Induction of a mesenchymal expression program in lung epithelial cells by wingless protein (Wnt)/?-catenin requires the presence of c-Jun N-terminal kinase-1 (JNK1).

ABSTRACT: Recent studies suggest the importance of the transition of airway epithelial cells (EMT) in pulmonary fibrosis, and also indicate a role for Wingless protein (Wnt)/?-catenin signaling in idiopathic pulmonary fibrosis. We investigated the possible role of the Wnt signaling pathway in inducing EMT in lung epithelial cells, and sought to unravel the role of c-Jun-N-terminal-kinase-1 (JNK1). The exposure of C10 lung epithelial cells or primary mouse tracheal epithelial cells (MTECs) to Wnt3a resulted in increases in JNK phosphorylation and nuclear ?-catenin content. Because the role of ?-catenin as a transcriptional coactivator is well established, we investigated T-cell factor/lymphocyte-enhancement factor (TCF/LEF) transcriptional activity in C10 lung epithelial cells after the activation of Wnt. TCF/LEF transcriptional activity was enhanced after the activation of Wnt, and this increase in TCF/LEF transcriptional activity was diminished after the small interfering (si)RNA-mediated ablation of JNK. The activation of the Wnt pathway by Wnt3a, or the expression of either wild-type or constitutively active ?-catenin (S37A), led to the activation of an EMT transcriptome, manifested by the increased mRNA expression of CArG box-binding factor-A, fibroblast-specific protein (FSP)-1, ?-smooth muscle actin (?-SMA), and vimentin, increases in the content of ?-SMA and FSP1, and the concomitant loss of zona occludens-1. The siRNA-mediated ablation of ?-catenin substantially decreased Wnt3a-induced EMT. The siRNA ablation of JNK1 largely abolished Wnt3a, ?-catenin, and ?-catenin S37a-induced EMT. In MTECs lacking Jnk1, Wnt3a-induced increases in nuclear ?-catenin, EMT transcriptome, and the content of ?-SMA or FSP1 were substantially diminished. These data show that the activation of the Wnt signaling pathway is capable of inducing an EMT program in lung epithelial cells through ?-catenin, and that this process is controlled by JNK1.

SUBMITTER: van der Velden JL 

PROVIDER: S-EPMC3488690 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature