 immunoprecipitates activated c-Jun in an IL-1 dependent manner and this activity was inhibited by the selective JNK inhibitor SP600125. Of interest, MEKK1 immunoprecipitates from IL-1-stimulated FLS appeared to activate c-Jun through the JNK pathway and TAK1 activation of c-Jun was dependent on JNK, ERK, and p38. These data indicate that MEKK2 is a potent activator of the JNK pathway in FLS and that signal complexes including MEKK2, MKK4, MKK7, and/or JNK are potential therapeutic targets in RA.
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PMID:Regulation of c-Jun N-terminal kinase by MEKK-2 and mitogen-activated protein kinase kinase kinases in rheumatoid arthritis. 1473 42

VEGF (vascular endothelial growth factor), an important angiogenesis factor, appears also to be involved in inflammatory processes. Recent studies have shown that VEGF and its receptors (VEGFR) are expressed on osteoarthritic, but not on normal adult, chondrocytes. To elucidate possible functions of VEGF in osteoarthritic cartilage, the effects of VEGF were studied on immortalized human chondrocytes. Activated matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, interleukin (IL)-1beta, IL-6, and tumour necrosis factor-alpha (TNF-alpha) were measured in culture supernatants by enzyme-linked immunosorbent assays, nitric oxide with the Griess reagent, and cell proliferation by [3H]thymidine incorporation. VEGFR-2 mRNA was quantified by real-time reverse transcription-polymerase chain reaction and the protein was identified by immuno-gold electron microscopy. Intracellular signal transduction effects were determined by western blots and electrophoretic mobility shift assays. The chondrocyte cell lines C28/I2, C20/A4, and T/C28a2/a4 expressed functionally active VEGFR-2. VEGF stimulation induced receptor phosphorylation, activation of the mitogen-activated protein kinases ERK 1/2, and long-lasting activation of the transcription factor AP-1 (activator protein-1). VEGF increased secreted MMP-1, MMP-3, and especially MMP-13, which could be effectively reduced by an inhibitor of VEGFR-2 kinase activity. Interestingly, VEGF diminished the expression of TIMP-1 and especially TIMP-2. Under hypoxic conditions, as occur in cartilage, the reduction in TIMP levels was even greater. Furthermore, VEGF induced IL-1beta, IL-6, TNF-alpha, and nitric oxide expression to a small extent and stimulated the proliferation of immortalized chondrocytes. These findings indicate that VEGF is an autocrine stimulator of immortalized chondrocytes that mediates mainly destructive processes in osteoarthritis.
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PMID:Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. 1499 3

Protein kinases, particularly mitogen-activated protein kinases and receptor-tyrosine kinases play crucial roles in mammalian cellular metabolism by regulating intracellular signaling pathways that control proliferation, differentiation, cytokine gene induction and cytokine responsiveness, matrix metalloproteinase gene expression, mechanical transduction, as well as programmed cell death (apoptosis). Many of these pathways are also important components of cartilage homeostasis because alterations in intracellular signaling pathways appear to play a prominent role in chondrocyte dysfunction that is part of osteoarthritis pathogenesis and disease progression. Several mitogen-activated protein kinases and receptor-tyrosine kinases have been characterized as participating in chondrocyte signaling pathways. They are c-Jun-amino-terminal protein kinase, p38 kinase, extracellular signal-regulated protein kinase, and Ror2. Janus kinases and signal transducers and activators of transcription factors (Janus kinase/signal transducers and activators of transcription pathway) are also implicated in modulating the chondrogenic phenotype. Mitogen-activated protein kinase activation is required for their role as phosphorylating enzymes. Activation results from mitogen-activated protein kinase phosphorylation carried out by at least seven upstream kinases known as mitogen-activated protein kinase kinases. Additional upstream kinases (for example, MKKKKs and MKKKs) often require low molecular weight GTP-binding proteins to mediate the mitogen-activated protein-kinase kinases cascade. Identifying the functions of mitogen-activated protein kinases in normal and aging cartilage and the extent to which mitogen-activated protein kinases may be altered in osteoarthritis cartilage and synovium will be critical for developing novel therapies for osteoarthritis management.
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PMID:Protein kinases in chondrocyte signaling and osteoarthritis. 1548 58

Rheumatoid arthritis (RA) causes a symmetric, inflammatory polyarthritis that results in joint destruction and significant disability. Signaling pathways that regulate the production of cytokines and destructive enzymes have been implicated in its pathogenesis and represent potential therapeutic targets. The IkappaB kinase (IKK)-related kinase, IKKepsilon/IKKi, which plays a pivotal role in regulating antiviral gene transcription, is constitutively expressed by cultured fibroblast-like synoviocytes (FLS) and could participate in the pathogenesis of RA. In the current studies we demonstrate that IKKepsilon protein is expressed in RA and osteoarthritis synovium and that the protein is found primarily in the synovial intimal lining. Functional studies in cultured FLS showed that IKKepsilon kinase activity is rapidly induced by cytokines, although IkappaB phosphorylation is significantly less compared with IKK2. Because NF-kappaB activation is similar in wild-type and IKKepsilon knockout murine FLS, studies were performed to identify an alternative substrate for IKKepsilon. Interestingly, c-Jun is a more efficient substrate for IKKepsilon immunocomplexes in human FLS and this activity appears to be independent of JNK. The functional relevance of IKKepsilon was examined using murine IKKepsilon(-/-) cultured FLS. IL-1-, TNF-alpha-, and LPS-mediated induction of matrix metalloproteinases, MMP3 and MMP13, is significantly decreased in the IKKepsilon(-/-) cells. These data suggest a novel role for the IKKepsilon complex in synovial inflammation, extracellular matrix destruction, and activation of the viral program and innate immune response in RA.
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PMID:Regulation of c-Jun phosphorylation by the I kappa B kinase-epsilon complex in fibroblast-like synoviocytes. 1587 44


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