IndraLab
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"Our findings demonstrated that miR-203a-3p was down-regulated in asthma serums, and overexpressed miR-203a-3p inhibited TGF-β1-induced EMT in asthma by regulating Smad3 pathway through targeting SIX1, suggesting a promising therapeutic approach for bronchial epithelial cell EMT in asthma."
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"In the current report, we have also demonstrated that Smad2- versus Smad3 specific responses are differentially regulated by km23-1 versus km23-2 in that blockade of endogenous km23-2 expression reduced TGFbeta stimulation of the Smad3 dependent transcriptional reporter SBE2-Luc, while km23-1 knockdown did not."
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"Interestingly, we also observed that different natural core variants isolated from tumor or non tumor nodules could differently bind Smad3, and consequently inhibit TGF-beta induced Smad3 transcriptional activity suggesting that the HCV core protein may modulate TGF-beta signaling and its downstream biological responses XREF_BIBR."
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"However, ectopic Smurf2 in Col2a1-Smurf2 transgenic chondrocytes does not induce the proteasomal degradation of these known targets identified in vitro but induces that of exogenous TGF-β activated phosphorylated Smad3, and decreases associated TGF-β/Smad3 signaling ex vivo [ xref ]."
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"Accordingly, activation of Smad3 by TGF-β prevents mitogenesis in CD8 + T cells by (i) inhibiting their production of IL-2; (ii) repressing their expression of c-Myc, cyclin D2, and cyclin E; and (iii) stimulating the expression of the CDKIs p15, p21, and p27 [ xref , xref , xref ]."
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"One of the major pro fibrotic cytokines is TGF-beta acting via (1) the canonical pathway to activate transcription factors Smad2 and Smad3, which, in complex with Smad4, act to induce the transcription of pro fibrotic molecules or (2) the non canonical, Smad independent pathways activating mitogen activated protein kinases, c-Jun terminal kinase, p38, and extracellular-signal regulated kinase to increase the transcription of other pro fibrotic cytokines as well as collagens and fibronectin."
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"Based on the experiment results that the serum IFN-γ was increased, and TGF-β was decreased as well as SMAD-7 expression was increased in tumor tissues from the immunized mice, we presumed that IFN-γ may specifically inhibit an early step in the TGF-β-induced activation of SMAD-3 through a receptor serine kinase that phosphorylates and activates the transcription factors SMAD-2 and SMAD-3."
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"Silencing or overexpression of LXRα had no effect on p-Smad3 or PAI-1 activation by TGF-β ( xref ,D), neither did we observe effects of the LXR agonist (T0191317) on the activity of a Smad-specific promoter-luciferase reporter (CAGA 12 -luc) ( xref ), nor did silencing of endogenous LXRα affect the activity of the CAGA 12 -luc reporter (unpublished results)."
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"Binding of TGFbeta to its receptor activates specific SMAD family members, and TGFbeta activated phosphor-SMAD3 directly binds to the Il9 locus, the Notch intracellular domain (NICD), and RBP-Jk (recombination signal binding protein for immunoglobulin kappa J region) [XREF_BIBR, XREF_BIBR]."
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"36 This duality of function of TGF-β in tumorigenesis was also further observed in another study, where a TGFbRI-independent SMAD3 activation by TGF-β resulted in a shift of TGF-β activity from tumor-suppressor to fibrogenic in HCV-chronically infected patients; in these patients, TGF-β activated c-JNK, which in turn phosphorylated SMAD3 into linker-phosphorylated SMAD3 (pSMAD3L) and led to extracellular matrix (ECM) deposition via upmodulating plasminogen activator inhibitor 1 (PAI-1), a process, which increased during liver disease course from chronic hepatitis through cirrhosis to HCC."
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"This study also reported that hydrogen sulfide (H2S) was required for Treg cell differentiation and function by promoting the expression of Tet1 and Tet2, which were recruited to the Foxp3 locus by TGFbeta activated Smad3 and IL2 activated Stat5 to maintain Foxp3 CNS2 demethylation and Treg-cell-associated immune homeostasis."
