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Results: 1 to 10 of 39

Publication Record


Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3- and p53-dependent fibrotic responses.
Samarakoon R, Helo S, Dobberfuhl AD, Khakoo NS, Falke L, Overstreet JM, Goldschmeding R, Higgins PJ
(2015) J Pathol 236: 421-32
MeSH Terms: Animals, Apoptosis, Aristolochic Acids, Cell Cycle Checkpoints, Cell Line, Cell Proliferation, Disease Models, Animal, Enzyme Inhibitors, Fibrosis, Gene Expression Regulation, Humans, Kidney Diseases, Kidney Tubules, Male, Mice, Inbred C57BL, PTEN Phosphohydrolase, Plasminogen Activator Inhibitor 1, RNA Interference, Signal Transduction, Smad3 Protein, Streptozocin, Transfection, Transforming Growth Factor beta1, Tumor Suppressor Protein p53, Ureteral Obstruction
Show Abstract · Added April 19, 2016
Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, α-SMA and fibronectin expression, compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53(Ser15) phosphorylation, with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGFβ1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFβ1 treatment and PTEN silencing potentiated epithelial cell death via p53-dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction, with accompanying PAI-1-dependent proliferative arrest, and cooperates with TGFβ1 to induce the expression of profibrotic genes and tubular apoptosis.
Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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25 MeSH Terms
Tumor suppressor ataxia telangiectasia mutated functions downstream of TGF-β1 in orchestrating profibrotic responses.
Overstreet JM, Samarakoon R, Cardona-Grau D, Goldschmeding R, Higgins PJ
(2015) FASEB J 29: 1258-68
MeSH Terms: Animals, Ataxia Telangiectasia Mutated Proteins, Cell Line, Epithelial Cells, Fibrosis, Gene Expression Regulation, Gene Knockdown Techniques, Humans, Kidney, Mice, Models, Biological, NADPH Oxidases, Phosphorylation, Rats, Signal Transduction, Smad3 Protein, Transforming Growth Factor beta1, Tumor Suppressor Protein p53
Show Abstract · Added April 19, 2016
Effective therapy to prevent organ fibrosis, which is associated with more than half of all mortalities, remains elusive. Involvement of tumor suppressor ataxia telangiectasia mutated (ATM) in the TGF-β1 pathway related to renal fibrosis is largely unknown. ATM activation (pATM(Ser1981)) increased 4-fold in the tubulointerstitial region of the unilateral ureteral obstruction-injured kidney in mice correlating with SMAD3 and p53(Ser15) phosphorylation and elevated levels of p22(phox) subunit of the NADPH oxidases (NOXs), and fibrotic markers, plasminogen activator inhibitor-1 (PAI-1), and fibronectin, when compared to contralateral (contra) or sham controls. In fact, ATM is rapidly phosphorylated at Ser(1981) by TGF-β1 stimulation. Stable silencing and pharmacologic inhibition of ATM ablated TGF-β1-induced p53 activation (>95%) and subsequent PAI-1, fibronectin, connective tissue growth factor, and p21 expression in human kidney 2 (HK-2) tubular epithelial cells and normal rat kidney-49 fibroblasts (NRK-49F). ATM or p53 depletion in HK-2 cells, moreover, bypassed TGF-β1-mediated cytostasis evident in control short hairpin RNA-expressing HK-2 cells. Interestingly, stable silencing of NOX subunits, p22(phox) and p47(phox), in HK-2 cells blocked TGF-β1-induced pATM(Ser1981) (>90%) and target gene induction via p53-dependent mechanisms. Furthermore, NRK-49F fibroblast proliferation triggered by conditioned media from TGF-β1-stimulated, control vector-transfected HK-2 cells decreased (∼ 50%) when exposed to conditioned media from ATM-deficient, TGF-β1-treated HK-2 cells. Thus, TGF-β1 promotes NOX-dependent ATM activation leading to p53-mediated fibrotic gene reprogramming and growth arrest in HK-2 cells. Furthermore, TGF-β1/ATM-initiated paracrine factor secretion by dysfunctional renal epithelium promotes interstitial fibroblast growth, suggesting a role of tubular ATM in mediating epithelial-mesenchymal cross-talk highlighting the translational benefit of targeting the NOX/ATM/p53 axis in renal fibrosis.
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18 MeSH Terms
Anti-remodeling and anti-fibrotic effects of the neuregulin-1β glial growth factor 2 in a large animal model of heart failure.
