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)

Hyperlipidemia is a recognized risk factor for atherosclerotic vascular disease. The underlying mechanisms that link lipoproteins and vascular disease are undefined. Connective tissue growth factor (CTGF) is emerging as a key determinant of progressive fibrotic diseases, and its expression is upregulated by diabetes. To define the mechanisms through which low-density lipoproteins (LDL) promote vascular injury, we evaluated whether LDL can modulate the expression of CTGF and collagen IV in human aortic endothelial cells (HAECs). Treatment of HAECs with LDL (50 microg/ml) for 24 h produced a significant increase in the mRNA and the protein levels of CTGF and collagen IV compared with unstimulated controls. To explore the mechanisms by which LDL regulates CTGF and collagen IV expression in HAECs, we determined first if CTGF and collagen IV are downstream targets for regulation by transforming growth factor-beta (TGF-beta). The results demonstrated that TGF-beta produced a concentration-dependent increase in the protein levels of CTGF. To assess whether the induction of CTGF in response to LDL is mediated via autocrine activation of TGF-beta, HAECs were treated with LDL for 24 h in the presence and absence of anti-TGF-beta neutralizing antibodies (anti-TGF-beta NA). The results demonstrated that the increase in CTGF induced by LDL was significantly inhibited by the anti-TGF-beta NA. To investigate the upstream mediators of TGF-beta on activity of CTGF in response to LDL, HAECs were treated with LDL for 24 h in the presence and absence of cell-permeable MAPK inhibitors. Inhibition of p38(mapk) activities did not affect LDL-induced TGF-beta1, CTGF, and collagen IV expression. On the other hand, SP-600125, a specific inhibitor of c-Jun NH(2)-terminal kinase, suppressed LDL-induced TGF-beta, CTGF, and collagen IV expression, and PD-98059, a selective inhibitor of p44/42(mapk), suppressed LDL-induced TGF-beta and CTGF expression. These findings are the first to implicate the MAPK pathway and TGF-beta as key players in LDL signaling, leading to CTGF and collagen IV expression in HAECs. The data also point to a potential mechanistic pathway through which lipoproteins may promote vascular injury.
 ...
PMID:Mechanisms of low-density lipoprotein-induced expression of connective tissue growth factor in human aortic endothelial cells. 1627 94

Epidermal growth factor (EGF) is a survival signal for transforming growth factor-beta (TGF-beta)-induced apoptosis in hepatocytes, phosphatidylinositol 3-kinase (PI 3-K) being involved in this effect. Here, we analyze the possible cross talks between EGF and TGF-beta signals to understand how EGF impairs the early pro-apoptotic events induced by TGF-beta. Data have indicated that neither SMAD nor c-Jun NH2 Terminal Kinase (JNK) activations are altered by EGF, which clearly interferes with events directly related to the radical oxygen species (ROS) production, impairing oxidative stress, p38 MAP kinase activation, and cell death. Activation of a NADPH-oxidase-like system, which is responsible for the early ROS production by TGF-beta, is completely inhibited by EGF, through a PI 3-K-dependent mechanism. Activity of RAC1 increases by TGF-beta, but also by EGF, and both act synergistically to get maximum effects. Fetal rat hepatocytes express nox4, in addition to nox1 and nox2, and TGF-beta clearly upregulates nox4. EGF blocks up-regulation of nox4 by TGF-beta. Interestingly, in the presence of PI 3-K inhibitors, EGF is not able to counteract the nox4 upregulation by TGF-beta. Taking together these results indicate that impairment of TGF-beta-induced NADPH oxidase activation by EGF is a RAC1-independent process and correlates with an inhibition of the mechanisms that address the increase of nox4 mRNA levels by TGF-beta.
 ...
PMID:EGF blocks NADPH oxidase activation by TGF-beta in fetal rat hepatocytes, impairing oxidative stress, and cell death. 1633 83

Because increased transforming growth factor-beta (TGFbeta) production by tumor cells contributes to cancer progression through paracrine mechanisms, identification of critical points that can be targeted to block TGFbeta production is important. Previous studies have identified the precise signaling components and promoter elements required for TGFbeta induction of TGFbeta1 expression in epithelial cells (Yue, J., and Mulder, K. M. (2000) J. Biol. Chem. 275, 30765-30773). To determine how regulation of TGFbeta3 expression differs from that of TGFbeta1, we identified the precise signaling pathways and transcription factor-binding sites that are required for TGFbeta3 gene expression. By using mutational analysis in electrophoresis mobility shift assays (EMSAs), we demonstrated that the c-AMP-responsive element (CRE) site in the TGFbeta3 promoter was required for TGFbeta-inducible TGFbeta3 expression. Electrophoresis mobility supershift assays indicated that CRE-binding protein 1 (CREB1) and Smad3 were the major components present in this TGFbeta-inducible complex. Furthermore, by using chromatin immunoprecipitation assays, we demonstrated that CREB-1, ATF-2, and c-Jun bound constitutively at the TGFbeta3 promoter (-100 to +1), whereas Smad3 bound at this site only after TGFbeta stimulation. In addition, inhibition of JNK and p38 suppressed TGFbeta induction of TGFbeta3 transactivation, whereas inhibition of ERK and protein kinase A had no effect. Small interfering RNA-CREB1 and small interfering RNA-Smad3 significantly inhibited TGFbeta stimulation of TGFbeta3 promoter reporter activity and TGFbeta3 production. Our results indicate that TGFbeta activation of the TGFbeta3 promoter CRE site, which leads to TGFbeta3 production, is required for TGFbetaRII, JNK, p38, and Smad3 but was independent of protein kinase A, ERK, and Smad4.
 ...
PMID:Requirement of Smad3 and CREB-1 in mediating transforming growth factor-beta (TGF beta) induction of TGF beta 3 secretion. 1689 11

Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Cytokines such as transforming growth factor-beta (TGF-beta) play a fundamental role in the development of tissue fibrosis by stimulating matrix deposition and other profibrotic responses, but less is known about pathways that might inhibit fibrosis. Increased cAMP formation inhibits myofibroblast differentiation and collagen production by cardiac fibroblasts, but the mechanism of this inhibition is not known. We sought to characterize the signaling pathways by which cAMP-elevating agents alter collagen expression and myofibroblast differentiation. Treatment with 10 microM forskolin or isoproterenol increased cAMP production and cAMP response element binding protein (CREB) phosphorylation in cardiac fibroblasts and inhibited serum- or TGF-beta-stimulated collagen synthesis by 37% or more. These same cAMP-elevating agents blunted TGF-beta-stimulated expression of collagen I, collagen III, and alpha-smooth muscle actin. Forskolin or isoproterenol treatment blocked the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) induced by TGF-beta despite the fact that these cAMP-elevating agents stimulated ERK1/2 activation on their own. cAMP-elevating agents also attenuated the activation of c-Jun NH(2)-terminal kinase and reduced binding of the transcriptional coactivator CREB-binding protein 1 to transcriptional complexes containing Smad2, Smad3, and Smad4. Pharmacological inhibition of ERK completely blocked TGF-beta-stimulated collagen gene expression, but expression of an active mutant of MEK was additive with TGF-beta treatment. Thus, cAMP-elevating agents inhibit the profibrotic effects of TGF-beta in cardiac fibroblasts largely through inhibiting ERK1/2 phosphorylation but also by reducing Smad-mediated recruitment of transcriptional coactivators.
 ...
PMID:cAMP inhibits transforming growth factor-beta-stimulated collagen synthesis via inhibition of extracellular signal-regulated kinase 1/2 and Smad signaling in cardiac fibroblasts. 1695 41

