scholarly journals Transforming growth factor-β1 impairs CFTR-mediated anion secretion across cultured porcine vas deferens epithelial monolayer via the p38 MAPK pathway

2013 ◽  
Vol 305 (8) ◽  
pp. C867-C876 ◽  
Author(s):  
Sheng Yi ◽  
Fernando Pierucci-Alves ◽  
Bruce D. Schultz
Keyword(s):  
Cystic Fibrosis ◽  
Growth Factor ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Vas Deferens ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Transforming Growth Factor Β1 ◽  
Anion Secretion ◽  
Tgf Β1

The goal of this study was to determine whether transforming growth factor-β1 (TGF-β1) affects epithelial cells lining the vas deferens, an organ that is universally affected in cystic fibrosis male patients. In PVD9902 cells, which are derived from porcine vas deferens epithelium, TGF-β1 exposure significantly reduced short-circuit current ( Isc) stimulated by forskolin or a cell membrane-permeant cAMP analog, 8-pCPT-cAMP, suggesting that TGF-β1 affects targets of the cAMP signaling pathway. Electrophysiological results indicated that TGF-β1 reduces the magnitude of current inhibited by cystic fibrosis transmembrane conductance regulator (CFTR) channel blockers. Real-time RT-PCR revealed that TGF-β1 downregulates the abundance of mRNA coding for CFTR, while biotinylation and Western blot showed that TGF-β1 reduces both total CFTR and apical cell surface CFTR abundance. These results suggest that TGF-β1 causes a reduction in CFTR expression, which limits CFTR-mediated anion secretion. TGF-β1-associated attenuation of anion secretion was abrogated by SB431542, a TGF-β1 receptor I inhibitor. Signaling pathway studies showed that the effect of TGF-β1 on Isc was reduced by SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK). TGF-β1 exposure also increased the amount of phospho-p38 MAPK substantially. In addition, anisomycin, a p38 MAPK activator, mimicked the effect of TGF-β1, which further suggests that TGF-β1 affects PVD9902 cells through a p38 MAPK pathway. These observations suggest that TGF-β1, via TGF-β1 receptor I and p38 MAPK signaling, reduces CFTR expression to impair CFTR-mediated anion secretion, which would likely compound the effects associated with mild CFTR mutations and ultimately would compromise male fertility.

scholarly journals JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts

2021 ◽  
Vol 22 (6) ◽  
pp. 2952
Author(s):  
Tzu-Yu Hou ◽  
Shi-Bei Wu ◽  
Hui-Chuan Kau ◽  
Chieh-Chih Tsai
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western Blots ◽  
Orbital Fibroblasts ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

Smad and p38-MAPK signaling mediates apoptotic effects of transforming growth factor-β1 in human airway epithelial cells

2004 ◽  
Vol 287 (3) ◽  
pp. L515-L524 ◽  
Author(s):  
Nidhi S. Undevia ◽  
Delbert R. Dorscheid ◽  
Bertha A. Marroquin ◽  
Wendy L. Gugliotta ◽  
Roberta Tse ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Protective Effect ◽  
P38 Mapk ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Smad Pathway ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) belongs to a family of multifunctional cytokines that regulate a variety of biological processes, including cell differentiation, proliferation, and apoptosis. The effects of TGF-β1 are cell context and cell cycle specific and may be signaled through several pathways. We examined the effect of TGF-β1 on apoptosis of primary human central airway epithelial cells and cell lines. TGF-β1 protected human airway epithelial cells from apoptosis induced by either activation of the Fas death receptor (CD95) or by corticosteroids. This protective effect was blocked by inhibition of the Smad pathway via overexpression of inhibitory Smad7. The protective effect is associated with an increase in the cyclin-dependent kinase inhibitor p21 and was blocked by the overexpression of key gatekeeper cyclins for the G1/S interface, cyclins D1 and E. Blockade of the Smad pathway by overexpression of the inhibitory Smad7 permitted demonstration of a TGF-β-mediated proapoptotic pathway. This proapoptotic effect was blocked by inhibition of the p38 MAPK kinase signaling with the inhibitor SB-203580 and was associated with an increase in p38 activity as measured by a kinase assay. Here we demonstrate dual signaling pathways involving TGF-β1, an antiapoptotic pathway mediated by the Smad pathway involving p21, and an apoptosis-permissive pathway mediated in part by p38 MAPK.

