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

Alcorn, John F.; Guala, Amy S.; Velden, Jos van der; McElhinney, Brian; Irvin, Charles G.; Davis, Roger J.; Janssen–Heininger, Yvonne M. W.

doi:10.1242/jcs.019455

Cited by 115 publications

(123 citation statements)

References 56 publications

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“…To determine whether JNK1 is required for mucus metaplasia, WT or JNK12/2 mice were sensitized and challenged with antigen and mucus levels were assessed by PAS staining. Antigen induced PAS positivity to a comparable extent in WT and JNK12/2 mice ( Figures 4A and 4B), indicating that JNK1 is not essential for airway epithelial mucus production, consistent with our previous observations (25).…”

Section: Antigen-induced Mucus Metaplasia Does Not Require Jnk1supporting

confidence: 91%

“…Previous work from this laboratory has shown that JNK1 is required for TGF-b1-induced profibrotic gene expression and EMT in primary airway epithelial cells (25). To directly test whether JNK1 is required for TGF-b1-induced profibrotic signaling in vivo, we evaluated the extent of profibrotic gene expression in WT and JNK12/2 mice after TGF-b1 instillation.…”

Section: Jnk1 Is Required For Expression Of Profibrotic Genes Inducedmentioning

confidence: 99%

“…A broader role for JNK in fibrosis is suggested by observations demonstrating that patients with IPF showed elevated phosphorylation of JNK in the airway epithelium and pulmonary endothelium (23,24). Finally, a recent study from our laboratory demonstrated that JNK1 plays a causal role in TGF-b1-induced epithelial to mesenchymal transition (EMT) and profibrotic gene expression, while JNK2 appears to play a minor role (25).…”

mentioning

confidence: 94%

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c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

Alcorn¹,

Velden²,

Brown³

et al. 2009

Am J Respir Cell Mol Biol

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Collagen deposition is observed in a diverse set of pulmonary diseases, and the unraveling of the molecular signaling pathways that facilitate collagen deposition represents an ongoing area of investigation. The stress-activated protein kinase, c-Jun N-terminal kinase 1 (JNK1), is activated by a large variety of cellular stresses and environmental insults. Recent work from our laboratory demonstrated the critical role of JNK1 in epithelial to mesenchymal transition. The goal of the present study was to examine the involvement of JNK1 in subepithelial collagen deposition in mice subjected to models of allergic airways disease and interstitial pulmonary fibrosis. Activation of JNK was slightly enhanced in lungs from mice subjected to sensitization and challenge with ovalbumin (Ova), and predominant localization of phospho-JNK was observed in the bronchial epithelium. While mice lacking JNK1 (JNK12/2 mice) displayed enhanced lung inflammation and cytokine production compared with wild-type (WT) mice, JNK12/2 mice accumulated less subepithelial collagen deposition in response to antigen, and showed decreased expression of profibrotic genes compared with WT animals. Furthermore, transforming growth factor (TGF)-b1 content in the bronchoalveolar lavage was diminished in JNK12/2 mice compared with WT animals subjected to antigen. Finally, we demonstrated that mice lacking JNK1 were protected against TGF-b1 and bleomycin-induced pro-fibrotic gene expression and pulmonary fibrosis. Collectively, these findings demonstrate an important requirement for JNK1 in promoting collagen deposition in multiple models of fibrosis.

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Section: Antigen-induced Mucus Metaplasia Does Not Require Jnk1supporting

confidence: 91%

Section: Jnk1 Is Required For Expression Of Profibrotic Genes Inducedmentioning

confidence: 99%

mentioning

confidence: 94%

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c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

Alcorn¹,

Velden²,

Brown³

et al. 2009

Am J Respir Cell Mol Biol

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“…There is compelling evidence that ERKs drive EMT in many experimental systems (Zavadil and Bottinger, 2005), and our previous work has demonstrated the role of ERKs in E-cadherin downregulation and EMT induction (Strippoli et al, 2008). However, the role of SAPKs is less studied, although some reports indicate that JNK is an EMT inducer, also in MCs (Alcorn et al, 2008;Liu, Q. et al, 2008). p38 appears to promote EMT during development and in tumors (Zavadil and Bottinger, 2005;Zohn et al, 2006;Liu, Y. et al, 2008); however, the role of p38 in EMT during chronic inflammatory disease has not been analyzed.…”

