UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 29-kDa amino-terminal fibronectin fragment (FN-f) has a potent chondrolytic effect and is thought to be involved in cartilage degradation in arthritis. However, little is known about signal transduction pathways that are activated by FN-f. Here we demonstrated that FN-f induced nitric oxide (NO) production from human articular chondrocytes. Expression of inducible nitric-oxide synthase (iNOS) mRNA and NO production were observed at 6 and 48 h after FN-f treatment, respectively. Interleukin-1beta (IL-1beta) mRNA up-regulation was stimulated by FN-f in human chondrocytes. To address the possibility that FN-f-induced NO release is mediated by IL-1beta production, the effect of IL-1 receptor antagonist (IL-1ra) was determined. IL-1ra partially inhibited FN-f-induced NO release although it almost completely inhibited IL-1beta-induced NO release. Tyrosine phosphorylation of focal adhesion kinase was induced transiently by FN-f treatment. Blocking antibodies to alpha(5) or beta(1) integrin and Arg-Gly-Asp-containing peptides did not inhibit FN-f-induced NO production. PP2, a Src family kinase inhibitor, or cytochalasin D, which selectively disrupts the network of actin filaments, inhibited both FAK phosphorylation and NO production induced by FN-f, but the phosphatidylinositol 3-kinase inhibitor wortmannin had no effect. Analysis of mitogen-activated protein kinases (MAPK) showed activation of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase, and p38 MAPK. High concentrations of SB203580, which inhibit both JNK and p38 MAPK, and PD98059 a selective inhibitor of MEK1/2 that blocks ERK activation, inhibited FN-f induced NO production. These data suggest that focal adhesion kinase and MAPK mediate FN-f induced activation of human articular chondrocytes.
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PMID:Focal adhesion kinase and mitogen-activated protein kinases are involved in chondrocyte activation by the 29-kDa amino-terminal fibronectin fragment. 1167 48

The megakaryoblastic CHRF-288 cell line was used to investigate signal transduction pathways responsible for proplateletlike formation (PPF). The role of fibronectin (FN) and protein kinase C (PKC) activation in PPF were examined. In the presence of serum and phorbol 12-myristate 13-acetate (PMA), a PKC activator, cells exhibited full megakaryocytic differentiation, manifested by adhesion, shape change, increased cell size, polyploidy, PPF, and expression of CD41(+), CD61(+), and CD62P(+). The same morphologic and phenotypic features were observed in serum-free cultures in the presence of FN/PMA. Only partial differentiation occurred when other integrin ligands were substituted for FN. FN alone induced minimal cell adhesion and spreading, while PMA alone induced only polyploidy without adhesion. Signal transduction changes involved the activation of the extracellular signal-regulated protein kinase 1 (ERK1)/ERK2 as well as c-Jun amino-terminal kinase 1 (JNK1)/stress-activated protein kinase (SAPK). Phosphoinositide-3 kinase and p38 were not stimulated under these conditions. Inhibitors were used to identify the causal relationship between signaling pathways and PPF. PD98059 and GF109203X, inhibitors of ERK1/ERK2 pathway and PKC, respectively, blocked PPF, while adhesion, spreading, and polyploidy were normal. These studies show that activation of ERK1/ERK2 mitogen-activated protein kinase pathway plays a critical role in PPF. The elucidation of the signal transduction pathway on megakaryocyte development and PPF is of crucial importance for understanding this unique biological process.
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PMID:Fibronectin- and protein kinase C-mediated activation of ERK/MAPK are essential for proplateletlike formation. 1198 11

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is critical for promoting the long-term survival of lung- or airway-based eosinophils. Previously, we have shown that fibronectin and tumor necrosis factor alpha induced autocrine production of GM-CSF that markedly enhanced eosinophil survival. Cytokine release was preceded by and dependent on messenger RNA (mRNA) stabilization. Here, we show that mitogen-activated protein kinase (MAPK) activation is responsible for GM-CSF mRNA stabilization in peripheral blood eosinophils (pbeos). Activation of extracellular signal-regulated kinase (ERK) but not p38 correlated with GM-CSF mRNA stability. Although ERK inhibition completely prevented GM-CSF mRNA stabilization, p38 inhibition had a partial effect. To establish which MAPK was crucial, we transduced pbeos with dominant-active TatMEK1(E) or TatMKK3b(E) proteins that selectively phosphorylate ERK or p38, respectively. These studies showed that ERK but not p38 was sufficient for GM-CSF mRNA stabilization. These data are in contradistinction to the c-Jun NH(2)-terminal kinase-mediated regulation of interleukin 2 and 3 mRNAs and suggest unique regulatory features for GM-CSF mRNA in eosinophils.
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PMID:Extracellular signal-regulated kinase mediates granulocyte-macrophage colony-stimulating factor messenger RNA stabilization in tumor necrosis factor-alpha plus fibronectin-activated peripheral blood eosinophils. 1201 Aug 6

