JNK mediates TGF-beta1-induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes.

In this study we analyzed the role of the c-Jun N-terminal kinases (JNK) pathway in the TGF-beta1 stimulation of urokinase-type plasminogen activator (uPA), initial stages of epithelial-mesenchymal transdifferentiation (EMT) and cell migration. TGF-beta1 induces JNK phosphorylation, c-Jun transactivation and AP1 activation. The involvement of JNK was evaluated using dominant negative mutants SEK-1 AL, JNK and cJun, depletion of JNK1,2 proteins by treatment of cells with antisense oligonucleotides, as well as the chemical inhibitor SP600125. Our results demonstrated that the JNK pathway is required in the TGF-beta1 enhancement of uPA, fibronectin, E-cadherin delocalization, actin re-organization and vimentin expression, concomitant with the induction of cell migration. These results allow us to suggest a role of JNK in the TGF-beta1 induction of EMT in relation with the stimulation of malignant properties of mouse transformed keratinocytes.