c-Jun NH(2)-terminal kinase (JNK), a member of the MAPK family of protein kinases, is a stress-response kinase that is activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through nonreceptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We recently demonstrated that the activation of JNK by this condition is initiated by ROI generated by mitochondrial electron transport and involves sequential activation of the proline-rich kinase 2 and the small GTP-binding factors Rac-1 and Cdc42. Here we present evidence that protein kinase C (PKC) and transforming growth factor-beta-activated kinase-1 (TAK-1) are also components of this pathway. Inhibition of PKC with the broad-range inhibitor calphostin C, the PKC-alpha/beta-selective inhibitor Go9367, or adenovirus-expressing dominant-negative PKC-alpha blocked the phosphorylation of proline-rich kinase 2 and JNK. Reoxygenation activated the mitogen-activated protein kinase kinase kinase, TAK-1, and promoted the formation of a complex containing Rac-1, TAK-1, and JNK but not apoptosis-stimulating kinase-1 or p21-activated kinase-1, which was detected within the first 10 min of reoxygenation. These results identify two new components, PKC and TAK-1, that have not been previously described in this signaling pathway.
 ...
PMID:PKC-alpha and TAK-1 are intermediates in the activation of c-Jun NH2-terminal kinase by hypoxia-reoxygenation. 1720 6

Cancer cells often gain advantage by reducing the tumor-suppressive activity of transforming growth factor-beta (TGF-beta) together with stimulation of its oncogenic activity as in Ras-transformed cells; however, molecular mechanisms remain largely unknown. TGF-beta activates both its type I receptor (TbetaRI) and c-Jun NH2-terminal kinase (JNK), which phosphorylate Smad2 and Smad3 at the COOH-terminal (pSmad2/3C) and linker regions (pSmad2/3L). Here, we report that Ras transformation suppresses TbetaRI-mediated pSmad3C signaling, which involves growth inhibition by down-regulating c-Myc. Instead, hyperactive Ras constitutively stimulates JNK-mediated pSmad2/3L signaling, which fosters tumor invasion by up-regulating plasminogen activator inhibitor-1 and matrix metalloproteinase-1 (MMP-1), MMP-2, and MMP-9. Conversely, selective blockade of linker phosphorylation by a mutant Smad3 lacking JNK-dependent phosphorylation sites results in preserved tumor-suppressive function via pSmad3C in Ras-transformed cells while eliminating pSmad2/3L-mediated invasive capacity. Thus, specific inhibition of the JNK/pSmad2/3L pathway should suppress cancer progression by shifting Smad-dependent signaling from oncogenesis to tumor suppression.
 ...
PMID:Reversible Smad-dependent signaling between tumor suppression and oncogenesis. 1754 85

Many of the signaling responses induced by transforming growth factor-beta (TGF-beta) are mediated by Smad proteins, but there is evidence that it can also signal independently of Smads. Here, we provide evidence that multiple signal pathways induced by TGF-beta1-including Src family tyrosine kinases (SFKs), generation of reactive oxygen species (ROS), de novo protein synthesis and E-cadherin-dependent cell-cell interactions-transactivate the epidermal growth factor receptor (EGFR), which in turn regulates expression of c-Fos and c-Jun. Immunoprecipitation and immunofluorescence staining showed that EGFR was phosphorylated on tyrosine in response to TGF-beta1. EGFR transactivation required the activation of SFKs and the production of ROS via NADPH oxidase, but was not dependent on metalloproteases or the release of EGF-like ligands. In addition, the production of ROS was dependent on signaling by specific SFKs as well as de novo protein synthesis. Stable transfection of E-cadherin into MDA-MB-231 cells as well as E-cadherin-blocking assays revealed that E-cadherin-mediated cell-cell interactions were also essential for EGFR transactivation. Finally, EGFR transactivation was involved in the expression of c-Fos and c-Jun via the extracellular signal-regulated kinase signaling cascade. Taken together our data suggest that ligand release-independent transactivation of EGFR may diversify early TGF-beta signaling and represent a novel pathway leading to TGF-beta-mediated gene expression.
 ...
PMID:Ligand release-independent transactivation of epidermal growth factor receptor by transforming growth factor-beta involves multiple signaling pathways. 1763 50