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"As shown in XREF_FIG E, when the linker region phosphorylation was compromised by S208A mutation introduced to Smad3, the inhibition of TGF-beta signal by NLK was impaired, leading to a higher level of transcriptional activation by TGF-beta compared with the wild-type Smad3 as control."
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"Ligation of TGF-beta to its cell surface receptor complex TbetaRII and TbetaRI initiates a signal transduction path-way by activating the proteins Smad2 and Smad3 (R-Smads), which in conjunction with the co-activator Smad4 (also known as DPC4 deleted in pancreatic carcinoma 4) co-operate with other transcription factors for the transcription of target genes."
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"However, the depletion of RBX1 or beta-TrCP, the components of the E3 ubiquitin ligase complex which is responsible for the ubiquitination of TGFbeta activated Smad3, could not lead to an accumulation of Smad3 in MDA-MB-231 cells whether TGFbeta stimulation or not, maybe other E3 ubiquitin ligase participate in this process."
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"Recent studies showed that one mechanism of inhibition of TGFβ-induced myofibroblast transformation and collagen synthesis is by increased competition for CBP/P300 with Smad signaling [ xref ]. xref showed that pSmad3 is activated by TGFβ within 4 h, and α-SM actin expression is significantly increased."
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"How TTK downregulates KLF5 remains unknown, but could be related to TGF-beta signaling, as TGF-beta downregulates KLF5 28 and TTK inhibition reduced the activation of SMAD3 by TGF-beta, potentially impacting the assembly of the transcriptional complex for KLF5 or altering the cellular localization and function of KLF5."
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"Smad3 is also phosphorylated at several sites in a linker region that bridges its highly conserved MH1 and MH2 domains; our recent data showed that phosphorylation at one of the linker sites, T179, allows TGF-β-activated Smad3 to interact with a RNA binding protein, poly(RC) binding protein 1 (PCBP1, also known as hnRNP E1), in the nucleus ( xref )."
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"Furthermore, TGF-beta blockade by means of either a neutralizing pan-TGF-beta antibody XREF_BIBR, SMAD7 overexpression XREF_BIBR, or treatment of cells with a TbetaRI small molecule inhibitor XREF_BIBR, inhibited basal SMAD3 and SMAD4 dependent transcriptional activity in melanoma cells."
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"As Smad3-deficiency had no effect on ILC2 development (Supplementary Fig. 5), we determined that TGF-β1 treatment induced a similar (or even stronger) increase in Il1rl1 mRNA level in Smad3 CHILP and ILC2p cells compared to their littermate WT control (Fig. 5a), suggesting a Smad3-independent pathway in ST2 upregulation.We then investigated non-canonical downstream of TGF-β signaling pathways involved in the induction of ST2 in ILC2 progenitors."
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"The experiments showed that TGF-β-induced Smad3 activation led to an increase in VISTA expression in various cell types including resting CD4-positive Jurkat T cells, primary human AML blasts derived from myeloid cell precursors, primary human embryonic cells, Wilms tumor cells, chronic AML cells and HaCaT keratinocytes."
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"In contrast, induction of protein inhibitor of activated Stat3 (PIAS3), a factor induced by Stat3 activation, significantly increased TGFbeta mediated Smad3 activation suggesting that TGFbeta-Smad signaling could be a negative feedback loop to inhibit Stat3 mediated proliferative signals."
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"Although many of the mutations in these genes are predicted to cause loss of function, there is evidence of increased TGFbeta signaling in the cells in the diseased aortic tissues of the patients with syndromic TAAD, including those with mutations in either FBN1, TGFBR1, TGFBR2, or SMAD3 [XREF_BIBR; XREF_BIBR; XREF_BIBR]."
sparser
"Different ligands can bind to TGF-β receptors on the cell surface, allowing regulatory messages to be transferred into the cell by activating the signaling effectors and the Sma- and Mad-related proteins (Smads) and ultimately interacting with deoxyribonucleic acid.[ xref ] Both Smad2 and Smad3 are activated by TGF-β, myostatin, or activin whereas Smad1, Smad5, and Smad8 are activated by bone morphogenetic proteins; the activation of these proteins results in the interaction with Smad4, leading to the modulation of target gene expression."