Galindo CL, Kasasbeh E, Murphy A, Ryzhov S, Lenihan S, Ahmad FA, Williams P, Nunnally A, Adcock J, Song Y, Harrell FE, Tran TL, Parry TJ, Iaci J, Ganguly A, Feoktistov I, Stephenson MK, Caggiano AO, Sawyer DB, Cleator JH
(2014) J Am Heart Assoc 3: e000773
MeSH Terms: Actins, Animals, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Fibrosis, Gene Expression Regulation, Heart Failure, Male, Mice, Inbred C57BL, Myocardial Contraction, Myocardium, Myofibroblasts, Neuregulin-1, Phosphorylation, Rats, Sprague-Dawley, Smad3 Protein, Swine, Time Factors, Transcription, Genetic, Ventricular Function, Left, Ventricular Remodeling
Show Abstract · Added March 15, 2017
BACKGROUND - Neuregulin-1β (NRG-1β) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 (GGF2) isoform of NRG-1β improves cardiac function in rodents after myocardial infarction (MI), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF2 on ventricular remodeling, cardiac function, and global transcription in post-MI swine, as well as potential mechanisms for anti-remodeling effects.
METHODS AND RESULTS - MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post-MI, survivors (n=13) received GGF2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post-MI, fractional shortening was higher (32.8% versus 25.3%, P=0.019), and left ventricular (LV) end-diastolic dimension lower (4.5 versus 5.3 cm, P=0.003) in GGF2-treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF2-treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG-1β reduces myoFbs, and suppresses TGFβ-induced phospho-SMAD3 as well as αSMA expression.
CONCLUSIONS - These results suggest that GGF2/NRG-1β prevents adverse remodeling after injury in part via anti-fibrotic effects in the heart.
© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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22 MeSH Terms
Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling.
Chen X, Wang H, Liao HJ, Hu W, Gewin L, Mernaugh G, Zhang S, Zhang ZY, Vega-Montoto L, Vanacore RM, Fässler R, Zent R, Pozzi A
(2014) J Clin Invest 124: 3295-310
MeSH Terms: Animals, Collagen, Epithelial-Mesenchymal Transition, Fibrosis, Integrin alpha1, Integrin alpha1beta1, Kidney, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad Proteins, Smad2 Protein, Smad3 Protein, Tyrosine, Ureteral Obstruction
Show Abstract · Added October 27, 2014
Tubulointerstitial fibrosis underlies all forms of end-stage kidney disease. TGF-β mediates both the development and the progression of kidney fibrosis through binding and activation of the serine/threonine kinase type II TGF-β receptor (TβRII), which in turn promotes a TβRI-mediated SMAD-dependent fibrotic signaling cascade. Autophosphorylation of serine residues within TβRII is considered the principal regulatory mechanism of TβRII-induced signaling; however, there are 5 tyrosine residues within the cytoplasmic tail that could potentially mediate TβRII-dependent SMAD activation. Here, we determined that phosphorylation of tyrosines within the TβRII tail was essential for SMAD-dependent fibrotic signaling within cells of the kidney collecting duct. Conversely, the T cell protein tyrosine phosphatase (TCPTP) dephosphorylated TβRII tail tyrosine residues, resulting in inhibition of TβR-dependent fibrotic signaling. The collagen-binding receptor integrin α1β1 was required for recruitment of TCPTP to the TβRII tail, as mice lacking this integrin exhibited impaired TCPTP-mediated tyrosine dephosphorylation of TβRII that led to severe fibrosis in a unilateral ureteral obstruction model of renal fibrosis. Together, these findings uncover a crosstalk between integrin α1β1 and TβRII that is essential for TβRII-mediated SMAD activation and fibrotic signaling pathways.
2 Communities
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23 MeSH Terms
Redox control of p53 in the transcriptional regulation of TGF-β1 target genes through SMAD cooperativity.