Although tumor necrosis factor (TNF) induces apoptosis and cell death in many tumor cells, some cancer cells are still resistant to the TNF-induced death signal. In this report, we showed that Smad7, an inhibitory Smad of transforming growth factor-beta (TGF-beta) signaling, can overcome the TNF resistance in human breast and gastric cancer cells. Overexpression of Smad7 induces the degradation of poly(ADP-ribose) polymerase and the activation of caspase cascade. Although c-Jun NH2-terminal kinase (JNK) signaling is involved in TNF-induced cell death, the expression of Smad7 does not synergize the activation of JNK. However, the activation of nuclear factor-kappaB (NF-kappaB), the cell survival factor, is markedly decreased in Smad7-stable cells. Furthermore, the expression of antiapoptotic target genes of NF-kappaB is significantly reduced in accordance with the level of Smad7. In addition, Smad7 mediates the inhibitory activity of TGF-beta on TNF-induced NF-kappaB activation and the synergistic activity of TGF-beta on TNF-induced apoptosis. These findings suggest that Smad7 sensitizes the tumor cells to TNF-induced apoptosis through the inhibition of expression of antiapoptotic NF-kappaB target genes.
 ...
PMID:Smad7 sensitizes tumor necrosis factor induced apoptosis through the inhibition of antiapoptotic gene expression by suppressing activation of the nuclear factor-kappaB pathway. 1790 69

Platelets induce osteoclastogenesis in total bone marrow cultures where hematopoietic cells can interact with stromal cells. Whether or not activated platelets directly act on hematopoietic cells to promote their differentiation into osteoclasts remains unknown. Here we report that platelet releasates (PRS) increase osteoclastogenesis in stroma-depleted, macrophage colony-stimulating factor (M-CSF)-dependent bone marrow cells when cultured in the presence of receptor activator of NF-kappaB ligand (RANKL). The increased number of tartrate-resistant acid phosphatase-positive multinucleated cells (MNC) was paralleled by an enhanced transcription of osteoclast specific genes. Osteoclastogenesis was observed with hematopoietic cells previously depleted of B-cells or T-cells. Immunoprecipitation of transforming growth factor-beta (TGF-beta) decreased the osteoclastogenic capacity of the PRS. PRS enhanced phosphorylation of Smad-2, a downstream signaling mediator of TGF-beta. PRS increased phosphorylation of p38 and c-Jun NH(2)-terminal kinase (JNK), whereas only blocking of p38 but not JNK signaling suppressed osteoclastogenesis. These results suggest that activated platelets can enhance osteoclastogenesis by providing a source of TGF-beta and by activating osteoclastogenic signaling pathways.
 ...
PMID:Activated platelets positively regulate RANKL-mediated osteoclast differentiation. 1795 25

Glial cell line-derived neurotrophic factor (GDNF), a distant member of the transforming growth factor-beta superfamily, was originally purified and cloned as a potent survival factor for midbrain dopaminergic neurons. Some studies have characterized the transcriptional regulation of the GDNF gene, but its regulatory mechanisms have yet to be well defined, especially under pathophysiological conditions. In this study, we used a pharmacological approach to study the expression of the rat GDNF gene induced by lipopolysaccharide (LPS) in primary cultures of glial cells. MG132, a blocker of nuclear factor kappaB (NF-kappaB) activation, did not apparently affect LPS-induced GDNF gene expression, whereas it attenuated the up-regulation of iNOS genes via Toll-like receptor (TLR) 4. In primary glial cultures, LPS increased the phosphorylation levels of c-Jun amino-terminal kinase 1 (JNK1) and p38 mitogen-activated protein kinase (MAPK); in primary microglial cultures, it enhanced phosphorylation of extracellular signal-regulated kinase (Erk). Of the several MAP kinase inhibitors tested, a JNK-specific inhibitor blocked LPS-induced GDNF transcription in primary cultures of microglia, but not of astrocytes. These results suggest that LPS up-regulates GDNF transcription through an NF-kappaB independent pathway, and that JNK is responsible for LPS-stimulated GDNF transcription in primary cultures of microglia.
 ...
PMID:NF-kappaB independent signaling pathway is responsible for LPS-induced GDNF gene expression in primary rat glial cultures. 1816 17


<< Previous 1 2 3 4 5 Next >>