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"In glioblastoma brain tumor cells, SMAD3 is activated by transforming growth factor-beta (TGF beta) and that forms a complex with FOXO3a to induce the expression of growth inhibitory gene such as p21 Cip1, while FOXG1 binds to FOXO3a and SMAD3 complex and blocks p21 Cip1 expression [XREF_BIBR]."
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"Generally, upon binding the TGF-β-type receptor type I and type II, the TGF-β-receptor complex phosphorylates and activates SMAD2 or SMAD3 and forms complexes with SMAD4, then translocates into the nucleus, mediates various gene expressions and affects a range of biological functions in the tumor microenvironment."
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"Individual analyses of the three predicted SBEs by ChIP assays (Fig. 3c) revealed that TGFβ strongly induced binding of SMAD3 to two SBE at residues 279-282 and at residues 384-387 (referred to SBE1 and SBE2, respectively) of MYST1 promoter sequence, but had only minor effects on the predicted binding site at residues 574-577 (referred to as SBE3) (Fig. 3c)."
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"Speaking of the antagonism of the two cytokines in their respective pathways, the increase of TNF-α can lead to the activation of AKT, and activated AKT can interact with Smad3, which leads to the inhibition of TGF-β pathway in regulatory T cells, so TNF-α can weaken the differentiation and function of Treg cells induced by TGF-β in autoimmune diseases through AKT and Smad3 signaling pathways (66)."
sparser
"Mechanistically, H 2 S sulfhydrates nuclear transcription factor Y subunit beta (NFYB) to facilitate its binding to the Tet1 and Tet2 promoters; Tet1 and Tet2 are then recruited to bind to Foxp3 by TGF-β-activated Smad3 and IL-2-activated Stat5 ( xref ; xref ), thus maintaining Foxp3 CNS2 demethylation and playing an important role in Treg cell-associated immune homeostasis ( xref )."
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"Upon ligand binding by TGF-beta1, type II TGF-beta receptors (TbetaRII) activate type I TGF-beta receptors (TbetaRI), recruiting and activating the intracellular mediators Smad2 and Smad3, which subsequently complex with Smad4 before translocating to the nucleus where the complex regulate gene transcription [XREF_BIBR]."
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"Induction of Smad3 and/or Smad4 transcription factors by the interaction of TGF-beta and receptors also leads to release of tissue factors (TFs) involved in the transcription of Cdc25A cyclin proteins as well as p15INK4 that in turn transcribe CDK4 and CDK6 cyclins responsible for the stimulation of Rb and E2F transcription factors."
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"This leads to the expression of a high quantity of a protein that is responsible for fibrosis, such as actin and type I collagen.39 Furthermore, linagliptin inhibited the endothelial-to-mesenchymal transition induced by transforming growth factor β2 (TGF-β2) in animal models, a transcription factor that plays an essential role in the process of fibrosis in cultivated human dermic microvascular endothelial cells, reducing the phosphorylation of TGF-β2–induced Smad3."
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"Transforming growth factor-beta (TGF-beta) activates not only TGF-beta type I receptor (Tbeta RI) but also c-Jun N-terminal kinase (JNK), converting the mediator Smad3 to two distinct phosphoisoforms : C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L)."
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"In contrast to the physiological role of TGF-beta that regulates cell growth and differentiation, the authors find that circulating, pathological levels of TGF-beta activate a SMAD3 signaling pathway in both proximal and distal skeletal muscles that leads to the oxidation and nitrosylation of the ryanodine receptor 5 (RyR1)."
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"We previously reported that in cancer cells, heightened mitogenic signaling allows TGF-β-activated Smad3 to interact with poly(RC) binding protein 1 (PCBP1) and together they regulate many alternative splicing events that favors expression of protein isoforms essential for EMT, cytoskeletal rearrangement, and adherens junction signaling."
eidos
"Transcription factor Smad3 is a key protein molecule downstream of TGF-beta signaling , Smad3 plays a key role in regulating TGF-beta to induce EMT and Smad3 transduces the signal from the cytoplasm to the nucleus after binding TGF-beta to its receptor [ 5 ] , nuclear localization of Smad3 would be a good indication of the activation of the TGF-beta pathway in tumor cells ."
