Adenoviral delivery of dominant-negative transforming growth factor β type II receptor up-regulates transcriptional repressor SKI-like oncogene, decreases matrix metalloproteinase 2 in hepatic stellate cell and prevents liver fibrosis in rats

2009 ◽  
Vol 11 (3) ◽  
pp. 207-219 ◽  
Author(s):  
Ana Marquez-Aguirre ◽  
Ana Sandoval-Rodriguez ◽  
Jaime Gonzalez-Cuevas ◽  
Miriam Bueno- Topete ◽  
Jose Navarro-Partida ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Matrix Metalloproteinase ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Matrix Metalloproteinase 2 ◽  
Type Ii ◽  
Adenoviral Delivery

scholarly journals Integrin β1Signaling Is Necessary for Transforming Growth Factor-β Activation of p38MAPK and Epithelial Plasticity

2001 ◽  
Vol 276 (50) ◽  
pp. 46707-46713 ◽  
Author(s):  
Neil A. Bhowmick ◽  
Roy Zent ◽  
Mayshan Ghiassi ◽  
Maureen McDonnell ◽  
Harold L. Moses
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Receptor Expression ◽  
Type I ◽  
Type Ii

Transforming growth factor-β (TGF-β) can induce epithelial to mesenchymal transdifferentiation (EMT) in mammary epithelial cells. TGF-β-meditated EMT involves the stimulation of a number of signaling pathways by the sequential binding of the type II and type I serine/threonine kinase receptors, respectively. Integrins comprise a family of heterodimeric extracellular matrix receptors that mediate cell adhesion and intracellular signaling, hence making them crucial for EMT progression. In light of substantial evidence indicating TGF-β regulation of various β1integrins and their extracellular matrix ligands, we examined the cross-talk between the TGF-β and integrin signal transduction pathways. Using an inducible system for the expression of a cytoplasmically truncated dominant negative TGF-β type II receptor, we blocked TGF-β-mediated growth inhibition, transcriptional activation, and EMT progression. Dominant negative TGF-β type II receptor expression inhibited TGF-β signaling to the SMAD and AKT pathways, but did not block TGF-β-mediated p38MAPK activation. Interestingly, blocking integrin β1function inhibited TGF-β-mediated p38MAPK activation and EMT progression. Limiting p38MAPK activity through the expression of a dominant negative-p38MAPK also blocked TGF-β-mediated EMT. In summary, TGF-β-mediated p38MAPK activation is dependent on functional integrin β1, and p38MAPK activity is required but is not sufficient to induce EMT.

scholarly journals Overexpression of a Kinase-deficient Transforming Growth Factor-β Type II Receptor in Mouse Mammary Stroma Results in Increased Epithelial Branching

1999 ◽  
Vol 10 (4) ◽  
pp. 1221-1234 ◽  
Author(s):  
Heather Joseph ◽  
Agnieszka E. Gorska ◽  
Philip Sohn ◽  
Harold L. Moses ◽  
Rosa Serra
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Branching Morphogenesis ◽  
Mammary Glands ◽  
Dominant Negative ◽  
Type Ii ◽  
Ductal Epithelium ◽  
Lateral Branching

Members of the transforming growth factor-β (TGF-β) superfamily signal through heteromeric type I and type II serine/threonine kinase receptors. Transgenic mice that overexpress a dominant-negative mutation of the TGF-β type II receptor (DNIIR) under the control of a metallothionein-derived promoter (MT-DNIIR) were used to determine the role of endogenous TGF-βs in the developing mammary gland. The expression of the dominant-negative receptor was induced with zinc and was primarily localized to the stroma underlying the ductal epithelium in the mammary glands of virgin transgenic mice from two separate mouse lines. In MT-DNIIR virgin females treated with zinc, there was an increase in lateral branching of the ductal epithelium. We tested the hypothesis that expression of the dominant-negative receptor may alter expression of genes that are expressed in the stroma and regulated by TGF-βs, potentially resulting in the increased lateral branching seen in the MT-DNIIR mammary glands. The expression of hepatocyte growth factor mRNA was increased in mammary glands from transgenic animals relative to the wild-type controls, suggesting that this factor may play a role in TGF-β-mediated regulation of lateral branching. Loss of responsiveness to TGF-βs in the mammary stroma resulted in increased branching in mammary epithelium, suggesting that TGF-βs play an important role in the stromal–epithelial interactions required for branching morphogenesis.

High Glucose Decreases Matrix Metalloproteinase-2 Activity in Rat Mesangial Cells via Transforming Growth Factor-β1

2001 ◽  
Vol 9 (4) ◽  
pp. 249-257 ◽  
Author(s):  
Rekha Singh ◽  
Ruo Hua Song ◽  
Nahid Alavi ◽  
Alfredo A. Pegoraro ◽  
Ashok K. Singh ◽  
...  
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Transforming Growth Factor Β ◽  
Matrix Metalloproteinase 2

scholarly journals Hepatic stellate cell–specific knockout of transcriptional intermediary factor 1γ aggravates liver fibrosis

2020 ◽  
Vol 217 (6) ◽  
Author(s):  
Eun Ju Lee ◽  
Injoo Hwang ◽  
Ji Yeon Lee ◽  
Jong Nam Park ◽  
Keun Cheon Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Embryonic Stem ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Promising Therapeutic Approach