Section: Introductionmentioning

confidence: 98%

p38 maintains E-cadherin expression by modulating TAK1–NF-κB during epithelial-to-mesenchymal transition

Strippoli

Benedicto

Foronda

et al. 2010

Journal of Cell Science

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SummaryEpithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells is a pathological process that occurs during peritoneal dialysis. EMT leads to peritoneal fibrosis, ultrafiltration failure and eventually to the discontinuation of therapy. Signaling pathways involved in mesothelial EMT are thus of great interest, but are mostly unknown. We used primary mesothelial cells from human omentum to analyze the role of the p38 MAPK signaling pathway in the induction of EMT. The use of specific inhibitors, a dominantnegative p38 mutant and lentiviral silencing of p38 demonstrated that p38 promotes E-cadherin expression both in untreated cells and in cells co-stimulated with the EMT-inducing stimuli transforming growth factor (TGF)-1 and interleukin (IL)-1. p38 inhibition also led to disorganization and downregulation of cytokeratin filaments and zonula occludens (ZO)-1, whereas expression of vimentin was increased. Analysis of transcription factors that repress E-cadherin expression showed that p38 blockade inhibited expression of Snail1 while increasing expression of Twist. Nuclear translocation and transcriptional activity of p65 NF-B, an important inducer of EMT, was increased by p38 inhibition. Moreover, p38 inhibition increased the phosphorylation of TGF--activated kinase 1 (TAK1), NF-B and IB. The effect of p38 inhibition on E-cadherin expression was rescued by modulating the TAK1-NF-B pathway. Our results demonstrate that p38 maintains E-cadherin expression by suppressing TAK1-NF-B signaling, thus impeding the induction of EMT in human primary mesothelial cells. This represents a novel role of p38 as a brake or 'gatekeeper' of EMT induction by maintaining E-cadherin levels.

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“…16 This same study showed that jnk2 -/-had no effect, illustrating the differential importance/roles of the 2 genes in these cells.…”

Section: Jnks Promote Epithelial-tomesenchymal Transition In Tumor Cellsmentioning

confidence: 88%

c-Jun N-Terminal Kinases Mediate a Wide Range of Targets in the Metastatic Cascade

2013

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Disseminated cancer cells rely on intricate interactions among diverse cell types in the tumor-associated stroma, vasculature, and immune system for survival and growth. Ubiquitous expression of c-Jun N-terminal kinase (jnk) genes in various cell types permits their control of metastasis. In early stages of metastasis, JNKs affect tumor-associated inflammation and angiogenesis as well as tumor cell migration and intravasation. Within the tumor stroma, JNKs are essential for the release of growth factors that promote epithelial-to-mesenchymal transition (EMT) in tumor cells. JNK3, the least ubiquitous isoform, facilitates angiogenesis by increasing endothelial cell migration. Importantly, JNK expression in tumor cells integrates stromal signals to promote tumor cell invasion. However, JNK isoforms differentially regulate migration toward the endothelial barrier. Once tumor cells enter the bloodstream, JNKs increase circulating tumor cell (CTC) survival and homing to tissues. By promoting fibrosis, JNKs improve CTC attachment to the endothelium. Once anchored, JNKs stimulate EMT to facilitate tumor cell extravasation and enhance the secretion of endothelial barrier disrupters. Tumor cells attract barrier-disrupting macrophages by JNK-dependent transcription of macrophage chemoattractant molecules. In the secondary tissue, JNKs are instrumental in the premetastatic niche and stimulate tumor cell proliferation. JNK expression in cancer cells stimulates tissue-remodeling macrophages to improve tumor colonization. However, in T-cells, JNKs alter cytokine production that increases tumor surveillance and inhibits the recruitment of tissue-remodeling macrophages. Therapeutically targeting JNKs for metastatic disease is attractive considering their promotion of metastasis; however, specific JNK tools are needed to determine their definitive actions within the context of the entire metastatic cascade.

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

Cited by 115 publications

References 56 publications

c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

p38 maintains E-cadherin expression by modulating TAK1–NF-κB during epithelial-to-mesenchymal transition

c-Jun N-Terminal Kinases Mediate a Wide Range of Targets in the Metastatic Cascade

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