Lysophosphatidic acid (LPA) is a bioactive lipid mediator and important component of serum. Studies over the past several years which have documented diverse effects of LPA on multiple types of airway cells and which suggest possible involvement of LPA in lung disease are reviewed here. LPA enhances contractility of airway smooth muscle. It also stimulates proliferation of cultured airway smooth muscle cells and exhibits a striking synergism with epidermal growth factor (EGF) for stimulating mitogenesis. Recent studies of the molecular components and signaling pathways mediating synergism are described, including LPA-induced upregulation of EGF receptors and activation of multiple transcription factors by both LPA and EGF. A model for the effects of LPA and EGF on mitogenesis that includes EGF receptor upregulation and synergism between Ras and Rho for activation of the transcription factor AP-1 is presented. LPA stimulates fibronectin secretion and filopodia extension in airway epithelial cells as well as proliferation and collagen gel contraction by lung fibroblasts. A hypothesis for LPA involvement in the airway repair and remodeling, which contribute to the pathology of asthma and other airway diseases, is presented, and future directions for research into the roles of LPA in airway function and disease are suggested.
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PMID:Lysophosphatidic acid in airway function and disease. 1206 34

To elucidate the underlying mechanisms in oxidative stress-related airway remodeling observed in chronic inflammatory pulmonary diseases such as asthma, we studied the effects of a thiol antioxidant, N-acetylcysteine (NAC), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG-1478, and tyrphostin-1 as a negative control for AG-1478 on an aldehydic product of lipid peroxidation 4-hydroxy-2-nonenal (HNE)-induced secretion of fibronectin by IMR-90 human lung fibroblasts. We also studied signal transduction pathways involved in the secretion of fibronectin evident after exposure of IMR-90 cells to HNE. Twenty-five-micromole HNE treatments of IMR-90 cells activated extracellular signal-regulated kinase p44/42 (Erk1/2) with little activation of p38 mitogen-activated protein kinase (p38MAPK) and no activation of c-Jun NH(2)-terminal kinase. HNE-induced secretion of fibronectin was inhibited by U-0126, an inhibitor of the Erk1/2 pathway, while no significant inhibition by SB-203580, an inhibitor of p38MAPK pathway, was observed. NAC and AG-1478, but not tyrphostin-1, inhibited HNE-induced fibronectin secretion accompanied by a pallarel inhibition of Erk1/2 activation. These data suggest that pulmonary oxidative stress-related lipid peroxidation may play an important role in developing airway remodeling through activating lung fibroblasts to further produce extracellular matrices, such as fibronectin, partly via activation of an EGFR-linked Erk1/2 signal transduction pathway, and that the antioxidant NAC and the EGFR tyrosine kinase inhibitor AG-1478 can be potentially useful in pulmonary diseases involving airway remodeling.
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PMID:4-Hydroxy-2-nonenal enhances fibronectin production by IMR-90 human lung fibroblasts partly via activation of epidermal growth factor receptor-linked extracellular signal-regulated kinase p44/42 pathway. 1246 Jul 40