Transforming growth factor β (TGFβ) is a crucial factor in fibrosis, and transcriptional intermediary factor 1γ (TIF1γ) is a negative regulator of the TGFβ pathway; however, its role in liver fibrosis is unknown. In this study, mesenchymal stem cells derived from human embryonic stem cells (hE-MSCs) that secrete hepatocyte growth factor (HGF) were used to observe the repair of thioacetamide (TAA)-induced liver fibrosis. Our results showed that TIF1γ was significantly decreased in LX2 cells when exposed to TGFβ1. Such decrease of TIF1γ was significantly prevented by co-culture with hE-MSCs. Interaction of TIF1γ with SMAD2/3 and binding to the promoter of the α-smooth muscle gene (αSMA) suppressed αSMA expression. Phosphorylation of cAMP response element–binding protein (CREB) and binding on the TIF1γ promoter region induced TIF1γ expression. Furthermore, hepatic stellate cell–specific TIF1γ-knockout mice showed aggravation of liver fibrosis. In conclusion, loss of TIF1γ aggravates fibrosis, suggesting that a strategy to maintain TIF1γ during liver injury would be a promising therapeutic approach to prevent or reverse liver fibrosis.

scholarly journals Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor β receptor type II mice

Hepatology ◽  
2009 ◽  
Vol 50 (5) ◽  
pp. 1494-1500 ◽  
Author(s):  
Katsunori Yoshida ◽  
Guo-Xiang Yang ◽  
Weici Zhang ◽  
Masanobu Tsuda ◽  
Koichi Tsuneyama ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Receptor Type ◽  
Type Ii ◽  
Autoimmune Cholangitis ◽  
Β Receptor

The Control of Matrix Metalloproteinase-2 Expression in Normal and Keratoconic Corneal Keratocyte Cultures

2000 ◽  
Vol 10 (4) ◽  
pp. 276-285 ◽  
Author(s):  
B.T. Parkin ◽  
V.A. Smith ◽  
D.L. Easty
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Early Phase ◽  
Transforming Growth Factor ◽  
Polyacrylamide Gel Electrophoresis ◽  
Transforming Growth Factor Β ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Dot Blot ◽  
Corneal Keratocytes

Purpose Early phase keratoconic comeas and their cultured keratocytes abnormally produce the Mr 62,000 form of the matrix metalloproteinase-2 (MMP-2). It is known that platelet derived growth factor (PDGF) and transforming growth factor-β (TGF-β) are involved in the regulation of MMP activity and tissue inhibitor of metalloproteinase (TIMP) production in non-ocular tissues. The purpose of this enquiry was to determine whether these growth factors also play a role in the activity and/or production of corneal MMP-2 and TIMP, and whether their activity could account for the existence of the Mr 62,000 form of MMP-2 in keratoconic corneas. Methods Confluent cultures of normal and early-phase keratoconic corneal keratocytes were established and incubated in serum-free media in the presence or absence of PDGF and TGF-β. The proteins secreted by these cells over periods of 7 days were harvested for analysis. The total protein produced was determined spectrophotometrically. MMP-2 was visualised by SDS-gelatin polyacrylamide gel electrophoresis and assayed using radiolabelled type IV collagen as substrate. The enzyme inhibitors, TIMP-1 and TIMP-2, were quantified by dot blot immunoassay. Results The addition of PDGF or TGF-β to the culture medium of keratoconic corneal keratocytes had no significant effect on overall protein production, MMP-2 activity or on the amounts of TIMP-1 and TIMP-2 secreted. These observations also applied to normal corneal keratocytes, with the exception that PDGF induced expression of the Mr 62,000 species of MMP-2. Conclusions PDGF may be involved in the production of the Mr 62,000 species of MMP-2 that is abnormally produced by early-phase keratoconic corneal keratocytes.

scholarly journals Established neointimal hyperplasia in vein grafts expands via TGF-β-mediated progressive fibrosis

2009 ◽  
Vol 297 (4) ◽  
pp. H1200-H1207 ◽  
Author(s):  
Zhihua Jiang ◽  
Ming Tao ◽  
Kerri A. Omalley ◽  
Danlu Wang ◽  
C. Keith Ozaki ◽  
...  
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Cellular Proliferation ◽  
Transforming Growth Factor ◽  
Neointimal Hyperplasia ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Matrix Metalloproteinase 2 ◽  
Vein Grafts

In weeks to months following implantation, neointimal hyperplasia (NIH) in vein grafts (VGs) transitions from a cellularized to a decellularized phenotype. The inhibition of early cellular proliferation failed to improve long-term VG patency. We have previously demonstrated that transforming growth factor-β1 (TGF-β1)/connective tissue growth factor (CTGF) pathways mediate a conversion of fibroblasts to myofibroblasts in the early VG (<2 wk). We hypothesize that these similar pathways drive fibrosis observed in the late VG lesion. Within rabbit VGs, real-time RT-PCR, Western blot analysis, ELISA, and immunohistochemistry were used to examine TGF-β/CTGF pathways in late (1–6 mo) NIH. All VGs exhibited a steady NIH growth ( P = 0.006) with significant reduction in cellularity ( P = 0.01) over time. Substantial TGF-β profibrotic activities, as evidenced by enhanced TGF-β1 activation, TGF-β receptor types I (activin receptor-like kinase 5)-to-II receptor ratio, SMAD2/3 phosphorylation, and CTGF production, persisted throughout the observation period. An increased matrix synthesis was accompanied by a temporal reduction of matrix metalloproteinase-2 ( P = 0.001) and -9 ( P < 0.001) activity. VG NIH is characterized by a conversion from a proproliferative to a profibrotic morphology. An enhanced signaling via TGF-β/CTGF coupled with reduced matrix metalloproteinase activities promotes progressive fibrotic NIH expansion. The modulation of late TGF-β/CTGF signaling may offer a novel therapeutic strategy to improve the long-term VG durability.

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