scholarly journals Phosphorylation of Smad7 at Ser-249 Does Not Interfere with Its Inhibitory Role in Transforming Growth Factor-β-dependent Signaling but Affects Smad7-dependent Transcriptional Activation

2001 ◽  
Vol 276 (17) ◽  
pp. 14344-14349 ◽  
Author(s):  
Lukasz Pulaski ◽  
Maréne Landström ◽  
Carl-Henrik Heldin ◽  
Serhiy Souchelnytskyi
Keyword(s):  
Growth Factor ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Inhibitory Role

scholarly journals Trypanosoma cruzi Induces the PARP1/AP-1 Pathway for Upregulation of Metalloproteinases and Transforming Growth Factor β in Macrophages: Role in Cardiac Fibroblast Differentiation and Fibrosis in Chagas Disease

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Subhadip Choudhuri ◽  
Nisha Jain Garg
Keyword(s):  
Growth Factor ◽  
Chagas Disease ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cardiac Fibroblast ◽  
Myofibroblast Differentiation ◽  
Content Type ◽  
Parp1 Inhibitors

ABSTRACT Chagas disease (CD), caused by Trypanosoma cruzi, is a degenerative heart condition. In the present study, we investigated the role of poly [ADP-ribose] polymerase 1/activator protein 1 (PARP1/AP-1) in upregulation of profibrotic macrophages (Mϕ) and subsequent development of cardiac fibrosis in CD. We used in vitro and in vivo models of T. cruzi infection and chemical and genetic inhibition of Parp1 to examine the molecular mechanisms by which Mϕ might augment profibrotic events in CD. Cultured (RAW 264.7 and THP-1) Mϕ infected with T. cruzi and primary cardiac and splenic Mϕ of chronically infected mice exhibited a significant increase in the expression, activity, and release of metalloproteinases (MMP2, MMP9, and MMP12) and the cytokine transforming growth factor β (TGF-β). Mϕ release of MMPs and TGF-β signaled the cardiac fibroblast to myofibroblast differentiation, as evidenced by a shift from S100A4 to alpha smooth muscle actin (α-SMA) expression. Incubation of infected Mϕ with MMP2 and MMP9 inhibitors resulted in 60 to 74% decline in TGF-β release, and MMP9 and PARP1 inhibitors resulted in 57 to 70% decline in Mϕ TGF-β-driven cardiac fibroblast differentiation. Likewise, histological studies showed a 12- to 16-fold increase in myocardial expression of CD68 (Mϕ marker) and its colocalization with MMP9/TGF-β, galectin-3, and vimentin in wild-type mice with CD. In comparison, chronically infected Parp1−/− mice exhibited a >50% decline in myocardial levels of Mϕ and associated fibrosis markers. Further study showed that PARP1 synergized with c-Fos and JunB AP-1 family members for transcriptional activation of profibrotic response after T. cruzi infection. We conclude that PARP1 inhibition offers a potential therapy for controlling the T. cruzi-driven fibroblast differentiation in CD through modulation of the Mϕ signaling of the AP-1–MMP9–TGF-β pathway. IMPORTANCE Cardiomyopathy is the most important clinical manifestation of T. cruzi-driven CD. Recent studies have suggested the detrimental role of the matrix metalloproteinases MMP2 and MMP9 in extracellular matrix (ECM) degradation during cardiac remodeling in T. cruzi infection. Peripheral TGF-β levels are increased in clinically symptomatic CD patients over those in clinically asymptomatic seropositive individuals. We provide the first evidence that during T. cruzi infection, Mϕ release of MMP2 and MMP9 plays an active role in activation of TGF-β signaling of ECM remodeling and cardiac fibroblast-to-myofibroblast differentiation. We also determined that PARP1 signals c-Fos- and JunB-mediated AP-1 transcriptional activation of profibrotic gene expression and demonstrated the significance of PARP1 inhibition in controlling chronic fibrosis in Chagas disease. Our study provides a promising therapeutic approach for controlling T. cruzi-driven fibroblast differentiation in CD by PARP1 inhibitors through modulation of the Mϕ signaling of the AP-1–MMP9–TGF-β pathway.