Fibronectin with IIICS region is present in rheumatoid synovium, and fibronectin fragments are increased in rheumatoid joints. We investigated the ability of COOH-terminal heparin-binding fibronectin fragment (COOH-HBFN-f) containing IIICS to induce matrix metalloproteinase (MMP) production and the role of mitogen-activated protein kinase (MAPK) pathway and CS-1 sequence that can bind alpha4beta1 integrin in MMP induction by COOH-HBFN-f in rheumatoid synovial fibroblasts (RSF). When RSF in monolayer culture were incubated with COOH-HBFN-f, COOH-HBFN-f stimulated the production of MMP-1, MMP-3, and MMP-13 by RSF in association with activation of extracellular signal-regulated kinase, p38 MAPK, and c-Jun NH(2)-terminal kinase. Immunoprecipitation of cell lysates demonstrated the presence of alpha4 integrin in cultured RSF. Similar to COOH-HBFN-f, treatment with CS-1 synthetic peptide derived from IIICS resulted in increased MMP production and activation of the kinases, although the MMP levels were low. Preincubation of RSF with anti-alpha4 integrin antibody resulted in partial suppression of the COOH-HBFN-f-stimulated MMP production. Inhibition studies using protein kinase inhibitors (PD98059 and SB203580) showed that those MAPK pathways contributed to MMP up-regulation by COOH-HBFN-f and CS-1. Thus, the present results have clearly shown that COOH-HBFN-f and CS-1 stimulate MMP production in association with activation of MAPK pathways in RSF. Integrin alpha4beta1 may be partially involved in the MMP induction by COOH-HBFN-f.
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PMID:Matrix metalloproteinase production by COOH-terminal heparin-binding fibronectin fragment in rheumatoid synovial cells. 1259 31

Primary normal human oral keratinocytes (NHOKs) terminally differentiate in serial subculture. To investigate whether this subculture-induced differentiation of NHOKs affects integrin expression and cell-matrix interaction, we studied the expression levels of integrin subunits and cellular response to the extracellular matrix (ECM) proteins in NHOKs at different population doublings. The phosphorylation statuses of focal adhesion kinase (FAK), extracellular signal regulated kinase (ERK), p38, and c-Jun amino-terminal kinase (JNK) were also determined in NHOK cells cultured on ECM proteins, to evaluate the functions of integrins with respect to cellular responses to ECM proteins. The expression levels of alpha3 and beta1 integrin subunits progressively decreased in NHOKs undergoing terminal differentiation. The ability of NHOKs to spread upon laminin and type I collagen significantly decreased in terminally differentiated oral keratinocytes. Keratinocyte migration was significantly increased on type I collagen for terminally differentiated NHOKs. Similar results were seen following preincubation of rapidly proliferating NHOKs with function-blocking antibodies to alpha3 or beta1 integrin subunit. In contrast, fibronectin had no effect on cellular responses in NHOKs, which were almost negligible in the expression levels of alpha5 integrin subunits. The extent of FAK phosphorylation in terminally differentiated NHOKs was notably lower than that of rapidly proliferating cells, but was enhanced in terminally differentiated cells that were cultured on type I collagen. Our results indicate that decreased expression of alpha3 and beta1 integrin subunits is responsible for differentiation-associated changes in cells behavior in terminally differentiated oral keratinocytes. Our data also show that the abrogation of the alpha5beta1 integrin function caused by omitting alpha5 subunit is linked to the loss of a cell-fibronectin interaction in human oral keratinocytes.
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PMID:Decreased expression of alpha3 and beta1 integrin subunits is responsible for differentiation-associated changes in cells behavior in terminally differentiated human oral keratinocytes. 1269 87

Tissue transglutaminase (tTG) serves as a potent and ubiquitous integrin-associated adhesion co-receptor for fibronectin on the cell surface and affects several key integrin functions. Here we report that in fibroblasts, activated H-Ras and Raf-1 oncogenes decrease biosynthesis, association with beta1 integrins, and surface expression of tTG because of down-regulation of tTG mRNA. In turn, the reduction of surface tTG inhibits adhesion of H-Ras- and Raf-1-transformed cells on fibronectin and, in particular, on its tTG-binding fragment I(6)II(1,2)I(7-9), which does not interact directly with integrins. Analysis of Ras/Raf downstream signaling with specific pharmacological inhibitors reveals that the decrease in tTG expression is mediated by the p38 MAPK, c-Jun NH2-terminal kinase, and phosphatidylinositol 3-kinase pathways. In contrast, increased activation of the ERK pathway by constitutively active MEK1 stimulates tTG mRNA expression, biosynthesis, and surface expression of tTG, whereas MEK inhibitors or dominant negative MEK1 exert an opposite effect. This modulation of surface tTG by ERK signaling alters adhesion of cells on fibronectin and its fragment that binds tTG. Furthermore, transient stimulation of ERK signaling in untransformed fibroblasts by adhesion on fibronectin or growth factors elevates tTG biosynthesis, increases complex formation with beta1 integrins, and raises surface expression of tTG. Finally, ERK activation is required for growth factor-induced redistribution of tTG on the surface of adherent fibroblasts and co-clustering of beta1 integrins and tTG at cell-matrix adhesion contacts. Together, our data indicate that down-regulation of surface tTG by Ras and Raf oncogenes contributes to adhesive deficiency of transformed fibroblasts, whereas stimulation of biosynthesis and surface expression of tTG by the MEK1/ERK module promotes and sustains cell-matrix adhesion of untransformed cells. Contrasting effects of Ras/Raf oncogenes and their immediate downstream signaling module, MEK1/ERK, on tTG expression are consistent with adhesive function of surface tTG.
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PMID:Opposing roles of Ras/Raf oncogenes and the MEK1/ERK signaling module in regulation of expression and adhesive function of surface transglutaminase. 1283 99

