JNK mediates TGF‐β1‐induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes

Santibáñez, Juan F.

doi:10.1016/j.febslet.2006.09.003

Cited by 89 publications

(77 citation statements)

References 34 publications

(37 reference statements)

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“…A crucial role for ERK, p38 and JNK MAPK signaling pathways in the genesis of EMT has been widely demonstrated; however, their effects appear to be cell-type specific (Grotegut et al, 2006;Santibanez, 2006;Bhowmick et al, 2001). Our results underline the importance of ERK signaling in the onset of mesothelial EMT in response to stimulation with TGF-β1 plus IL-1β.…”

Section: Research Articlesupporting

confidence: 55%

Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway

Strippoli¹,

Benedicto²,

Pérez-Lozano³

et al. 2008

Disease Models &Amp; Mechanisms

101

110

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SUMMARYEpithelial-to-mesenchymal transition (EMT) occurs in fibrotic diseases affecting the kidney, liver and lung, and in the peritoneum of patients undergoing peritoneal dialysis. EMT in the peritoneum is linked to peritoneal membrane dysfunction, and its establishment limits the effectiveness of peritoneal dialysis. The molecular regulation of EMT in the peritoneum is thus of interest from basic and clinical perspectives. Treatment of primary human mesothelial cells (MCs) with effluent from patients undergoing peritoneal dialysis induced a genuine EMT, characterized by downregulated E-cadherin and cytokeratin expression, cell scattering, and spindle-like morphology. This EMT was replicated by co-stimulation with transforming growth factor (TGF)-β1 and interleukin (IL)-1β. Retroviral overexpression of a mutant inhibitor of kappaB (IκB) demonstrated that NF-κB activation is required for E-cadherin and cytokeratin downregulation during EMT. Pre-treatment with the MAP kinase kinase (MEK)-1/2 inhibitor U0126 showed that cytokinetriggered NF-κB nuclear translocation and transcriptional activity are mediated by activation of extracellular regulated kinase (ERK). Cytokine-mediated induction of mRNA expression of the transcription factor Snail1, a repressor of E-cadherin expression and a potent inducer of EMT, was prevented by blockade of ERK or NF-κB. Finally, blockade of ERK/NF-κB signaling in ex vivo MCs that were cultured from peritoneal dialysis effluents reverted cells to an epithelioid morphology, upregulated E-cadherin and cytokeratin expression, and downregulated Snail1 expression. Modulation of the ERK/NF-κB/Snail1 pathway may provide a means of counteracting the progressive structural and functional deterioration of the peritoneal membrane during peritoneal dialysis.

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Section: Research Articlesupporting

confidence: 55%

Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway

Strippoli¹,

Benedicto²,

Pérez-Lozano³

et al. 2008

Disease Models &Amp; Mechanisms

101

110

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“…Interactions between TGF-␤ and p38 MAPK appear to occur in a limited cell type-dependent fashion (mammary epithelial cells and colon cancer cells) in vitro (113), where it appears to confirm a migratory phenotype. TGF-␤ activation of JNK has also recently been implicated in EMT in transformed keratinocytes, although a previous study did not find evidence for JNK activation (15,87). There is limited evidence for involvement of PI3K in a Rho-dependent fashion leading to cytoskeletal changes but not full EMT in TGF-␤-treated NMuMG mammary epithelial cells (6) and for induction of EMT in lens epithelial cells in a Snail-dependent fashion (14), whereas PI3K is not required for Ras-mediated EMT (32).…”

Section: Tgf-␤ and Emtmentioning

confidence: 85%

TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease

Willis¹,

Borok²

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

906

764

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Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to fibrosis following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor (TGF)-β induces EMT in alveolar epithelial cells (AEC) in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II (AT2) cells in lung tissue from patients with idiopathic pulmonary fibrosis (IPF), suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to fibrosis in adult tissues following injury, focusing especially on the critical role of TGF-β and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of fibrotic lung disease. Treatment for fibrosis of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.

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“…In addition, an inhibitor of JNK or antisense RNA constructs blocked TGF-β1-induced mesenchymal gene expression in a keratinocyte cell line (Santibanez, 2006). Furthermore, a recent study demonstrated that degradation of caveolin-1 plays a crucial role in lung fibrosis, and, importantly, that the loss of caveolin-1 was crucial in the activation of JNK in response to TGF-β1 in lung fibroblasts .…”

Section: Discussionmentioning

confidence: 99%

Jun N-terminal kinase 1 regulates epithelial-to-mesenchymal transition induced by TGF-β1

Alcorn

Guala

Velden

et al. 2008

Journal of Cell Science

115

110

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Transforming growth factor β1 (TGF-β1) is a cardinal cytokine in the pathogenesis of airway remodeling, and promotes epithelial-to-mesenchymal transition (EMT). As a molecular interaction between TGF-β1 and Jun N-terminal kinase (JNK) has been demonstrated, the goal of this study was to elucidate whether JNK plays a role in TGF-β1-induced EMT. Primary cultures of mouse tracheal epithelial cells (MTEC) from wild-type, JNK1–/– or JNK2–/– mice were comparatively evaluated for their ability to undergo EMT in response to TGF-β1. Wild-type MTEC exposed to TGF-β1 demonstrated a prominent induction of mesenchymal mediators and a loss of epithelial markers, in conjunction with a loss of trans-epithelial resistance (TER). Significantly, TGF-β1-mediated EMT was markedly blunted in epithelial cells lacking JNK1, while JNK2–/– MTEC underwent EMT in response to TGF-β1 in a similar way to wild-type cells. Although Smad2/3 phosphorylation and nuclear localization of Smad4 were similar in JNK1–/– MTEC in response to TGF-β1, Smad DNA-binding activity was diminished. Gene expression profiling demonstrated a global suppression of TGF-β1-modulated genes, including regulators of EMT in JNK1–/– MTEC, in comparison with wild-type cells. In aggregate, these results illuminate the novel role of airway epithelial-dependent JNK1 activation in EMT.

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JNK mediates TGF‐β1‐induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes

Cited by 89 publications

References 34 publications

Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway

Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway

TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease

Jun N-terminal kinase 1 regulates epithelial-to-mesenchymal transition induced by TGF-β1

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