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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extensive studies have demonstrated that transforming growth factor-beta (TGF-beta) plays an important role in the progression of renal diseases. TGF-beta exerts its biological functions mainly through its downstream signalling molecules, Smad2 and Smad3. It is now clear that Smad3 is critical for TGF-beta's pro-fibrotic effect, whereas the functions of Smad2 in fibrosis in response to TGF-beta still need to be determined. Our recent studies have demonstrated that Smad signalling is also a critical pathway for renal fibrosis induced by other pro-fibrotic factors, such as angiotensin II and advanced glycation end products (AGE). These pro-fibrotic factors can activate Smads directly and independently of TGF-beta. They can also cause renal fibrosis via the ERK/p38 MAP kinase-Smad signalling cross-talk pathway. In contrast, blockade of Smad2/3 activation by overexpression of an inhibitory Smad7 prevents collagen matrix production induced by TGF-beta, angiotensin II, high glucose and AGE and attenuates renal fibrosis in various animal models including rat obstructive kidney, remnant kidney and diabetic kidney diseases. Results from these studies indicate that Smad signalling is a key and final common pathway of renal fibrosis. In addition, TGF-beta has anti-inflammatory and immune-regulatory properties. Our most recent studies demonstrated that TGF-beta transgenic mice are protected against renal inflammation in mouse obstructive and diabetic models. Upregulation of renal Smad7, thereby blocking NF.kappaB activation via induction of IkappaBalpha, is a central mechanism by which TGF-beta inhibits renal inflammation. In conclusion, TGF-beta signals through Smad2/3 to mediate renal fibrosis, whereas induction of Smad7 inhibits renal fibrosis and inflammation. Thus, targeting Smad signalling by overexpression of Smad7 may have great therapeutic potential for kidney diseases.
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PMID:Transforming growth factor-beta and Smad signalling in kidney diseases. 1570 82

Activin has previously been shown to act as a nerve cell survival factor and to have neurotrophic effects on neurons. However, the role of activin in regulating neurotransmitter expression in the central nervous system and the exact mechanisms involved in this process are poorly understood. In the present study, we report that activin A and basic fibroblast growth factor (bFGF) synergistically increased the protein level of tyrosine hydroxylase (TH), and also greatly increased the TH mRNA level, in both mouse E14 striatal primary cell cultures and the hippocampal neuronal cell line HT22. Activin A and bFGF cooperatively stimulated nuclear translocation of Smad3 and specifically activated ERK1/2, but not p38 or JNK. Interestingly, a specific inhibitor for MEK, U0126, efficiently blocked the induction of TH promoter activity by activin A and bFGF, indicating that activin A collaborated with bFGF signaling to induce the TH gene through selective activation of ERK-type MAP kinase in mouse striatal and HT22 cells. These data suggest that activin A may act in concert with bFGF for the development of TH-positive neurons.
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PMID:Synergistic activity of activin A and basic fibroblast growth factor on tyrosine hydroxylase expression through Smad3 and ERK1/ERK2 MAPK signaling pathways. 1574 8

Smad3 is phosphorylated by ERK MAP kinase upon EGF treatment. We have mapped the ERK phosphorylation sites to Ser 207, Ser 203, and Thr 178 in Smad3. We show that, upon EGF treatment, Smad3 is rapidly phosphorylated in these sites, peaking at approximately 15-30 min and that MEK1 inhibitors PD98059 and U0216 inhibit Smad3 phosphorylation induced by EGF. Ser 207 is the best ERK site in Smad3. Its phosphorylation shows the highest EGF induction in Smad3. It is also a very sensitive site to EGF treatment, significantly responding to low concentrations of EGF. These three sites are also phosphorylated by recombinant ERK2 in vitro. We have compared the kinetic parameters of Smad3 with those of ELK1 and MBP for ERK2. We further show that mutation of the ERK phosphorylation sites increases the ability of Smad3 to stimulate a Smad target gene, suggesting that ERK phosphorylation inhibits Smad3 activity.
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PMID:Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3. 1615 66