Overstreet JM, Samarakoon R, Meldrum KK, Higgins PJ
(2014) Cell Signal 26: 1427-36
MeSH Terms: Acetylation, Animals, Cell Line, DNA-Binding Proteins, Enzyme Activation, Epithelial Cells, Fibroblasts, Fibrosis, Gene Expression Regulation, Humans, Keratinocytes, Kidney Diseases, Kidney Tubules, Mice, Mice, Knockout, NADPH Oxidases, Phosphorylation, Plasminogen Activator Inhibitor 1, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Signal Transduction, Smad3 Protein, Transcriptional Activation, Transforming Growth Factor beta1, Tumor Suppressor Protein p53
Show Abstract · Added April 19, 2016
Transforming growth factor-β1 (TGF-β1) regulates the tissue response to injury and is the principal driver of excessive scarring leading to fibrosis and eventual organ failure. The TGF-β1 effectors SMAD3 and p53 are major contributors to disease progression. While SMAD3 is an established pro-fibrotic factor, the role of p53 in the TGF-β1-induced fibrotic program is not clear. p53 gene silencing, genetic ablation/subsequent rescue, and pharmacological inhibition confirmed that p53 was required for expression of plasminogen activator inhibitor-1 (PAI-1), a major TGF-β1 target gene and a key causative element in fibrotic disorders. TGF-β1 regulated p53 activity by stimulating p53(Ser15 and 9) phosphorylation and acetylation, promoting interactions with activated SMADs and subsequent binding of p53/SMAD3 to the PAI-1 promoter in HK-2 human renal tubular epithelial cells and HaCaT human keratinocytes. Immunohistochemistry revealed prominent co-induction of SMAD3, p53 and PAI-1 in the tubular epithelium of the obstructed kidney consistent with a potential in vivo role for p53 and SMADs in TGF-β1-driven renal fibrosis. TGF-β1-initiated phosphorylation of p53(Ser15) and up-regulation of expression of several pro-fibrotic genes, moreover, was dependent on the rapid generation of reactive oxygen species (ROS). shRNA silencing of the p22(Phox) subunit of NADP(H) oxidases in HK-2 cells partially attenuated (over 50%) p53(Ser15) phosphorylation and PAI-1 induction. These studies highlight the role of free radicals in p53 activation and subsequent pro-fibrotic reprogramming by TGF-β1 via the SMAD3-p53 transcriptional axis. Present findings provide a rationale for therapeutic targeting of SMAD3-p53 in aberrant TGF-β1 signaling associated with renal fibrosis.
Copyright © 2014 Elsevier Inc. All rights reserved.
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27 MeSH Terms
Transforming growth factor β regulates P-body formation through induction of the mRNA decay factor tristetraprolin.
Blanco FF, Sanduja S, Deane NG, Blackshear PJ, Dixon DA
(2014) Mol Cell Biol 34: 180-95
MeSH Terms: 3' Untranslated Regions, AU Rich Elements, Animals, Binding Sites, Cell Line, Cell Proliferation, Cellular Senescence, Colon, Cytoplasmic Structures, Intestinal Mucosa, Mice, Mice, Knockout, Promoter Regions, Genetic, RNA Processing, Post-Transcriptional, RNA Stability, RNA, Messenger, Rats, Signal Transduction, Smad3 Protein, Transcriptional Activation, Transforming Growth Factor beta, Tristetraprolin
Show Abstract · Added March 7, 2014
Transforming growth factor β (TGF-β) is a potent growth regulator and tumor suppressor in normal intestinal epithelium. Likewise, epithelial cell growth is controlled by rapid decay of growth-related mRNAs mediated through 3' untranslated region (UTR) AU-rich element (ARE) motifs. We demonstrate that treatment of nontransformed intestinal epithelial cells with TGF-β inhibited ARE-mRNA expression. This effect of TGF-β was promoted through increased assembly of cytoplasmic RNA processing (P) bodies where ARE-mRNA localization was observed. P-body formation was dependent on TGF-β/Smad signaling, as Smad3 deletion abrogated P-body formation. In concert with increased P-body formation, TGF-β induced expression of the ARE-binding protein tristetraprolin (TTP), which colocalized to P bodies. TTP expression was necessary for TGF-β-dependent P-body formation and promoted growth inhibition by TGF-β. The significance of this was observed in vivo, where colonic epithelium deficient in TGF-β/Smad signaling or TTP expression showed attenuated P-body levels. These results provide new insight into TGF-β's antiproliferative properties and identify TGF-β as a novel mRNA stability regulator in intestinal epithelium through its ability to promote TTP expression and subsequent P-body formation.
1 Communities
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22 MeSH Terms
Induction of renal fibrotic genes by TGF-β1 requires EGFR activation, p53 and reactive oxygen species.
