IndraLab
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"TGF-beta1 binds to TGF-beta type I receptor, a transmembrane protein with Ser/Thr kinase domain, and then phosphorylates Smad2 and Smad3, which regulates the expression of downstream target genes and subsequently contributes to promoting EMT and metastasis of many cancer cells [XREF_BIBR]."
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"However, as with the inhibitor SB431542, ADSCs significantly inhibited cell proliferation and migration and the expression of extracellular matrix proteins (collagen-I, collagen-III, FN and alpha-SMA), but also suppressed the protein expression of transforming growth factor beta1 (TGF-beta1), phosphorylated (p-) mothers against decapentaplegic homolog (Smad) 2, p-Smad3 and Smad7 in HSFs and KFs."
sparser
"Among its three isoforms, namely TGF-β1, 2 and 3, all types of renal cells total can produced TGF-β1 [ xref ] and acts as a pro-fibrotic regulator in several ways: i) Fibrotic proteins such as FN and collagen I can be induced by TGF-β1independently; and ii) TGF-β1 can induced the phosphorylation of Smad2 and Smad3, and then formed the oligomeric complexes includingSmad2, Smad3 and Smad4 [ xref ]."
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"TGF-beta1 induced the phosphorylation of Smad3 and p130Cas as well as epithelial-mesenchymal transition (EMT) accompanied by the downregulation of the expression of E-cadherin, a marker of epithelial cells, and the upregulation of the expression of N-cadherin, or Snail, a marker of mesenchymal cells, in human HSC-2 cells and mouse SCCVII cells."
sparser
"In agreement with this possibility are experiments in PANC-1 cells, in which direct silencing of Smad2 via siRNA transfection did not only augment TGF-β1-induced Smad3 phosphorylation [ xref ], p21 WAF1 expression and growth inhibition (Additional file xref Figure S1 and Ref. [ xref ]), but also potentiated TGF-β1-induction of Smad3-regulated genes such as MMP2 and BGN (see Figure xref )."
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"Further mechanistic studies showed that in myoblasts, IGF-1 treatment could inhibit TGFbeta1 stimulated Smad3 phosphorylation and increase phosphorylated-AKT- (P-AKT-) Smad3 interactions, thus impeding nuclear translocation of Smad3 and thereby reducing the expression of fibrotic genes."
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"SSc fibroblasts showed normal Smad3 phosphorylation (pSmad3) in response to stimulation with TGFbeta1 that was not influenced by integrin modulating therapies, but uniquely showed TGFbeta1 dependent phosphorylation of ERK1/2 (pERK1/2), when compared to control fibroblasts, that was normalized upon treatment with either beta1aAb or beta3bAb (XREF_SUPPLEMENTARY)."
reach
"Similarly, TGF-beta1 signaling through its type 1 receptor activin receptor like kinase 5 (ALK5) leads to phosphorylation of SMAD3, inducing transcription of SMAD3-target genes such as COL2 and ACAN [XREF_BIBR], while signaling through ALK1 leads to phosphorylation of SMAD1/5/8 and transcription of catabolic genes such as COLX and MMP13 [XREF_BIBR]."
trips
"Furthermore, CTRP6 had no effect on TGF-β1-induced Smad3 phosphorylation and nuclear translocation, whereas significantly decreased TGF-β1-induced RhoA activation and myocardin-related transcription factor-A (MRTF-A) nuclear translocation, and these effects were blocked by AMPK or Akt inhibition."
trips
"Evaluation of JNK1-deficient lung epithelial cells demonstrated that TGF-β1-induced terminal phosphorylation of Smad3 was similar, whereas phosphorylation of mitogen-activated protein kinase sites in the linker regions of Smad3 was diminished, in JNK1-deficient cells compared with wild-type cells."
sparser
"Similarly, pretreatment with the PPARγ agonists rosiglitazone (1.0 μmol/l) and pioglitazone (10 μmol/l) for 24 h completely blocked TGF-β1-induced CTGF and periostin mRNA expression (Supplementary Figure 2a and b,) and inhibited TGF-β1-induced Smad3 phosphorylation (Supplementary Figure 2c and d,)."
sparser
"TGF-β1 significantly phosphorylated Smad3, +/- high D-glucose from 15 min onwards; **P<0.01. (M–O) Image of Western blots immunostained for cellular phospho-serine 204 of Smad3 LR protein in PTECs under various treatments and time points. (P–R) Data points for cellular phospho-serine 204 of Smad3 LR protein (∼25 kDa) abundance normalised for total protein."
sparser
"In contrast to an Activin receptor-like kinase 5 (Alk5) inhibitor, C8 and GSK3008348 failed to inhibit TGF-β1 induced SMAD3 and SMAD2 phosphorylation, but inhibited TGF-β-induced phosphorylation of ERK1/2 and STAT3, suggesting that αVβ1 integrin is involved in non-canonical TGF-β signaling pathways."
sparser
"However, co-treatment with TSA completely prevented TGF-beta1-induced morphologic changes and significantly prevented TGF-beta1-induced downregulation of E-cadherin and upregulation of collagen type I. Treatment with TSA did not alter TGF-beta1-induced phosphorylation of Smad2 and Smad3 but induced several inhibitory factors of TGF-beta1 signals, such as inhibitors of DNA binding/differentiation 2 (Id2) and BMP-7."
sparser
"Moreover, we also investigated the potential anti-fibrotic properties of ML290 by evaluating its ability to promote markers such as matrix metalloproteinase (MMP)-2 and inhibit the pro-fibrotic actions of TGF-β1-induced Smad-2 and Smad-3 phosphorylation in primary human cardiac fibroblasts, representing key fibrosis-producing cells."
sparser
"siRNA mediated suppression of Nrf2 in H6c7-pBp, H6c7-kras and Colo357 cells, as demonstrated by detection of reduced levels of endogenous total-Nrf2 (see Fig. xref ), enhanced basal as well as TGF-β1 induced phosphorylation of p38 and Smad3 along with an elevated expression of p21."
sparser
"Furthermore, we [ xref ] and others [ xref , xref ] demonstrated that STAT3 signaling is involved in the development of TILs in UUO mice, in association with NF-κB-mediated inflammatory responses [ xref , xref ], and TGF-β1-dependent phosphorylation of Smad3 that promotes STAT3 activation in injured kidneys [ xref , xref ]."
| PMC
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"In particular, when miR-155 silences C/EBPbeta in the cancer cells, autocrine production of TGFbeta1 or downstream phosphorylation of Smad3 is not perturbed, confirming that the in vivo effects are due to a switch in TGFbeta response, and not due to ineffective TGFbeta signalling."
reach
"Among its three isoforms, namely TGF-beta1, 2 and 3, all types of renal cells total can produced TGF-beta1 [XREF_BIBR] and acts as a pro fibrotic regulator in several ways : i) Fibrotic proteins such as FN and collagen I can be induced by TGF-beta1independently; and ii) TGF-beta1 can induced the phosphorylation of Smad2 and Smad3, and then formed the oligomeric complexes includingSmad2, Smad3 and Smad4 [XREF_BIBR]."
reach
"Exposure of Met 5A cells to TSP-1 increased TGF-beta1 secretion, expression and bioactivity, triggered Smad3 phosphorylation, upregulated the expression of mesenchymal molecules including fibronectin, collagen type III, alpha-smooth muscle actin, Snail, and decreased calretinin expression."
sparser
"In human lung fibroblasts or bronchial smooth muscle cells, we demonstrated that an increase in the intracellular glutathione level suppressed TGF-beta1-induced phosphorylation of Smad3, while inhibiting TGF-beta1-induced expressions of CTGF, collagen type1, fibronectin and transformation into myofibroblasts, which are characterized by the expression of alpha-smooth muscle actin."
trips
"In human lung fibroblasts or bronchial smooth muscle cells, we demonstrated that an increase in the intracellular glutathione level suppressed TGF-beta1-induced phosphorylation of Smad3, while inhibiting TGF-beta1-induced expressions of CTGF, collagen type1, fibronectin and transformation into myofibroblasts, which are characterized by the expression of alpha-smooth muscle actin."
sparser
"Once activated, TGF-β1 binds to its receptor and stimulates phosphorylation of the transcription factor Smad3, which in turn forms a complex with Smad4 and co-translocates into the nucleus to induce expression of target genes, including the differentiation marker proteins α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and the main ECM component, collagen 1A1 (COL1A1) [ xref , xref ]."
sparser
"In SKOV3 cells, TGF-β1 alone induced phosphorylation of SMAD2 and SMAD3, denoting the activation of these two R-SMADs; co-treatment with OFE reduced the levels of p-SMAD2 (4 μg/mL, P = 0.002 vs. control group; 20 μg/mL, P = 0.001 vs. control group) and p-SMAD3 (4 μg/mL, P = 0.035 vs. control group; 20 μg/mL, P = 0.004 vs. control group), whereas the total expression of SMAD2/3 remained unchanged (Fig. xref )."
sparser
"The TGF-β1 neutralizing antibody, as expected, completely blocked TGF-β1-stimulated SMAD3 phosphorylation as well as fibronectin induction and repression of E-cadherin expression in CMV-Con cultures even at the lowest dose tested (20 μg/mL) ( xref ), confirming functionality of the antibody."
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"The next day, 23 nL of test compound or positive control, a TGFbeta1 receptor (ALK5) inhibitor, SB525334 (CASRN : 356559-20-1, Sigma-Aldrich), was added into assay plates, followed by addition of 1 mul of 1.5 ng/mL human TGFbeta1 (R&D Systems, Minneapolis, MN) to stimulate SMAD3 phosphorylation."
sparser
"Furthermore, CTRP6 had no effect on TGF-β1-induced Smad3 phosphorylation and nuclear translocation, whereas significantly decreased TGF-β1-induced RhoA activation and myocardin-related transcription factor-A (MRTF-A) nuclear translocation, and these effects were blocked by AMPK or Akt inhibition."
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"A remarkable finding is that the inhibitory effect of kaempferol on increased Smad3 linker phosphorylation by TGF-beta1 treatment was specifically limited to Thr179 residue, but not to other linker sites, and it was sufficient to reverse TGF-beta1-induced EMT and migration in A549 cells by expression of Smad3 T179V alone."
sparser
"BMP2 can, in turn, down-regulate TGFβ effects in the same cells via attenuating the expression of the ligand itself and its own receptors, thus resulting in a reduction in TGFβ1 dependent SMAD3 phosphorylation, as well as the expression of αSMA, fibronectin, and more generally, EMT markers [ xref ]."
sparser
"The expression of pSmad3C and p21 was markedly up-regulated by TGF-β stimulation and/or IL-37b overexpression; however, the expression of pSmad3C and the up-regulation of p21 was dramatically abolished in the presence of SIS3 which selectively inhibits TGF-β1-dependent Smad3 phosphorylation (Figure xref )."
sparser
"The activated type I receptors then propagate the signal by phosphorylating a family of transcription factors, called receptor-activated Smads ( R-Smads ). xref , xref BMP receptors activate Smad1, Smad5 and Smad8, whereas Smad2 and Smad3 are phosphorylated by the activin and the TGF-[BETA]β receptors."
sparser
"Given that ROS plays an important role in the activation of the TGF-β/Smad signaling pathway, we compared the effects of 100 μM of bergenin and 5 mM of NAC on the phosphorylation of Smad3, and the results showed that both can reduce the increase in Smad3 phosphorylation caused by TGF-β1 ( xref D,E)."
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"As expected, the addition of TGF-beta1 to the culture induced the rapid phosphorylation of Smad3 in neurosphere cultures from young adult mice, and this phosphorylation was specifically blocked by the anti-TGF-beta blocking antibody or SB-505124, which is a selective inhibitor of TbetaRI (Alk5) (XREF_FIG)."
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"On the other hand, we found that TGFbeta1 treatment caused a facilitation of Smad3 phosphorylation and translocation to the nucleus induced by status epilepticus (SE) in wild-type (Smad3 (+/+)) mice, and this treatment also caused a promotion of gamma-aminobutyric acid-ergic synaptogenesis impaired by SE in Smad3 (+/+) as well as in Smad3 (-/-) mice, but more dramatic promotion in Smad3 (+/+) mice."
sparser
"SB431542 inhibited TGFβ1-induced SMAD3 phosphorylation and abrogated the small basal expression of pSMAD3 seen in control cultures without exogenous TGFβ, indicating autocrine activity ( xref ), as the growth medium supplements contained minimal TGFβ activity and did not account for the baseline activity ( xref )."
sparser
"In the TGF-β signaling pathway, TGF-β1 receptor kinases phosphorylate Smad2 and Smad3 in the C-terminal residue, which further forms a complex with Smad4 and promotes nuclear translocation of the complex to regulate downstream gene expression, resulting in stimulation of EMT [ xref – xref ]."
sparser
"Our data showing that fortilin inhibits TGF-β1-induced Smad3 phosphorylation (Fig. xref ) suggest that fortilin inhibits the recruitment of TGFβRI to TGFβRII by preventing TGF-β1 from ligating TGFβRII but not by preventing the formed TGF-β1-TGFβRII complex from recruiting TGFβR1, as the TGF-β1-TGFβRII interaction is stronger than the TGF-β1-fortilin interaction (1.49 nM xref versus 94.5–210.5 nM, Fig. xref )."
sparser
"TGF-β1 induced the phosphorylation of Smad3 and p130Cas as well as epithelial-mesenchymal transition (EMT) accompanied by the downregulation of the expression of E-cadherin, a marker of epithelial cells, and the upregulation of the expression of N-cadherin, or Snail, a marker of mesenchymal cells, in human HSC-2 cells and mouse SCCVII cells."