Pancreatic stellate cells (PSCs) are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting ECMs such as collagen and fibronectin. IL-1beta has been assumed to participate in pancreatic fibrosis by activating PSCs. Activated PSCs secrete various cytokines that regulate PSC function. In this study, we have examined IL-1beta secretion from culture-activated PSCs as well as its regulatory mechanism. RT-PCR and ELISA have demonstrated that PSCs express IL-1beta mRNA and secrete IL-1beta peptide. Inhibition of TGF-beta(1) activity secreted from PSCs by TGF-beta(1)-neutralizing antibody attenuated IL-1beta secretion from PSCs. Exogenous TGF-beta(1) increased IL-1beta expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative (dn)Smad2/3 expression reduced both basal and TGF-beta(1)-stimulated IL-1beta expression and secretion by PSCs. Coexpression of Smad3 with dnSmad2/3 restored IL-1beta expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. In contrast, coexpression of Smad2 with dnSmad2/3 did not alter them. Furthermore, inhibition of IL-1beta activity secreted from PSCs by IL-1beta-neutralizing antibody attenuated TGF-beta(1) secretion from PSCs. Exogenous IL-1beta enhanced TGF-beta(1) expression and secretion by PSCs. IL-1beta activated ERK, and PD-98059, a MEK1 inhibitor, blocked IL-1beta enhancement of TGF-beta(1) expression and secretion by PSCs. We propose that an autocrine loop exists between TGF-beta(1) and IL-1beta in activated PSCs through Smad3- and ERK-dependent pathways.
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PMID:Autocrine loop between TGF-beta1 and IL-1beta through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells. 1637 39

This study examined the effect of wild-type Smad3 gene on the osteoblastic differentiation of rat bone marrow-derived mesenchymal stem cells in vitro. Bone marrow-derived mesenchymal stem cells (MSCs) were stably transfected with the complexes of pcDNA3. 0-Myc-Smad3 or pcDNA3. 0-Myc-Smad3deltaC and Lipofectamine reagent. Immunofluorescence staining was performed to evaluate the c-Myc signal in MSCs. The cell proliferation was detected by MTT method. To clarify the osteoblastic characteristics in stably transfected MSCs, alkaline phosphatase (ALP) mRNA and core binding factor alpha1 (Cbfa1) mRNA were investigated by RT-PCR, and ALP activity and mineralization were examined by p-nitrophenolphosphate method and alizarin red staining respectively. PD98059, a specific inhibitor of the ERK signaling pathway, was used to determine the role of ERK in Smad3-MSCs osteoblastic differentiation. c-Myc signal was detected in Smad3-MSCs and Smad3 deltaC-MSCs. The proliferation of Smad3-MSCs was slower than that of Smad3deltaC-MSCs or V-MSCs. The relative levels of ALP mRNA and Cbfal mRNA in Smad3-MSCs, as well as ALP activity and mineralization, were markedly higher than those in Smad3deltaC-MSCs or V-MSCs. Although ALP activity and mineralization were slightly lower in Smad3-MSCs treated with PD98059 than in those without PD98059 treatment, no significant difference was found between them (P > 0.05). It is concluded that the wild-type Smad3 gene, which is a crucial component promoting bone formation, can inhibit the proliferation of MSCs and enhance the osteoblastic differentiation of uncommitted MSCs and the maturation of committed MSCs independent of the ERK signaling pathway.
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PMID:Wild-type Smad3 gene enhances the osteoblastic differentiation of rat bone marrow-derived mesenchymal stem cells in vitro. 1669 23

