Program in Molecular Medicine
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
Transforming growth factor beta1 (TGF-beta1) is a cardinal cytokine in the pathogenesis of airway remodeling, and promotes epithelial-to-mesenchymal transition (EMT). As a molecular interaction between TGF-beta1 and Jun N-terminal kinase (JNK) has been demonstrated, the goal of this study was to elucidate whether JNK plays a role in TGF-beta1-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-beta1. Wild-type MTEC exposed to TGF-beta1 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-beta1-mediated EMT was markedly blunted in epithelial cells lacking JNK1, while JNK2-/- MTEC underwent EMT in response to TGF-beta1 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-beta1, Smad DNA-binding activity was diminished. Gene expression profiling demonstrated a global suppression of TGF-beta1-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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Citation: J Cell Sci. 2008 Apr 1;121(Pt 7):1036-45. doi: 10.1242/jcs.019455. Epub 2008 Mar 11. Link to article on publisher's sitePublisher PDF posted after 12 months as allowed by the publisher's author rights policy at http://jcs.biologists.org/content/rights-permissions.
Lung, EMT, TGF-β, JNK, SMAD, Mouse
Alcorn, John F.; Guala, Amy S.; van der Velden, Jos; McElhinney, Brian; Irvin, Charles G.; Davis, Roger J.; and Janssen-Heininger, Yvonne M.W., "Jun N-terminal kinase 1 regulates epithelial-to-mesenchymal transition induced by TGF-beta1" (2008). Davis Lab. 67.