Rho kinase mediates transforming growth factor-β1-induced vasculogenic mimicry formation: involvement of the epithelial–mesenchymal transition and cancer stemness activity

2020 ◽  
Vol 52 (4) ◽  
pp. 411-420 ◽  
Author(s):  
Xue Zhang ◽  
Jigang Zhang ◽  
Heming Zhou ◽  
Gaolin Liu ◽  
Qin Li
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Vasculogenic Mimicry ◽  
Rho Kinase ◽  
Transforming Growth Factor Β1 ◽  
Cell Phenotype ◽  
Mesenchymal Transition ◽  
Tgf Β1

Abstract Vasculogenic mimicry (VM), a newly defined pattern of tumor blood supply, has been identified in several malignant tumors, including hepatocellular carcinoma (HCC). Rho kinase (ROCK) plays an important role in various types of cancers. However, whether ROCK participates in transforming growth factor-β1 (TGF-β1)-induced VM formation is unclear. Here, we evaluated the role of ROCK in TGF-β1-induced VM formation in HCC. Our findings showed that the TGF-β1/ROCK signaling pathway is involved in VM formation by inducing the epithelial–mesenchymal transition. Furthermore, TGF-β1 and ROCK were found to play distinct roles in the cancer stem cell phenotype during VM formation. These results provide insights into potential antitumor therapies for inhibiting VM by targeting the TGF-β1/ROCK signaling pathway in HCC.

Transforming Growth Factor-β1 Inhibits the Maturation of Dendritic Cells Via Toll-Like Receptor 4 Signaling Pathway.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3861-3861
Author(s):  
Haibo Mou ◽  
Maofang Lin ◽  
He Huang
Keyword(s):  
Dendritic Cells ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
P38 Kinase ◽  
Toll Like Receptor 4 ◽  
Tgf Β1

Abstract We have demonstrated that transforming growth factor-β1(TGF-β1) inhibits the maturation of mouse bone marrow derived dendritic cells (DCs). TGF-β1 treated DCs (TGFβ-DCs) are resistant to maturation stimulus -lipopolysaccharide (LPS) and might have some correlation with the down-modulation of Toll-like receptor 4 (TLR4) expression. It was known TLR4 binds LPS from Gram-negative bacteria, triggering signaling pathways that lead to the activation of NF-κB, ERK1/2 and p38 MAPK and ensuing gene expression of proinflammatory factors. In the current study, we further estimated the activities of NF-κB, ERK1/2 and p38 proteins involved in TLR4 signaling pathway. Using EMSA method, we found the NF-κB DNA binding activity in immature DCs (imDCs) was significantly increased in response to LPS, but addition of TGF-β1 to DCs inhibited NF-κB binding. Moreover, TGF-β1 was effective in suppressing LPS-induced activation of ERK1/2 and p38 kinase, the level of phosphorylation of ERK1/2 and p38 kinase were lower than imDCs measured by Western Blot. After treatment of imDCs and TGFβ-DCs with LPS for 24 h, the production of IL-12p70 of TGFβ-DCs was significantly less than that of imDCs(115.4±15.2 pg/ml vs 517.0±29.7 pg/ml, P<0.01), but the level of Th2 cytokine-IL-10 was elevated(132.1±17.5 pg/ml vs 75.1±16.6 pg/ml, P<0.05), indicating that exposure to TGF-β1 impaired the capability of DCs to produce high amounts of bioactive IL-12p70. According to the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), the expressions of chemokines MIP-1α mRNA on TGFβ-DCs after LPS stimulation were lower than imDCs at each time point. The lower expressions of MCP-1 and IP-10 on TGFβ-DCs at irregular pattern after LPS treatment, whereas the expressions RANTES were no different. Hence, the results suggested TGF-β1 maybe directly inhibit TLR4 expression on DCs, and then interfere with the activity of downstream key proteins, such as NF-κB, ERK1/2 and p38. Ultimately, TGF-β1 treated DCs were resistance to LPS, down-regulated the expression of costimulatory molecular on DCs and decreased the secretion of inflammatory cytokines.

scholarly journals Human Papillomavirus Type 5 E6 Oncoprotein Represses the Transforming Growth Factor β Signaling Pathway by Binding to SMAD3

2006 ◽  
Vol 80 (24) ◽  
pp. 12420-12424 ◽  
Author(s):  
Jose-Andres Mendoza ◽  
Yves Jacob ◽  
Patricia Cassonnet ◽  
Michel Favre
Keyword(s):  
Human Papillomavirus ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Cellular Transformation ◽  
Transforming Growth Factor Β ◽  
Transforming Growth Factor Β1 ◽  
E6 Oncoprotein ◽  
E6 Protein ◽  
Tgf Β1

ABSTRACT Mechanisms of cellular transformation associated with human papillomavirus type 5 (HPV5), which is responsible for skin carcinomas in epidermodysplasia verruciformis (EV) patients, are poorly understood. Using a yeast two-hybrid screening and molecular and cellular biology experiments, we found that HPV5 oncoprotein E6 interacts with SMAD3, a key component in the transforming growth factor β1 (TGF-β1) signaling pathway. HPV5 E6 inhibits SMAD3 transactivation by destabilizing the SMAD3/SMAD4 complex and inducing the degradation of both proteins. Interestingly, the E6 protein of nononcogenic EV HPV9 failed to interact with SMAD3, suggesting that downregulation of the TGF-β1 signaling pathway could be a determinant in HPV5 skin carcinogenesis.

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