scholarly journals Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes

2016 ◽  
Vol 212 (4) ◽  
pp. 425-438 ◽  
Author(s):  
Adi D. Dubash ◽  
Chen Y. Kam ◽  
Brian A. Aguado ◽  
Dipal M. Patel ◽  
Mario Delmar ◽  
...  
Keyword(s):  
Gene Expression ◽  
P38 Mapk ◽  
Electromechanical Coupling ◽  
Transforming Growth Factor ◽  
Mapk Signaling ◽  
Conditional Knockout ◽  
Mitogen Activated Protein Kinase ◽  
Junctional Complex ◽  
Plakophilin 2 ◽  
Tgf Β1

Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor β1 (TGF-β1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.

p38 MAPK activation by TGF-β1 increases MLC phosphorylation and endothelial monolayer permeability

2002 ◽  
Vol 282 (1) ◽  
pp. L146-L154 ◽  
Author(s):  
Peter L. Goldberg ◽  
Darren E. MacNaughton ◽  
Richard T. Clements ◽  
Fred L. Minnear ◽  
Peter A. Vincent
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
P38 Mapk ◽  
Transforming Growth Factor ◽  
Control Level ◽  
Mitogen Activated Protein Kinase ◽  
Endothelial Monolayer ◽  
Mapk Activation ◽  
Monolayer Permeability ◽  
Tgf Β1

Transforming growth factor (TGF)-β1 increases endothelial monolayer permeability and myosin light chain phosphorylation (MLC-P) beginning 1–2 h posttreatment, suggesting that changes in gene expression may be required for these responses. The role of extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38 MAPK) was investigated because both kinases have been implicated in regulating gene expression after TGF-β1. ERK1/2 phosphorylation increased threefold above the control level, and the increase was temporally associated with the increase in MLC-P. Inhibition of ERK1/2 phosphorylation with the MAPK kinase inhibitor U-0126 did not prevent the increase in either monolayer permeability or MLC-P. p38 MAPK phosphorylation increased fourfold above the control level, but unlike ERK1/2, this increase peaked 30 min and 1 h post-TGF-β1 treatment. Inhibition of p38 MAPK activity with SB-203580 prevented the increases in both monolayer permeability and MLC-P. Treatment of the monolayers with cycloheximide in conjunction with TGF-β1-inhibited MLC-P, showing a requirement for protein synthesis. These studies demonstrate that p38 MAPK activation and subsequent protein synthesis are part of the signal transduction pathway leading to the TGF-β1-induced increases in monolayer permeability and MLC-P.

scholarly journals Isorhamnetin Inhibits Liver Fibrosis by Reducing Autophagy and Inhibiting Extracellular Matrix Formation via the TGF-β1/Smad3 and TGF-β1/p38 MAPK Pathways

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Ning Liu ◽  
Jiao Feng ◽  
Xiya Lu ◽  
Zhilu Yao ◽  
Qing Liu ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Liver Fibrosis ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Transforming Growth Factor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Duct Ligation ◽  
Mapk Signaling Pathways ◽  
Tgf Β1

Objective. Liver fibrosis is a consequence of wound-healing responses to chronic liver insult and may progress to liver cirrhosis if not controlled. This study investigated the protection against liver fibrosis by isorhamnetin. Methods. Mouse models of hepatic fibrosis were established by intraperitoneal injection of carbon tetrachloride (CCl4) or bile duct ligation (BDL). Isorhamnetin 10 or 30 mg/kg was administered by gavage 5 days per week for 8 weeks in the CCl4 model and for 2 weeks in the BDL model. Protein and mRNA expressions were assayed by western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction. Results. Isorhamnetin significantly inhibited liver fibrosis in both models, inhibiting hepatic stellate cell (HSC) activation, extracellular matrix (ECM) deposition, and autophagy. The effects were associated with downregulation of transforming growth factor β1 (TGF-β1) mediation of Smad3 and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Conclusion. Isorhamnetin protected against liver fibrosis by reducing ECM formation and autophagy via inhibition of TGF-β1-mediated Smad3 and p38 MAPK signaling pathways.

O-linked β-N-acetylglucosamine supports p38 MAPK activation by high glucose in glomerular mesangial cells

2011 ◽  
Vol 301 (4) ◽  
pp. E713-E726 ◽  
Author(s):  
Howard Goldberg ◽  
Catharine Whiteside ◽  
I. George Fantus
Keyword(s):  
Diabetic Nephropathy ◽  
P38 Mapk ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Mesangial Cells ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Glomerular Mesangial Cells ◽  
Matrix Accumulation