TGF-beta (transforming growth factor-beta) is implicated in the pathogenesis of diabetic nephropathy. We previously demonstrated that up-regulation of type II TGF-beta receptor (TbetaRII) induced by high glucose might contribute to distal tubular hypertrophy [Yang, Guh, Yang, Lai, Tsai, Hung, Chang and Chuang (1998) J. Am. Soc. Nephrol. 9, 182-193]. We have elucidated the mechanism by using cultured Madin-Darby canine kidney cells. Enhancer assay and electrophoretic-mobility-shift assay were used to estimate the involvement of transcription factors. Western blotting and an in vitro kinase assay were used to evaluate the level and activity of protein kinase. We showed that glucose (100-900 mg/dl) induced an increase in mRNA level and promoter activity of TbetaRII (note: 'mg/dl' are the units commonly used in diabetes studies). The promoter region -209 to -177 appeared to contribute to positive transactivation of TbetaRII promoter by comparing five TbetaRII-promoter-CAT (chloramphenicol acetyl-transferase) plasmids. Moreover, the transcription factor AP-1 (activator protein 1) was significantly activated and specifically binds to TbetaRII promoter (-209 to -177). More importantly, we found that atypical PKC iota might be pivotal for high glucose-induced increase in both AP-1 binding and TbetaRII promoter activity. First, high glucose induced cytosolic translocation, activation and autophosphorylation of PKC iota. Secondly, antisense PKC iota expression plasmids attenuated high-glucose-induced increase in AP-1 binding and TbetaRII promoter activity; moreover, sense PKC iota expression plasmids enhanced these instead. Finally, we showed that antisense PKC iota expression plasmids might partly attenuate a high-glucose/TGF-beta1-induced increase in fibronectin. We conclude that PKC iota might mediate high-glucose-induced increase in TbetaRII promoter activity. In addition, antisense PKC iota expression plasmid effectively suppressed up-regulation of TbetaRII and fibronectin in hyperglycaemic distal-tubule cells.
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PMID:Regulation of type II transforming-growth-factor-beta receptors by protein kinase C iota. 1284 49

Overexpression of the integrin-linked kinase (ILK) was shown to increase c-Jun-dependent transcription. We now show that this effect of ILK involves the c-Jun transcriptional coactivator, nascent polypeptide-associated complex and coactivator alpha (alpha-NAC). ILK phosphorylated alpha-NAC on residue Ser-43 upon adhesion of cells to fibronectin. Co-expression of constitutively active ILK with alpha-NAC led to the nuclear accumulation of the coactivator. Conversely, alpha-NAC remained in the cytoplasm of cells transfected with a dominant-negative ILK mutant, and a mutated alpha-NAC at phosphoacceptor position Ser-43 (S43A) also localized outside of the nucleus. The S43A alpha-NAC mutant could not potentiate the effect of ILK on c-Jun-dependent transcription. We conclude that ILK-dependent phosphorylation of alpha-NAC induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-NAC by ILK is required for the potentiation of c-Jun-mediated responses by the kinase. The results represent one of the rare examples of a transcriptional coactivator shuttling between the cytosol and the nucleus.
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PMID:Integrin-linked kinase regulates the nuclear entry of the c-Jun coactivator alpha-NAC and its coactivation potency. 1529 25

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