Samarakoon R, Dobberfuhl AD, Cooley C, Overstreet JM, Patel S, Goldschmeding R, Meldrum KK, Higgins PJ
(2013) Cell Signal 25: 2198-209
MeSH Terms: Animals, Benzothiazoles, Connective Tissue Growth Factor, Endothelium, Vascular, ErbB Receptors, Fibroblasts, Fibrosis, Gene Expression Regulation, Isoquinolines, Mice, Mink, Myocytes, Smooth Muscle, Pyridines, Pyrroles, Quinazolines, Rats, Reactive Oxygen Species, Renal Insufficiency, Chronic, Serpin E2, Signal Transduction, Smad2 Protein, Smad3 Protein, Toluene, Transforming Growth Factor beta1, Tumor Suppressor Protein p53, Tyrphostins
Show Abstract · Added April 19, 2016
While transforming growth factor-β (TGF-β1)-induced SMAD2/3 signaling is a critical event in the progression of chronic kidney disease, the role of non-SMAD mechanisms in the orchestration of fibrotic gene changes remains largely unexplored. TGF-β1/SMAD3 pathway activation in renal fibrosis (induced by ureteral ligation) correlated with epidermal growth factor receptor(Y845) (EGFR(Y845)) and p53(Ser15) phosphorylation and induction of disease causative target genes plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) prompting an investigation of the mechanistic involvement of EGFR and tumor suppressor p53 in profibrotic signaling. TGF-β1, PAI-1, CTGF, p53 and EGFR were co-expressed in the obstructed kidney localizing predominantly to the tubular and interstitial compartments. Indeed, TGF-β1 activated EGFR and p53 as well as SMAD2/3. Genetic deficiency of either EGFR or p53 or functional blockade with AG1478 or Pifithrin-α, respectively, effectively inhibited PAI-1and CTGF induction and morphological transformation of renal fibroblasts as did SMAD3 knockdown or pretreatment with the SMAD3 inhibitor SIS3. Reactive oxygen species (ROS)-dependent mechanisms initiated by TGF-β1 were critical for EGFR(Y845) and p53(Ser15) phosphorylation and target gene expression. The p22(Phox) subunit of NADPH oxidase was also elevated in the fibrotic kidney with an expression pattern similar to p53 and EGFR. EGF stimulation alone initiated, albeit delayed, c-terminal SMAD3 phosphorylation (that required the TGF-β1 receptor) and rapid ERK2 activation both of which are necessary for PAI-1 and CTGF induction in renal fibroblasts. These data highlight the extensive cross-talk among SMAD2/3, EGFR and p53 pathways essential for expression of TGF-β1-induced fibrotic target genes.
© 2013.
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26 MeSH Terms
Transforming growth factor β induces expression of connective tissue growth factor in hepatic progenitor cells through Smad independent signaling.
Ding ZY, Jin GN, Liang HF, Wang W, Chen WX, Datta PK, Zhang MZ, Zhang B, Chen XP
(2013) Cell Signal 25: 1981-92
MeSH Terms: Connective Tissue Growth Factor, DNA-Binding Proteins, Gene Expression Regulation, Hepatocytes, Humans, Liver, Liver Cirrhosis, MAP Kinase Signaling System, Signal Transduction, Smad2 Protein, Smad3 Protein, Stem Cells, Transforming Growth Factor beta
Show Abstract · Added February 26, 2014
Hepatic progenitor cells (HPCs) are activated in the chronic liver injury and are found to participate in the progression of liver fibrosis, while the precise role of HPCs in liver fibrosis remains largely elusive. In this study, by immunostaining of human liver sections, we confirmed that HPCs were activated in the cirrhotic liver and secreted transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF), both of which were important inducers of liver fibrosis. Besides, we used HPC cell lines LE/6 and WB-F344 as in vitro models and found that TGF-β induced secretion of CTGF in HPCs. Moreover, TGF-β signaling was intracrine activated and contributed to autonomous secretion of CTGF in HPCs. Furthermore, we found that TGF-β induced expression of CTGF was not mediated by TGF-β activated Smad signaling but mediated by TGF-β activated Erk, JNK and p38 MAPK signaling. Taken together, our results provide evidence for the role of HPCs in liver fibrosis and suggest that the production of CTGF by TGF-β activated MAPK signaling in HPCs may be a therapeutic target of liver fibrosis.
Copyright © 2013 Elsevier Inc. All rights reserved.
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13 MeSH Terms
TGF-β signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities.