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"Mechanism study revealed that the phosphorylation of Smad3 linker region induced by TGF-beta1 was required for the induction of EMT and cell migration, and selective downregulation of the phosphorylation of Smad3 at Thr179 residue (not Ser204, Ser208, and Ser213) in the linker region was responsible for the inhibition by kaempferol of TGF-beta1-induced EMT and cell migration."
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"In cultured HK-2 cells, TGF-beta1 dramatically up-regulated TbetaRI expression and phosphorylated levels of Smad 2 and Smad 3, but down-regulated Smad7 expression, consistent with the data in vivo, and confirmed the characteristics of TGF-beta and Smads signaling in EMT [XREF_BIBR]."
sparser
"Jang et al showed that inhibiting the TGF-β type I receptor, activin receptor-like kinase 5 (ALK5) using the synthetic inhibitor IN-1130 suppresses the subsequent TGF-β1-induced phosphorylation of Smad2 and Smad3 and nuclear accumulation of Smad proteins in human fibroblasts of PD-plaque."
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"In SKOV3 cells, TGF-beta1 alone induced phosphorylation of SMAD2 and SMAD3, denoting the activation of these two R-SMADs; co-treatment with OFE reduced the levels of p-SMAD2 (4mug/mL, P = 0.002 vs. control group; 20mug/mL, P = 0.001 vs. control group) and p-SMAD3 (4mug/mL, P = 0.035 vs. control group; 20mug/mL, P = 0.004 vs. control group), whereas the total expression of SMAD2/3 remained unchanged."
sparser
"It acts as a competitive ATP-binding site kinase inhibitor and has been shown to inhibit the in vitro phosphorylation of Smad3 and Smad2, but has no effect on Smad-independent pathways such as ERK, JNK, or p38 MAPK. xref SIS3 (specific inhibitor of Smad3) is a cell-permeable pyrrolopyridine compound that selectively inhibits TGFβ1-dependent Smad3 phosphorylation and Smad3-mediated cellular signaling with no effect on Smad2, p38 MAPK, ERK, or PI3K signaling. xref Smad3 is a receptor-activated molecule that, once phosphorylated by a member of the TGFβ receptor I family, i.e., ALK 4, 5, or 7, combines with Smad4 and the R-Smad/Smad4 complex then undergoes nuclear translocation and stimulates gene expression."
sparser
"Antisense treatment for Smad7 is sufficient for restoring TGF-β1-induced Smad3 phosphorylation in the biopsy specimens, which is followed by reduced expression of the Th1 subset markers IFN-γ and T-bet. xref These data suggest that the downregulation of TGF-β1 signaling by H. pylori infection promotes the ongoing tissue-damaging Th1 response."
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"Interaction of TGF-beta1 with its receptors induces Smad3 phosphorylation; phosphorylated Smad3 together with Smad4 is then translocated to the nucleus where it transcriptionally drives expression of numerous profibotic genes, including collagen 1 and connective tissue growth factor (CTGF)."
sparser
"Peroxisome proliferator-activated receptor gamma activated by rosiglitazone inhibits the transforming growth factor-beta1 -induced phosphorylation of Smad3 and the increased connective tissue growth factor expression as well as inhibits the secretion of type I collagen in biliary fibroblasts."
sparser
"TGF-β1-induced early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release, whereas Src-mediated chronic EGFR transactivation and ERK1/2 activation participate in Smad3 activation in a relatively modest and delayed manner."
sparser
"In contrast, soybean oil based lipid emulsions did not inhibited EMT, and surprisingly increased myofibroblast markers such as vimentin, αSMA and col type I. The molecular approach revealed that Omegaven® is able to inhibit the increase of TGFβ1-induced Smad3, ERK1/2 and Akt phosphorylation as part of the EMT process previously described in other systems xref ."
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"In their studies, blockage of TGF-beta1 signaling using SB431542 significantly reduced Smad3 phosphorylation and expression.We suspected that the expressed level of P-Smad 2/3 would be also reduced in SB treated group, in which SB431542 played a role until 3 days in the rat arterial injury model, but after 7 days to 14 days, the expression of P-Smad2/3 was increased after injecting with SB431542."
rlimsp
"Moreover, TGF-β1 expression and phosphorylation of TGF-β downstream signal Smad3 was stimulated by co-culture of macrophages with cardiac fibroblasts, while IL-6 neutralizing antibody decreased TGF-β1 expression and Smad3 phosphorylation in co-culture of macrophage and fibroblast."