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"Transfection of an activated Ras with a mutation enabling the activation of the PI3-kinase pathway alone mimicked the EGF and TGF-beta potentiation of Smad3 transactivation, and TAM-67 abolished this effect, suggesting that the PI3-kinase pathway stimulates Smad3 via AP-1 stimulation."
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"The disappearance of antifibrogenic BMP-7 in the early stages of renal disease has been associated with the progression of renal fibrosis [ xref ], and antifibrotic BMP-7 activates smad5 to inhibit smad6, which induces the translocation of TGF-β-activated smad3 to the nucleus [ xref ]."
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"More than that, restoration experiment proved that the effect on EMT induced by miR-203a-3p up-regulation could be rescued by SIX1 overexpression.As reported, Smad3 was an important regulator of TGF-β1 signaling pathway [34] and could be activated by TGF-β1 to regulate various cellular functions [35]."
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"To gain further insights into how serine and tyrosine deficient mutants affect TGF-beta/Alk5/Smad3 pathway downstream of Smad3, we have performed RT-PCR to determine mRNA levels of the two target genes of Smad3, namely PAI-1 and Col-1 in control and treated with TGF-beta (1 ng/ml; 48 h) pBABE, WT-Cav-2, S23/36A-Cav-2, and Y19/27F-Cav -2 MLECs."
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"How TTK downregulates KLF5 remains unknown, but could be related to TGF-β signaling, as TGF-β downregulates KLF5 xref and TTK inhibition reduced the activation of SMAD3 by TGF-β (Fig. xref ), potentially impacting the assembly of the transcriptional complex for KLF5 or altering the cellular localization and function of KLF5."
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"In addition, high levels of pSmad3 in the non lens ectoderm may depend on a Wnt2b mediated feed-forward loop : canonical Wnt signalling not only stabilizes beta-catenin but also Smad3 through inhibition of GSK3beta XREF_BIBR XREF_BIBR XREF_BIBR, suggesting that sustained TGF-beta signalling is required to activate Smad3."
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"One molecular mechanism that could contribute to the anti-tumor effects of 1,25D 3 was revealed in a study showing an inhibition of TGF-β-induced epithelial-to-mesenchymal transition (EMT) and fibrosis mediated by an interaction between ligand-bound VDR and the TGF-β-activated transcription factor Smad3 ( xref )."
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"[XREF_BIBR] Both Smad2 and Smad3 are activated by TGF-beta, myostatin, or activin whereas Smad1, Smad5, and Smad8 are activated by bone morphogenetic proteins; the activation of these proteins results in the interaction with Smad4, leading to the modulation of target gene expression."
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"Our preliminary data have shown that SIS3, a specific inhibitor of Smad3 phosphorylation, blocked TGFbeta induced activation of Smad3, but had no effect on the TGFbeta-GM-CSF-ERK pathway, as TGFbeta still significantly inhibited GM-CSF-induced phosphorylation of ERK in the presence of SIS3 (unpublished data)."
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"The EOB phenotype was observed in mice lacking the type I BMP receptor genes, Acvr1 and Bmpr1a, the R-Smad genes, Smad 1 and Smad5, and the Co-Smad gene, Smad 4, but not in mice lacking the type II TGFbeta receptor gene Tgfbr2 and the activin and TGFbeta activated R-Smad genes, Smad2 and Smad3."
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"Also, phosphorylation of Smad3 mediated by CDK2 and CDK4 inhibits its transcriptional activity (Liu, xref ; Buxton and Duan, xref ), and Smad3-PIAS ( protein inhibitor of activated STAT ) interaction suppresses Smad3 activation by TGFβ and favors its SUMOilation (Imoto et al., xref )."
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"Internalization of TGFbeta receptors via clathrin coated pits into the early endosome promotes TGFbeta and Smad3 signaling while lipid-raft and caveolar internalization promotes Smad7-Smurf dependent receptor degradation, thus inhibiting the canonical TGFbeta signaling [XREF_BIBR]."
