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

Laboratorio de Biologia Celular, Instituto de Nutrición y Tecnología de los Alimentos, INTA, Universidad de Chile, Casilla 138, Santiago 11, Chile.
FEBS Letters (Impact Factor: 3.17). 11/2006; 580(22):5385-91. DOI: 10.1016/j.febslet.2006.09.003
Source: PubMed


In this study we analyzed the role of the c-Jun N-terminal kinases (JNK) pathway in the TGF-beta1 stimulation of urokinase-type plasminogen activator (uPA), initial stages of epithelial-mesenchymal transdifferentiation (EMT) and cell migration. TGF-beta1 induces JNK phosphorylation, c-Jun transactivation and AP1 activation. The involvement of JNK was evaluated using dominant negative mutants SEK-1 AL, JNK and cJun, depletion of JNK1,2 proteins by treatment of cells with antisense oligonucleotides, as well as the chemical inhibitor SP600125. Our results demonstrated that the JNK pathway is required in the TGF-beta1 enhancement of uPA, fibronectin, E-cadherin delocalization, actin re-organization and vimentin expression, concomitant with the induction of cell migration. These results allow us to suggest a role of JNK in the TGF-beta1 induction of EMT in relation with the stimulation of malignant properties of mouse transformed keratinocytes.

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Available from: Juan F Santibanez
    • "It is also known that besides Smad-dependent signaling (canonical), TGF-b also induces Smad-independent signaling (non-canonical) via a number of additional cascades including MAP kinases (Hocevar et al, 1999; Yu et al, 2002; Chaudhury & Howe, 2009; Zhang, 2009; Gui et al, 2012). Chemical inhibition of these non-canonical signaling pathways including JNK or perturbation of their components alters EMT, suggesting their important function during epithelial to mesenchymal transition (Santibanez, 2006; Alcorn et al, 2008; Liu et al, 2008; Gui et al, 2012). However, the contribution of JNK pathway to global transcriptional reprogramming underlying cell-fate changes during EMT remains elusive. "
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    ABSTRACT: The epithelial to mesenchymal transition (EMT) is a biological process in which cells lose cell-cell contacts and become motile. EMT is used during development, for example, in triggering neural crest migration, and in cancer metastasis. Despite progress, the dynamics of JNK signaling, its role in genomewide transcriptional reprogramming, and involved downstream effectors during EMT remain largely unknown. Here, we show that JNK is not required for initiation, but progression of phenotypic changes associated with EMT. Such dependency resulted from JNK-driven transcriptional reprogramming of critical EMT genes and involved changes in their chromatin state. Furthermore, we identified eight novel JNK-induced transcription factors that were required for proper EMT. Three of these factors were also highly expressed in invasive cancer cells where they function in gene regulation to maintain mesenchymal identity. These factors were also induced during neuronal development and function in neuronal migration in vivo. These comprehensive findings uncovered a kinetically distinct role for the JNK pathway in defining the transcriptome that underlies mesenchymal identity and revealed novel transcription factors that mediate these responses during development and disease. © 2015 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
    No preview · Article · Jul 2015 · The EMBO Journal
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    • "Such activation of Jnk is required for UV-induced apoptosis in primary murine embryonic fibroblasts and to maintain the mitochondrial apoptosis signaling pathway [37]. Jnk1 and their target transcription factor AP1 (Jun/Fos) have also been previously implicated in EMT [38], [39], [40]. In line with these observations, Jnk1 can phosphorylate paxillin, a focal adhesion adaptor, required for the formation of focal adhesion plaques and for efficient cell migration [41]. "
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    ABSTRACT: We have identified the zinc-finger transcription factor Kruppel-like factor 4 (Klf4) among the transcription factors that are significantly downregulated in their expression during epithelial-mesenchymal transition (EMT) in mammary epithelial cells and in breast cancer cells. Loss and gain of function experiments demonstrate that the down-regulation of Klf4 expression is required for the induction of EMT and for metastasis . In addition, reduced Klf4 expression correlates with shorter disease-free survival of subsets of breast cancer patients. Yet, reduced expression of Klf4 also induces apoptosis in cells undergoing TGFβ-induced EMT. Chromatin immunoprecipitation/deep-sequencing in combination with gene expression profiling reveals direct Klf4 target genes, including E-cadherin (), N-cadherin (), vimentin (), β-catenin (), VEGF-A (), endothelin-1 () and Jnk1 (). Thereby, Klf4 acts as a transcriptional activator of epithelial genes and as a repressor of mesenchymal genes. Specifically, increased expression of Jnk1 () upon down-regulation of its transcriptional repressor Klf4 is required for EMT cell migration and for the induction of apoptosis. The data demonstrate a central role of Klf4 in the maintenance of epithelial cell differentiation and the prevention of EMT and metastasis.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "Then, it could be asked what mediates EMT in the inflamed prostate. Inflammatory cytokines can induce EMT in cancerous and non-cancerous tissues through ERK, MAPK, p38, or NF-kB signaling pathways [43] [44] [45] [46]. In addition, HIF-1α is known to be an EMT inducer, because it induces the expressions of EMTpromoting transcription factors and of extracellular matrix-degrading or -modifying enzymes [12] [47] [48]. "
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    ABSTRACT: Benign prostatic hyperplasia (BPH) commonly occurs in older men with chronic prostatitis. Although BPH is frequently accompanied by inflammation, it is unclear whether inflammation underlies prostate enlargement. Recently, we reported that hypoxia-inducible factor 1α (HIF-1α), which is known to be induced by proinflammatory cytokines, is involved in testosterone-induced prostate hyperplasia. Therefore, we hypothesized that cytokines secreted from infiltrated macrophages under inflammatory conditions stimulate prostate enlargement by up-regulating HIF-1α. In the present study, we injected lipopolysaccharide (LPS) into rat prostates to mimic prostatitis and evaluated prostate hyperplasia 14days later. Epithelial cells of LPS-treated prostates were found to be highly proliferative and HIF-1α levels in prostrate tissues to be elevated. When prostate epithelial cells were incubated in conditioned medium from macrophages activated with LPS, they robustly expressed HIF-1α, and under these conditions IL-1β, IL-6, and TNF-α cytokines were found to mediate HIF-1α induction. In addition, HIF-1α was found to enhance the expression of Twist, which initiates epithelial-mesenchymal transition (EMT). Furthermore, profound EMT features were observed in LPS-treated rat prostates, and the natural HIF-1α inhibitors ascorbate and curcumin were found to attenuate EMT and prostate hyperplasia both in vivo and in vitro. Based on these results, we propose that HIF-1α mediates prostate enlargement under inflammatory conditions, and we suggest that HIF-1α be viewed as a promising target for blocking the transition from prostatitis to BPH.
    Full-text · Article · Sep 2012 · Biochimica et Biophysica Acta
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