TGF-β and the Smad Signaling Pathway Support Transcriptomic Reprogramming during Epithelial-Mesenchymal Cell Transition

Valcourt, Ulrich; Kowanetz, Marcin; Niimi, Hideki; Heldin, Carl‐Henrik; Moustakas, Aristidis

doi:10.1091/mbc.e04-08-0658

Cited by 536 publications

(504 citation statements)

References 56 publications

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“…19 GSEA revealed a significant overlap between the Fra-1-derived gene sets and the genes upregulated in EpRas cells upon TGF-β-induced EMT 21 (Table 1a). Genes associated with c-Myb 29 or with promoters occupied by Smad2/3, 30 two TFs connected to TGF-β and EMT, 31,32 were also enriched (Table 1b) Figure S6a, Figures 5a and b). Slug, encoded by snai2, was also increased (Figures 5a and b), whereas mRNA of snai1/Snail was moderately elevated and the protein undetectable (Figure 5a and data not shown).…”

Section: Resultsmentioning

confidence: 99%

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models. Epithelial-to-mesenchymal transition (EMT) is a complex biological programme that occurs in physiological processes during embryonic development and wound healing as well as in pathological conditions, such as organ fibrosis and carcinogenesis. During EMT, cells lose epithelial features and acquire mesenchymal characteristics. The acquisition of a mesenchymal state by malignant cancer cells is associated with decreased cell-cell adhesion, and increased migratory and invasive properties, which are crucial for metastasis. [1][2][3][4][5] The adherens junction (AJ) protein E-cadherin, encoded by cdh1, is a central determinant of the epithelial state and its downregulation is the hallmark of EMT. A number of molecular pathways converging on E-cadherin have been implicated in EMT. Transcription factors (TF) of the Snail, Zeb and Twist families, initially identified as regulators of epithelialmesenchymal plasticity during morphogenesis were shown to orchestrate EMT by...

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Section: Resultsmentioning

confidence: 99%

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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“…Smad3-dependent reduction of the cell adhesion protein Ecadherin in human proximal tubular cells (hPTC) is paralleled by a Smad2-dependent induction of metallomatrix proteinase 2 [52]. Microarray analysis of TGF-β1-induced EMT in mouse and human epithelial cells demonstrates a critical requirement for Smad signalling in the regulation of all tested target genes [52] and an acute need for stringent control of Smad signalling in order to protect the cells from unwanted responses to TGF-β. Indeed, a safeguard mechanism exists in the form of inhibitory Smads and transcriptional co-repressors [53].…”

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confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

170

187

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Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signaling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signaling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.

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“…Here we propose Id2 as one of the culprit genes. Several upstream regulators of Id2 have been suggested including Smad4, nmyc, cyclin D1, and D2, BMP, TGFb, GATA4 (Valcourt et al, 2005;Song et al, 2007;Lim et al, 2008;Nakahiro et al, 2010), and finally Tbx5 and Nkx2.5 (Moskowitz et al, 2007). The Smad-Id2 pathway appears to be particularly relevant in the etiology of the observed congenital malformations as Smad7 mutant mice have a cardiovascular phenotype that includes ventricular septal defects, ventricular noncompaction, and outflow tract malformations (Chen et al, 2009) and myocardial specific inactivation of Smad4 causes myocardial hypoplasia (Song et al, 2007).…”

Section: Arterial Pole Abnormalitiesmentioning

confidence: 99%

Expression of Id2 in the second heart field and cardiac defects in Id2 knock‐out mice

Jongbloed

Vicente‐Steijn

Douglas

et al. 2011

Developmental Dynamics

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The inhibitor of differentiation Id2 is expressed in mesoderm of the second heart field, which contributes myocardial and mesenchymal cells to the primary heart tube. The role of Id2 in cardiac development is insufficiently known. Heart development was studied in sequential developmental stages in Id2 wildtype and knockout mouse embryos. Expression patterns of Id2, MLC-2a, Nkx2.5, HCN4, and WT-1 were analyzed. Id2 is expressed in myocardial progenitor cells at the inflow and outflow tract, in the endocardial and epicardial lineage, and in neural crest cells. Id2 knockout embryos show severe cardiac defects including abnormal orientation of systemic and pulmonary drainage, abnormal myocardialization of systemic and pulmonary veins, hypoplasia of the sinoatrial node, large interatrial communications, ventricular septal defects, double outlet right ventricle, and myocardial hypoplasia. Our results indicate a role for Id2 in the second heart field contribution at both the arterial and the venous poles of the heart.

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TGF-β and the Smad Signaling Pathway Support Transcriptomic Reprogramming during Epithelial-Mesenchymal Cell Transition

Cited by 536 publications

References 56 publications

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Expression of Id2 in the second heart field and cardiac defects in Id2 knock‐out mice

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