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"Given our new findings, we propose that transcription factors Smad3 (CNS1), Stat5 (CNS2) and c-Rel (CNS3) function as initiators for Foxp3 induction by opening up the three regulatory regions, each CNS being initiated by distinct signaling processes (Smad3 activated by TGF-beta signaling in CNS1, Stat5 activated by Il-2rgamma, TCR and TGF-beta signaling in CNS2 and c-Rel activated by TCR signaling in CNS3)."
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"Consistent with these data, reduced TGF-beta signaling in Smad3 +/- mice or DNTbetaRII mice also relieves the suppression of osteoblast differentiation by TGF-beta, which is exerted by Smad3 and histone deacetylases XREF_BIBR XREF_BIBR, thereby contributing to increased BMD XREF_BIBR XREF_BIBR."
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"Moreover, our data presented here cannot distinguish whether Smad3 was solely activated by TGFβ in vivo, given that angiotensin II could also activate the Smad pathway independently of TGFβ in rat aortic arteries. xref In addition, conditional Smad3 knockout specifically in SMCs will benefit further delineation of Smad3‐directed regulations in vivo."
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"Therefore, TGFβ1 stimulation for 1 day was selected in the downstream study of HLF-1 cells.Western blot analysis revealed that SDC-1 downregulation by SDC-1 siRNA strongly inhibited the levels of TGFβ1-induced p-Smad3 and collagen I in HLF-1 cells compared with those in the TGFβ1-treated group (
Figures 6F-H, O-Q
)."
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"A direct cross talk between the Notch and TGF-beta signaling pathways comes from a recent study in which a direct interaction between Notch intracellular domain and Smad-3 was demonstrated, and activation of Smad-3 by TGF-beta led to an enhancement of Notch induced Hes1 gene transcription."
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"After activation, the TGFbeta receptor (comprised of two transmembrane serine/threonine kinases - TbetaRI and TbetaRII) phosphorylates and activates Smad2 and Smad3 proteins which complex with co-Smad (Smad4), translocate to the nucleus and transcribe genes whose products regulate scarring (reviewed by (Finnson et al., 2013)."
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"As expected, TGF-β activated Smad-mediated transcriptional regulatory genes Smad6 , Smad7 , Gadd45b , Smad3 and Serpine1 were upregulated (> 2-fold) in non-glandular colonies whereas Smad6 , Serpine1 and Tgfbi genes were downregulated (> 2-fold) in glandular colonies confirming IPA analysis (Figure xref )."
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"Our experiments show that in macrophages all three TGF-beta isoforms rapidly activate Smad3, but have minimal effects on activation of non Smad pathways (XREF_FIG), suggesting that the effects of TGF-betas on macrophages may be predominantly mediated through Smad dependent signaling."
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"Because several studies by Sorrentino et al and Yamashita et al have shown that TGF-beta activates JNK by mediating Smad independent signaling [XREF_BIBR, XREF_BIBR] and our previous study showed that MUC1 expression induces TGF-beta1 secretion (data not shown) in HCC cells, we sought to investigate whether MUC1 induced TGF-beta secretion could activate JNK and mediate Smad3 signaling."
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"We show that TGF-beta and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35 positive nuclear speckles, and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E."
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"This kinase phosphorylates the TGFβ-activated Smad3 (pSmad3) in such a way as to prevent the translocation of pSmad3/Smad4 heterodimers to the nucleus. xref Once phosphorylated by PKG-1a, Smad3 has a high affinity for cytosolic beta2-tubulin, resulting in its sequestration in the cytoplasm. xref Other research suggests that PKG activity may interfere with TGFβ signalling by promoting the proteasomal degradation of Smad3. xref Not surprisingly, agents with boost cellular levels of cGMP have also been shown to oppose tissue fibrosis and TGFβ activity. xref "
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"While we have previously described that loss of TGF-β/Smad3 signaling in Col2a1-Smurf2 transgenic chondrocytes might represent a mechanism of Smurf2-induced OA in Col2a1-Smurf2 transgeni c mice, Smurf2 mainly induces ubiquitination of phosphorylated Smad3 activated by exogenous TGF-β in chondrocytes, and only slightly affects the basal level of phosphorylated Smad3 in resting chondrocytes [ xref ], indicating that Smurf2-mediated loss of TGF-β/Smad3 signaling in chondrocytes may not be a dominant mechanism underlying Smurf2-induced OA in Col2a1-Smurf2 transgenic mice."