We have shown that Smad3, an intracellular signal transducer for transforming growth factor-beta1 (TGF-beta1), is required to elicit the full histological manifestations of obliterative airway disease in a tracheal transplant model. This suggests that chronic allograft rejection results in TGF-beta1-induced Smad3 activation that leads to airway obliteration through fibroproliferation and increased matrix deposition. In other systems, these latter events are causally related to the transdifferentiation of fibroblasts into myofibroblasts, but their role in obliterative bronchiolitis (OB) after lung transplantation is unknown. We confirmed the presence of myofibroblasts inside affected airways associated with experimental OB using immunohistochemistry. Studying airway fibroblasts in vitro, we observed increased myofibroblast transdifferentiation in response to TGF-beta1, evidenced by increased alpha-smooth muscle actin mRNA and protein expression. In Smad3-null fibroblasts, TGF-beta1 induction of myofibroblast transdifferentiation was greatly diminished but not abolished, suggesting the presence of Smad3-independent pathways. Further studies revealed that small molecule inhibitors of p38 (SB203580) and MEK/ERK (U1026) further reduced the remaining effect of TGF-beta1 in Smad3-deficient fibroblasts. Together, these studies suggest that in chronic allograft rejection, TGF-beta1 stimulates myofibroblast transdifferentiation through Smad3-dependent and -independent signals, contributing to the excessive matrix deposition that characterizes obliterative bronchiolitis.
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PMID:Myofibroblast transdifferentiation in obliterative bronchiolitis: tgf-beta signaling through smad3-dependent and -independent pathways. 1679 22

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.
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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.
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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

In cancer, Transforming Growth Factor beta (TGFbeta) increases proliferation and promotes invasion via selective loss of signalling pathways. Oesophageal adenocarcinoma arises from Barrett's oesophagus, progresses rapidly and is usually fatal. The contribution of perturbed TGFbeta signalling in the promotion of metastasis in this disease has not been elucidated. We therefore investigated the role of TGFbeta in Barrett's associated oesophageal adenocarcinoma using a panel of cell lines (OE33, TE7, SEG, BIC, FLO). 4/5 adenocarcinoma cell lines failed to cell cycle arrest, down-regulate c-Myc or induce p21 in response to TGFbeta, and modulation of a Smad3/4 specific promoter was inhibited. These hyperproliferative adenocarcinoma cell lines displayed a TGFbeta induced increase in the expression of the extracellular matrix degrading proteinases, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1), which correlated with an invasive cell phenotype as measured by in vitro migration, invasion and cell scattering assays. Inhibiting ERK and JNK pathways significantly reduced PAI and uPA induction and inhibited the invasive cell phenotype. These results suggest that TGFbeta Smad-dependent signalling is perturbed in Barrett's carcinogenesis, resulting in failure of growth-arrest. However, TGFbeta can promote PAI and uPA expression and invasion through MAPK pathways. These data would support a dual role for TGFbeta in oesophageal adenocarcinoma.
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PMID:Selective loss of TGFbeta Smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines. 1726 80

In addition to classic Smad signaling pathways, the pleiotropic immunoregulatory cytokine TGF-beta1 can activate MAP kinases, but a role for TGF-beta1-MAP kinase pathways in T cells has not been defined heretofore. We have shown previously that TGF-beta1 inhibits Th1 development by inhibiting IFN-gamma's induction of T-bet and other Th1 differentiation genes, and that TGF-beta1 inhibits receptor-proximal IFN-gamma-Jak-Stat signaling responses. We now show that these effects of TGF-beta1 are independent of the canonical TGF-beta1 signaling module Smad3, but involve a specific MAP kinase pathway. In primary T cells, TGF-beta1 activated the MEK/ERK and p38 MAP kinase pathways, but not the JNK pathway. Inhibition of the MEK/ERK pathway completely eliminated the inhibitory effects of TGF-beta1 on IFN-gamma responses in T cells, whereas inhibition of the p38 pathway had no effect. Thus, TGF-beta1's inhibition of IFN-gamma signaling in T cells is mediated through a highly specific Smad3 independent, MEK/ERK-dependent signaling pathway.
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PMID:TGF-beta 1 inhibition of IFN-gamma-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent. 1740 40


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