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 Positive and Negative Regulation of the Transforming Growth Factor β/Activin Target Gene goosecoid by the TFII-I Family of Transcription Factors

2005 ◽  
Vol 25 (16) ◽  
pp. 7144-7157 ◽  
Author(s):  
Manching Ku ◽  
Sergei Y. Sokol ◽  
Jack Wu ◽  
Maria Isabel Tussie-Luna ◽  
Ananda L. Roy ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Transcriptional Activation ◽  
Target Gene ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Related Factor ◽  
P19 Cells ◽  
Binding Factor ◽  
Opposing Effects

ABSTRACT Goosecoid (Gsc) is a homeodomain-containing transcription factor present in a wide variety of vertebrate species and known to regulate formation and patterning of embryos. Here we show that in embryonic carcinoma P19 cells, the transcription factor TFII-I forms a complex with Smad2 upon transforming growth factor β (TGFβ)/activin stimulation, is recruited to the distal element (DE) of the Gsc promoter, and activates Gsc transcription. Downregulation of endogenous TFII-I by small inhibitory RNA in P19 cells abolishes the TGFβ-mediated induction of Gsc. Similarly, Xenopus embryos with endogenous TFII-I expression downregulated by injection of TFII-I-specific antisense oligonucleotides exhibit decreased Gsc expression. Unlike TFII-I, the related factor BEN (binding factor for early enhancer) is constitutively recruited to the distal element in the absence of TGFβ/activin signaling and is replaced by the TFII-I/Smad2 complex upon TGFβ/activin stimulation. Overexpression of BEN in P19 cells represses the TGFβ-mediated transcriptional activation of Gsc. These results suggest a model in which TFII-I family proteins have opposing effects in the regulation of the Gsc gene in response to a TGFβ/activin signal.

A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-β

Cell ◽  
1988 ◽  
Vol 52 (3) ◽  
pp. 405-414 ◽  
Author(s):  
Pellegrino Rossi ◽  
Gerard Karsenty ◽  
Anita B. Roberts ◽  
Nanette S. Roche ◽  
Michael B. Sporn ◽  
...  
Keyword(s):  
Growth Factor ◽  
Binding Site ◽  
Transcriptional Activation ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Nuclear Factor ◽  
Nuclear Factor 1 ◽  
Collagen Promoter

scholarly journals Smad3-Smad4 and AP-1 Complexes Synergize in Transcriptional Activation of the c-Jun Promoter by Transforming Growth Factor β

1999 ◽  
Vol 19 (3) ◽  
pp. 1821-1830 ◽  
Author(s):  
Carolyn Wong ◽  
Elissa M. Rougier-Chapman ◽  
Joshua P. Frederick ◽  
Michael B. Datto ◽  
Nicole T. Liberati ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Binding Site ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
The Other ◽  
Promoter Activation ◽  
Complex Process ◽  
Transcription Factor Complex

ABSTRACT Transcriptional regulation by transforming growth factor β (TGF-β) is a complex process which is likely to involve cross talk between different DNA responsive elements and transcription factors to achieve maximal promoter activation and specificity. Here, we describe a concurrent requirement for two discrete responsive elements in the regulation of the c-Jun promoter, one a binding site for a Smad3-Smad4 complex and the other an AP-1 binding site. The two elements are located 120 bp apart in the proximal c-Jun promoter, and each was able to independently bind its corresponding transcription factor complex. The effects of independently mutating each of these elements were nonadditive; disruption of either sequence resulted in complete or severe reductions in TGF-β responsiveness. This simultaneous requirement for two distinct and independent DNA binding elements suggests that Smad and AP-1 complexes function synergistically to mediate TGF-β-induced transcriptional activation of the c-Jun promoter.

scholarly journals Transforming Growth Factor β/Smad3 Signaling Regulates IRF-7 Function and Transcriptional Activation of the Beta Interferon Promoter

2004 ◽  
Vol 24 (3) ◽  
pp. 1411-1425 ◽  
Author(s):  
Jing Qing ◽  
Cheng Liu ◽  
Lisa Choy ◽  
Rui-Yun Wu ◽  
Joseph S. Pagano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Negative Interference ◽  
Rapid Induction ◽  
Dominant Negative Interference ◽  
Smad3 Expression

ABSTRACT The rapid induction of alpha interferon (IFN-α) and IFN-β expression plays a critical role in the innate immune response against viral infection. We studied the effects of transforming growth factor β (TGF-β) and its intracellular effectors, the Smads, on the function of IRF-7, an essential transcription factor for IFN-α and -β induction. IRF-7 interacted with Smads, and IRF-7, but not IRF-3, cooperated with Smad3 to activate IFN-β transcription. This transcriptional cooperation occurred at the IRF-binding sequences in the IFN-β promoter, and dominant-negative interference with TGF-β receptor signaling and Smad3 function decreased IRF-7-mediated transcription. Furthermore, elimination of Smad3 expression in Smad3−/− fibroblasts delayed and decreased double-stranded RNA-induced expression of endogenous IFN-β, whereas restoration of Smad3 expression enhanced IFN-β induction. The IRF-7-Smad3 cooperativity resulted from the regulation of the transactivation activity of IRF-7 by Smad3, and dominant-negative interference with Smad3 function decreased IRF-7 activity. Consistent with the regulation by Smad3, the transcriptional activity of IRF-7 depended on and was regulated by TGF-β signaling. Our studies underscore a role of TGF-β/Smad3 signaling in IRF-7-mediated induction of IFN-β expression.