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"Moreover, atRA equivalently suppresses Th17 cell differentiation induced by IL-6 and TGF-beta between WT and Smad3 KO mice, further indicating a redundant role of SMAD3 in Th17 cell differentiation and implicating that other TGF-beta downstream signaling pathways may be required for Th17 cell development."
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"Thus, by preventing Smad3 activation by TGF-β, c-Abl expression and activity favor the induction of MET and senescence programs via Smad1/5/8- and Smad2-dependent transcriptional programs (Figure xref .) Future studies need to assess whether the pro-BMP activities of c-Abl transpire through alterations in either the production of BMP ligands ( i.e. , increased) or antagonists ( i.e. , decreased), as well as determine the extent which c-Abl orchestrates TβRI-mediated activation of Smad1/5/8 in TNBCs."
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"For example, signal transducer and activator of transcription 6 (STAT6), which is activated by IL-4, probably binds Region I located upstream of the promoter, and IL-4-activated STAT6 and TGF-β-activated SMAD3 and SMAD4 bind Region IV located 9 Kb upstream of the promoter xref ."
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"Prolonged TGF-β treatment did not change the basal amount of Smad3 activation following starvation and did not impair the TGF-β-induced Smad3 activation ( xref ) nor the TGF-β-induced expression of transcript encoding PAI1 and Smad7 ( xref ), suggesting that the prolonged exposure to TGF-β did not render the cells refractory to TGF-β signaling."
eidos
"Transforming growth factor-beta has been indicated to activate downstream Smad2 and Smad3 to promote the formation of their complex and their phosphorylation.29 Moreover , SB431542 , a TGF-beta1 inhibitor , diminished cell invasion in MM cells , which was mediated via the TGF-beta1 / Smad2 / matrix metallopeptidase 3 signaling pathway ."
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"A direct cross talk between the Notch and TGF-β signaling pathways comes from a recent study in which a direct interaction between Notch intracellular domain and Smad-3 was demonstrated, and activation of Smad-3 by TGF-β led to an enhancement of Notch-induced Hes1 gene transcription ( xref )."
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"The membrane-anchored cytoplasmic SARA or structurally and functionally related Hgs/Hrs proteins facilitate and stabilize the association of activated Smad2 and Smad3 with type I receptors, and thus promote TGF-β-induced Smad2 and Smad3 activation ( xref , xref , xref , xref , xref – xref )."
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"The current study is limited in this regard with respect to understanding the cell specific effects of a loss of Smad3 throughout the regenerative response though it is clear that TGFbeta mediated Smad3 activation provides both pro proliferative and potentially inhibitor signals during liver regeneration."
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"Although further study will be needed to investigate the regulation of TGF-b 1 on the interaction of LFA-1 on PBMCs and ICAM-1 on RTECs, the up-regulation of TGF-b 1 concentrations of the co-culture media of HK-2 cells and PBMCs also suggested In the EMT of RTECs, smad2 and smad3 were mainly mediated by TGF-b 1 [33] ."
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"36 This duality of function of TGF-β in tumorigenesis was also further observed in another study, where a TGFbRI-independent SMAD3 activation by TGF-β resulted in a shift of TGF-β activity from tumor-suppressor to fibrogenic in HCV-chronically infected patients; in these patients, TGF-β activated c-JNK, which in turn phosphorylated SMAD3 into linker-phosphorylated SMAD3 (pSMAD3L) and led to extracellular matrix (ECM) deposition via upmodulating plasminogen activator inhibitor 1 (PAI-1), a process, which increased during liver disease course from chronic hepatitis through cirrhosis to HCC."