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First published online 11 March 2008
doi: 10.1242/jcs.019455

Journal of Cell Science 121, 1036-1045 (2008)
Published by The Company of Biologists 2008
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Research Article

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

John F. Alcorn1, Amy S. Guala1, Jos van der Velden1, Brian McElhinney1, Charles G. Irvin2, Roger J. Davis3 and Yvonne M. W. Janssen-Heininger1,*

1 Department of Pathology, University of Vermont, Burlington, VT 05405, USA
2 Department of Medicine, University of Vermont, Burlington, VT 05405, USA
3 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA

* Author for correspondence (e-mail: yvonne.janssen{at}uvm.edu)

Accepted 10 January 2008

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.

Key words: Lung, EMT, TGF-β, JNK, SMAD, Mouse






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