Hyperglycemia augments flux through the hexosamine biosynthetic pathway and subsequent O-linkage of single β- N-acetyl-d-glucosamine moieties to serine and threonine residues on cytoplasmic and nuclear proteins ( O-GlcNAcylation). Perturbations in this posttranslational modification have been proposed to promote glomerular matrix accumulation in diabetic nephropathy, but clear evidence and mechanism are lacking. We tested the hypothesis that O-GlcNAcylation enhances profibrotic signaling in rat mesangial cells. An adenovirus expressing shRNA directed against O-GlcNAc transferase (OGT) markedly reduced basal and high-glucose-stimulated O-GlcNAcylation. Interestingly, O-GlcNAc depletion prevented high-glucose-induced p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase phosphorylation. Downstream of p38, O-GlcNAc controlled the expression of plasminogen activator inhibitor-1, fibronectin, and transforming growth factor-β, important factors in matrix accumulation in diabetic nephropathy. Treating mesangial cells with thiamet-G, a highly selective inhibitor of O-GlcNAc-specific hexosaminidase ( O-GlcNAcase), increased O-GlcNAcylation and p38 phosphorylation. The high-glucose-stimulated kinase activity of apoptosis signal-regulating kinase 1 (ASK1), an upstream MAPK kinase kinase for p38 that is negatively regulated by Akt, was inhibited by OGT shRNA. Akt Thr308 and Ser473 phosphorylation were enhanced following OGT shRNA expression in high-glucose-exposed mesangial cells, but high-glucose-induced p38 phosphorylation was not attenuated by OGT shRNA in cells pretreated with the phosphatidylinositol 3-kinase inhibitor LY-294002. OGT shRNA also reduced high-glucose-stimulated reactive oxygen species (ROS) formation. In contrast, diminished O-GlcNAcylation caused elevated ERK phosphorylation and PKCδ membrane translocation. Thus, O-GlcNAcylation is coupled to profibrotic p38 MAPK signaling by high glucose in part through Akt and possibly through ROS.

scholarly journals Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes

2016 ◽  
Vol 213 (3) ◽  
pp. 2133OIA12
Author(s):  
Adi D. Dubash ◽  
Chen Y. Kam ◽  
Brian A. Aguado ◽  
Dipal M. Patel ◽  
Mario Delmar ◽  
...  
Keyword(s):  
Gene Expression ◽  
P38 Mapk ◽  
Plakophilin 2 ◽  
Tgf Β1

scholarly journals Identification of genomic targets downstream of p38 mitogen-activated protein kinase pathway mediating tumor necrosis factor-α signaling

2007 ◽  
Vol 31 (2) ◽  
pp. 343-351 ◽  
Author(s):  
Cindy Zer ◽  
George Sachs ◽  
Jai Moo Shin
Keyword(s):  
Gene Expression ◽  
P38 Mapk ◽  
Proinflammatory Cytokines ◽  
Quantitative Polymerase Chain Reaction ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Gene Expressions ◽  
Tnf Α ◽  
Induced Genes ◽  
Sb 203580

Inhibition of p38 MAPK suppresses the expression of proinflammatory cytokines such as TNF-α and IL-1β in macrophages and fibroblast-like synoviocytes (FLS). However, there have been no genomewide studies on the gene targets of p38 MAPK signaling in synoviocytes. Microarray technology was applied to generate a comprehensive analysis of all genes regulated by the p38 MAPK signaling pathway in FLS. Gene expression levels were measured with Agilent oligonucleotide microarrays. Four independent sets of mRNA modulated by TNF-α and vehicle were used to measure the change of gene expression due to TNF-α, and three experiments were done to ascertain the effect of SB-203580, a p38 MAPK inhibitor, on TNF-α-induced genes. Microarray data were validated by RT-quantitative polymerase chain reaction. One hundred forty-one significantly expressed genes were more than twofold upregulated by TNF-α. Thirty percent of these genes were downregulated by the p38 inhibitor SB-203580, whereas 67% of these genes were not significantly changed. The SB-203580-inhibited genes include proinflammatory cytokines such as interleukins and chemokines, proteases including matrix metallopeptidases, metabolism-related genes such as cyclooxygenases and phosphodiesterase, genes involved in signal transduction, and genes encoding for transcription factors, receptors, and transporters. Approximately one-third of the TNF-α-induced genes in FLS are regulated by the p38 MAPK signal pathway, showing that p38 MAPK is a possible target for suppressing proinflammatory gene expressions in rheumatoid arthritis.

scholarly journals Role of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis

2019 ◽  
Vol 317 (5) ◽  
pp. L678-L689 ◽  
Author(s):  
Nikos Xylourgidis ◽  
Kisuk Min ◽  
Farida Ahangari ◽  
Guoying Yu ◽  
Jose D. Herazo-Maya ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
P38 Mapk ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Lung Fibroblasts ◽  
Dual Specificity ◽  
M1 Macrophage ◽  
Deficient Mice ◽  
Tgf Β1

Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP-5) is a member of the dual-specificity family of protein tyrosine phosphatases that negatively regulates p38 MAPK and the JNK. MKP-5-deficient mice exhibit improved muscle repair and reduced fibrosis in an animal model of muscular dystrophy. Here, we asked whether the effects of MKP-5 on muscle fibrosis extend to other tissues. Using a bleomycin-induced model of pulmonary fibrosis, we found that MKP-5-deficient mice were protected from the development of lung fibrosis, expressed reduced levels of hydroxyproline and fibrogenic genes, and displayed marked polarization towards an M1-macrophage phenotype. We showed that the profibrogenic effects of the transforming growth factor-β1 (TGF-β1) were inhibited in MKP-5-deficient lung fibroblasts. MKP-5-deficient fibroblasts exhibited enhanced p38 MAPK activity, impaired Smad3 phosphorylation, increased Smad7 levels, and decreased expression of fibrogenic genes. Myofibroblast differentiation was attenuated in MKP-5-deficient fibroblasts. Finally, we found that MKP-5 expression was increased in idiopathic pulmonary fibrosis (IPF)-derived lung fibroblasts but not in whole IPF lungs. These data suggest that MKP-5 plays an essential role in promoting lung fibrosis. Our results couple MKP-5 with the TGF-β1 signaling machinery and imply that MKP-5 inhibition may serve as a therapeutic target for human lung fibrosis.

scholarly journals RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1569 ◽  
Author(s):  
Rabea Zinn ◽  
Hannah Otterbein ◽  
Hendrik Lehnert ◽  
Hendrik Ungefroren
Keyword(s):  
Gene Expression ◽  
Cell Migration ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Migratory Activity ◽  
Tgf Β1

The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown to potently inhibit transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition (EMT) in pancreatic and breast epithelial cells, but the underlying mechanism has remained obscure. Using a panel of pancreatic ductal adenocarcinoma (PDAC)-derived cell lines of different differentiation stages, we show that RAC1B is more abundantly expressed in well differentiated as opposed to poorly differentiated cells. Interestingly, RNA interference-mediated knockdown of RAC1B decreased expression of the epithelial marker protein E-cadherin, encoded by CDH1, and enhanced its TGF-β1-induced downregulation, whereas ectopic overexpression of RAC1B upregulated CDH1 expression and largely prevented its TGF-β1-induced silencing of CDH1. Conversely, knockdown of RAC1B, or deletion of the RAC1B-specific exon 3b by CRISPR/Cas-mediated genomic editing, enhanced basal and TGF-β1-induced upregulation of mesenchymal markers like Vimentin, and EMT-associated transcription factors such as SNAIL and SLUG. Moreover, we demonstrate that knockout of RAC1B enhanced the cells’ migratory activity and derepressed TGF-β1-induced activation of the mitogen-activated protein kinase ERK2. Pharmacological inhibition of ERK1/2 activation in RAC1B-depleted cells rescued cells from the RAC1B knockdown-induced enhancement of cell migration, TGF-β1-induced downregulation of CDH1, and upregulation of SNAI1. We conclude that RAC1B promotes epithelial gene expression and suppresses mesenchymal gene expression by interfering with TGF-β1-induced MEK-ERK signaling, thereby protecting cells from undergoing EMT and EMT-associated responses like acquisition of cell motility.

scholarly journals Selective Regulation of c-jun Gene Expression by Mitogen-Activated Protein Kinases via the 12-O-Tetradecanoylphorbol-13-Acetate- Responsive Element and Myocyte Enhancer Factor 2 Binding Sites

2005 ◽  
Vol 25 (9) ◽  
pp. 3784-3792 ◽  
Author(s):  
Midori Kayahara ◽  
Xin Wang ◽  
Cathy Tournier
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cell Fate ◽  
P38 Mapk ◽  
Physiological Role ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Cascades ◽  
Mitogen Activated Protein

ABSTRACT To further understand how the mitogen-activated protein kinase (MAPK) signaling pathways regulate AP-1 activity, we have elucidated the physiological role of these cascades in the regulation of c-jun gene expression. c-Jun is a crucial component of AP-1 complexes and has been shown in vitro to be a point of integration of numerous signals that can differentially affect its expression as well as its transcriptional activity. Our strategy was based on the use of (i) genetically modified fibroblasts deficient in components of the MAPK cascades and (ii) pharmacological reagents. The results demonstrate that c-Jun NH2-terminal protein kinase (JNK) is essential for a basal level of c-Jun expression and for c-Jun phosphorylation in response to stress. In addition to JNK, p38 MAPK or ERK1/2 and ERK5 are required for mediating UV radiation- or epidermal growth factor (EGF)-induced c-Jun expression, respectively. Further studies indicate that p38 MAPK inhibits the activation of JNK in response to EGF, causing a down-regulation of c-Jun. Overall, these data provide important insights into the mechanisms that ultimately determine the function of c-Jun as a regulator of cell fate.

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