Roles of p38 MAPK and JNK in TGF-β1-induced Human Alveolar Epithelial to Mesenchymal Transition

Chen, Haihua; Zhou, Xianlong; Shi, Yulu; Yang, Jiong

doi:10.1016/j.arcmed.2013.01.004

Cited by 66 publications

(49 citation statements)

References 26 publications

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“…Notably, TGF-β can directly activate JNK through TRAF6 binding to TGF-β receptors (Sorrentino et al, 2008; Yamashita et al, 2008), and TRAF6 KD blocked EMT in mouse mammary cell lines (Yamashita et al, 2008). Moreover, in human A549 lung cancer cell lines, EMT following radiation (Jung et al, 2007) or TGF-β1 stimulation is JNK dependent (Chen et al, 2013). Lastly, JNK is essential for the cooperative metastasis of scrib/Ras V12 tumors in Drosophila (Igaki et al, 2006).…”

Section: A Force For Evil: Cell Extrusion In Diseasementioning

confidence: 99%

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

2018

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Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Here, we delineate the diverse functions of cell extrusion during development and disease. We emphasize the expanding role for apoptotic cell extrusion in exerting morphogenetic forces, as well as the strong intersection of cell extrusion with cell competition, a homeostatic mechanism that eliminates aberrant or unfit cells. While cell competition and extrusion can exert potent, tumor-suppressive effects, dysregulation of either critical homeostatic program can fuel cancer progression.

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Section: A Force For Evil: Cell Extrusion In Diseasementioning

confidence: 99%

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

2018

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“…Previous studies have shown that TGF-b1/Smad signaling and HMGB1 take part in the process of EMT (He et al, 2007;Chen et al, 2013Chen et al, , 2014. However, is HMGB1 involved in the activation of TGF-b1/Smad signaling in the EMT process?…”

Section: Resultsmentioning

confidence: 96%

“…Among the reported inducers, transforming growth factorb1 (TGF-b1) is a main mediator of EMT and is the key cytokine in abnormal tissue remodeling, particularly in PF (Willis et al, 2005;Chen et al, 2013). TGF-b latency binding protein 1, which facilitates the release and activation of the biologically latent form TGF-b1, is detected primarily in alveolar macrophages and epithelial cells lining honeycomb cysts in areas of advanced PF (Khalil et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling

et al. 2015

J Pharmacol Exp Ther

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Epithelial-to-mesenchymal transition (EMT) is a crucial event in the cellular origin of myofibroblasts that secrete extracellular matrix in the progression of pulmonary fibrosis (PF). Highmobility group box 1 (HMGB1) is a novel mediator of EMT. However, whether this process involves the recognized transforming growth factor-b1 (TGF-b1)/Smad signaling that also contributes to EMT in PF has not yet been elucidated. Here, we developed a model of PF induced by bleomycin (BLM) in rats and conducted several simulation experiments in A549 (human) and RLE-6TN (rat) alveolar epithelial cell (AEC) lines to unravel the role of TGF-b1/Smad2/3 signaling in HMGB1-mediated EMT. We found that the levels of serum HMGB1 and lung hydroxyproline were severely elevated after BLM administration. Moreover, the protein expression of HMGB1, TGF-b1, phosphorylated Smad2/3 (p-Smad2/3), and mesenchymal markers including a-smooth muscle actin, vimentin, and type I collagen were significantly increased with the reduced protein expression of an epithelial marker (E-cadherin) in the rat model by Western blot or immunohistochemical analysis. In addition, the uptake of both exogenous TGF-b1 and HMGB1 by AECs could induce EMT; meanwhile, HMGB1 dramatically enhanced TGF-b1 expression and triggered Smad2/3 phosphorylation. In contrast, TGF-b1 deficiency evidently ameliorated HMGB1-mediated EMT with reduced p-Smad2/3 in A549 cells. It provides new insights that HMGB1 release from injured lungs promotes AEC damage through induction of the EMT process, in which TGF-b1/Smad2/3 signaling is activated and contributes to PF. These results suggest that HMGB1 may constitute a therapeutic target for developing antifibrotic agents for abnormal lung remodeling.

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“…Martin-Martin et al (2011) reported that cyclosporine A-induced increased TGF-β1 may not be sufficient to trigger the Smad pathway but may trigger the ERK1/2 signaling pathway. Other authors reported that TGF-β1 induced A549 alveolar epithelial cells to undergo epithelial-mesenchymal transition partially via p38 MAPK and JNK activation in lung epithelial cells [31]. There is evidence that the activation of the ERK 1/2 signaling is linked to the TGF-β1 induced modulation of tight junction permeability and wound closure [32], [33].…”

Section: Discussionmentioning

confidence: 97%

Developmental Changes of TGF-β1 and Smads Signaling Pathway in Intestinal Adaption of Weaned Pigs

et al. 2014

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Weaning stress caused marked changes in intestinal structure and function. Transforming growth factor-β1 (TGF-β1) and canonical Smads signaling pathway are suspected to play an important regulatory role in post-weaning adaptation of the small intestine. In the present study, the intestinal morphology and permeability, developmental expressions of tight junction proteins and TGF-β1 in the intestine of piglets during the 2 weeks after weaning were assessed. The expressions of TGF-β receptor I/II (TβRI, TβRII), smad2/3, smad4 and smad7 were determined to investigate whether canonical smads signaling pathways were involved in early weaning adaption process. The results showed that a shorter villus and deeper crypt were observed on d 3 and d 7 postweaning and intestinal morphology recovered to preweaning values on d 14 postweaning. Early weaning increased (P<0.05) plasma level of diamine oxidase (DAO) and decreased DAO activities (P<0.05) in intestinal mucosa on d 3 and d 7 post-weaning. Compared with the pre-weaning stage (d 0), tight junction proteins level of occludin and claudin-1 were reduced (P<0.05) on d 3, 7 and 14 post-weaning, and ZO-1 protein was reduced (P<0.05) on d 3 and d 7 post-weaning. An increase (P<0.05) of TGF-β1 in intestinal mucosa was observed on d 3 and d 7 and then level down on d 14 post-weaning. Although there was an increase (P<0.05) of TβR II protein expression in the intestinal mucosa on d3 and d 7, no significant increase of mRNA of TβRI, TβRII, smad2/3, smad4 and smad7 was observed during postweaning. The results indicated that TGF-β1 was associated with the restoration of intestinal morphology and barrier function following weaning stress. The increased intestinal endogenous TGF-β1 didn't activate the canonical Smads signaling pathway.

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Roles of p38 MAPK and JNK in TGF-β1-induced Human Alveolar Epithelial to Mesenchymal Transition

Cited by 66 publications

References 26 publications

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling

Developmental Changes of TGF-β1 and Smads Signaling Pathway in Intestinal Adaption of Weaned Pigs

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