Samarakoon R, Overstreet JM, Higgins PJ
(2013) Cell Signal 25: 264-8
MeSH Terms: ErbB Receptors, Fibrosis, Humans, NADPH Oxidases, Oxidation-Reduction, Plasminogen Activator Inhibitor 1, Reactive Oxygen Species, Signal Transduction, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta, Tumor Suppressor Protein p53
Show Abstract · Added April 19, 2016
During development of TGF-β1-initiated fibroproliferative disorders, NADPH oxidases (NOX family members) generate reactive oxygen species (ROS) resulting in downstream transcription of a subset genes encoding matrix structural elements and profibrotic factors. Prominent among the repertoire of disease-implicated genes is the TGF-β1 target gene encoding the potent profibrotic matricellular protein plasminogen activator inhibitor-1 (PAI-1 or SERPINE1). PAI-1 is the major physiologic inhibitor of the plasmin-based pericellular cascade and a causative factor in the development of vascular thrombotic and fibroproliferative disorders. ROS generation in response to TGF-β1 stimulation is rapid and precedes PAI-1 induction; engagement of non-SMAD (e.g., EGFR, Src kinase, MAP kinases, p53) and SMAD2/3 pathways are both required for PAI-1 expression and are ROS-dependent. Recent findings suggest a novel role for p53 in TGF-β1-induced PAI-1 transcription that involves ROS generation and p53/SMAD interactions. Targeting ROS and ROS-activated cellular events is likely to have therapeutic implications in the management of fibrotic disorders, particularly in the context of prolonged TGF-β1 signaling.
Copyright © 2012 Elsevier Inc. All rights reserved.
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12 MeSH Terms
5-HT(2B) antagonism arrests non-canonical TGF-β1-induced valvular myofibroblast differentiation.
Hutcheson JD, Ryzhova LM, Setola V, Merryman WD
(2012) J Mol Cell Cardiol 53: 707-14
MeSH Terms: Actins, Animals, Aortic Diseases, Aortic Valve, Calcinosis, Cell Differentiation, Cells, Cultured, Gene Expression, Indoles, Microfilament Proteins, Muscle Proteins, Myofibroblasts, Phosphorylation, Plasminogen Activator Inhibitor 1, Promoter Regions, Genetic, Protein Processing, Post-Translational, Protein Transport, Pyridines, Receptor, Serotonin, 5-HT2B, Serotonin 5-HT2 Receptor Antagonists, Signal Transduction, Smad3 Protein, Sus scrofa, Transcriptional Activation, Transforming Growth Factor beta1, Urea, p38 Mitogen-Activated Protein Kinases, src-Family Kinases
Show Abstract · Added February 12, 2015
Transforming growth factor-β1 (TGF-β1) induces myofibroblast activation of quiescent aortic valve interstitial cells (AVICs), a differentiation process implicated in calcific aortic valve disease (CAVD). The ubiquity of TGF-β1 signaling makes it difficult to target in a tissue specific manner; however, the serotonin 2B receptor (5-HT(2B)) is highly localized to cardiopulmonary tissues and agonism of this receptor displays pro-fibrotic effects in a TGF-β1-dependent manner. Therefore, we hypothesized that antagonism of 5-HT(2B) opposes TGF-β1-induced pathologic differentiation of AVICs and may offer a druggable target to prevent CAVD. To test this hypothesis, we assessed the interaction of 5-HT(2B) antagonism with canonical and non-canonical TGF-β1 pathways to inhibit TGF-β1-induced activation of isolated porcine AVICs in vitro. Here we show that AVIC activation and subsequent calcific nodule formation is completely mitigated by 5-HT(2B) antagonism. Interestingly, 5-HT(2B) antagonism does not inhibit canonical TGF-β1 signaling as identified by Smad3 phosphorylation and activation of a partial plasminogen activator inhibitor-1 promoter (PAI-1, a transcriptional target of Smad3), but prevents non-canonical p38 MAPK phosphorylation. It was initially suspected that 5-HT(2B) antagonism prevents Src tyrosine kinase phosphorylation; however, we found that this is not the case and time-lapse microscopy indicates that 5-HT(2B) antagonism prevents non-canonical TGF-β1 signaling by physically arresting Src tyrosine kinase. This study demonstrates the necessity of non-canonical TGF-β1 signaling in leading to pathologic AVIC differentiation. Moreover, we believe that the results of this study suggest 5-HT(2B) antagonism as a novel therapeutic approach for CAVD that merits further investigation.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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28 MeSH Terms