Smad3 is key to TGF-β-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis

Roberts, Anita B.; Tian, Fei; Byfield, Stacey DaCosta; Stuelten, Christina H.; Ooshima, Akira; Saika, Shizuya; Flanders, Kathleen C.

doi:10.1016/j.cytogfr.2005.09.008

Cited by 321 publications

(257 citation statements)

References 67 publications

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“…Several studies in different cell types have already aimed at distinguishing between the specific roles of Smad2 and Smad3, which share biochemical properties, in TGFβ signaling. The majority of these data were obtained from the assessment of transcriptional responses in Smad2 and Smad3 knockout cells, including fibroblasts, hepatocytes, as well as epithelial cells from lens and renal tubules (19)(20)(21)(22)(23)(24). Both of these latter types of epithelial cell also undergo EMT in response to TGFβ, which has been proposed to contribute to fibrosis in the kidney or in the lens after injury.…”

Section: Discussionmentioning

confidence: 99%

Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells

Dzwonek

Preobrazhenska

Cazzola

et al. 2009

Molecular Cancer Research

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Smad2 and Smad3 are intracellular mediators of transforming growth factor β (TGFβ) signaling that share various biochemical properties, but data emerging from functional analyses in several cell types indicate that these two Smad proteins may convey distinct cellular responses. Therefore, we have investigated the individual roles of Smad2 and Smad3 in mediating the cytostatic and proapoptotic effects of TGFβ as well as their function in epithelial-to-mesenchymal transition. For this purpose, we transiently depleted mouse mammary epithelial cells (Nme) of Smad2 and/or Smad3 mainly by a strategy relying on RNaseH-induced degradation of mRNA. The effect of such depletion on hallmark events of TGFβ-driven epithelial-to-mesenchymal transition was analyzed, including dissolution of epithelial junctions, formation of stress fibers and focal adhesions, activation of metalloproteinases, and transcriptional regulation of acknowledged target genes. Furthermore, we investigated the effect of Smad2 and Smad3 knockdown on the TGFβ-regulated transcriptome by microarray analysis. Our results identify Smad3 as a key factor to trigger TGFβ-regulated events and ascribe tumor suppressor as well as oncogenic activities to this protein. (Mol Cancer Res 2009;7(8):1342-53)

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Section: Discussionmentioning

confidence: 99%

Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells

Dzwonek

Preobrazhenska

Cazzola

et al. 2009

Molecular Cancer Research

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“…Additionally, FAK activation by TGF-β1 is mediated via a transcription-dependent process that is associated with upregulation of fibronectin and its integrin receptor subunits [12]. Crosstalk between these two pro-survival pathways and the specific role(s) of SMAD3, a key regulator of TGF-β1 pro-fibrotic signalling [24], in the delayed activation of FAK and AKT have not been defined.…”

Section: Tgf-β1-induced Fak But Not Akt Activation Is Dependent On mentioning

confidence: 99%

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Horowitz

Rogers

Sharma

et al. 2007

Cellular Signalling

223

177

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Transforming growth factor-β (TGF-β) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/antiapoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-β1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-β1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-β1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-β1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-β1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these prosurvival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-β1 in tissue fibrosis and tumour-promotion.

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“…This assumption is supported by retrospective studies showing a definite correlation between high amounts of ERa and low PAI-1 expression [35,37]. The pro-invasive capacity of Smad3 is extensively reviewed by Roberts [38], and there is also evidence for a pro-metastatic potential of c-fos, demonstrated in hormone receptor negative breast cancer cells [39]. Both oncogenic proteins were strongly diminished in the presence of ERa.…”

Section: Discussionmentioning

confidence: 94%

Estrogen receptor α attenuates transforming growth factor-β signaling in breast cancer cells independent from agonistic and antagonistic ligands

Stope

Popp²,

Knabbe³

et al. 2009

Breast Cancer Res Treat

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To investigate a presumed crosstalk between estrogen receptor a (ERa) and the TGF-b signaling pathway in breast cancer, we analyzed the TGF-b-induced expression of the plasminogen activator inhibitor 1 (PAI-1) gene in ER-positive MCF-7 cells. After siRNA-mediated knock-down of endogenous ERa, the transcription level of PAI-1 was upregulated, pointing to an attenuation of TGF-b signaling by the presence of ERa. We verified these findings by a vice versa approach using a primary ER-negative cell model transiently overexpressing either ERa or ERb. We found that ERa, but not ERb, led to a strong inhibition of the TGF-b1 signal, monitored by TGF-b reporter assays. This attenuation was completely independent of receptor stimulation by b-estradiol (E2) or inhibition by the pure antagonist ICI 182.780 (ICI). Our results indicate a permanent repression of PAI-1 by ERa and suggest a ligand-independent crosstalk between ERa and TGF-b signaling in breast cancer cells.

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Smad3 is key to TGF-β-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis

Cited by 321 publications

References 67 publications

Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells

Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Estrogen receptor α attenuates transforming growth factor-β signaling in breast cancer cells independent from agonistic and antagonistic ligands

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