scholarly journals BF-1 Interferes with Transforming Growth Factor β Signaling by Associating with Smad Partners

2000 ◽  
Vol 20 (17) ◽  
pp. 6201-6211 ◽  
Author(s):  
Changlin Dou ◽  
Jun Lee ◽  
Bo Liu ◽  
Fang Liu ◽  
Joan Massague ◽  
...  
Keyword(s):  
Growth Factor ◽  
Dna Binding ◽  
Growth Inhibition ◽  
Progenitor Cells ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Transforming Growth Factor Β ◽  
Reporter System ◽  
Transcriptional Responses

ABSTRACT The winged-helix (WH) BF-1 gene, which encodes brain factor 1 (BF-1) (also known as foxg1), is essential for the proliferation of the progenitor cells of the cerebral cortex. Here we show that BF-1-deficient telencephalic progenitor cells are more apt to leave the cell cycle in response to transforming growth factor β (TGF-β) and activin. We found that ectopic expression of BF-1 in vitro inhibits TGF-β mediated growth inhibition and transcriptional activation. Surprisingly, we found that the ability of BF-1 to function as a TGF-β antagonist does not require its DNA binding activity. Therefore, we investigated whether BF-1 can inhibit Smad-dependent transcriptional responses by interacting with Smads or Smad binding partners. We found that BF-1 does not interact with Smads. Because the identities of the Smad partners mediating growth inhibition by TGF-β are not clearly established, we examined a model reporter system which is known to be activated by activin and TGF-β through Smads and the WH factor FAST-2. We demonstrate that BF-1 associates with FAST-2. This interaction is dependent on the same region of protein which mediates its ability to interfere with the antiproliferative activity of TGF-β and with TGF-β-dependent transcriptional activation. Furthermore, the interaction of FAST-2 with BF-1 is mediated by the same domain which is required for FAST-2 to interact with Smad2. We propose a model in which BF-1 interferes with transcriptional responses to TGF-β by interacting with FAST-2 or with other DNA binding proteins which function as Smad2 partners and which have a common mode of interaction with Smad2.

scholarly journals Transforming Growth Factor β-Induced Smad1/5 Phosphorylation in Epithelial Cells Is Mediated by Novel Receptor Complexes and Is Essential for Anchorage-Independent Growth

2008 ◽  
Vol 28 (22) ◽  
pp. 6889-6902 ◽  
Author(s):  
Amanda C. Daly ◽  
Rebecca A. Randall ◽  
Caroline S. Hill
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Anchorage Independent Growth ◽  
Receptor Complexes ◽  
Morphogenetic Protein ◽  
Growth Inhibitory ◽  
Simultaneous Activation

ABSTRACT Transforming growth factor β (TGF-β) signals predominantly through a receptor complex comprising ALK5 and TβRII to activate receptor-regulated Smads (R-Smads) Smad2 and Smad3. In endothelial cells, however, TGF-β can additionally activate Smad1 and Smad5. Here, we report that TGF-β also strongly induces phosphorylation of Smad1/5 in many different normal epithelial cells, epithelium-derived tumor cells, and fibroblasts. We demonstrate that TβRII and ALK5, as well as ALK2 and/or ALK3, are required for TGF-β-induced Smad1/5 phosphorylation. We show that the simultaneous activation of the R-Smads Smad2/3 and Smad1/5 by TGF-β results in the formation of mixed R-Smad complexes, containing, for example, phosphorylated Smad1 and Smad2. The prevalence of these mixed R-Smad complexes explains why TGF-β-induced Smad1/5 phosphorylation does not result in transcriptional activation via bone morphogenetic protein (BMP)-responsive elements, which bind activated Smad1/5-Smad4 complexes that are induced by BMP stimulation. Thus, TGF-β induces two parallel pathways: one signaling via Smad2-Smad4 or Smad3-Smad4 complexes and the other signaling via mixed R-Smad complexes. Finally, we assess the function of the novel arm of TGF-β signaling and show that TGF-β-induced Smad1/5 activation is not required for the growth-inhibitory effects of TGF-β but is specifically required for TGF-β-induced anchorage-independent growth.

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