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Vol. 20, Issue 7, 2121-2129, April 1, 2009

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Loss of E-Cadherin–mediated Cell–Cell Contacts Activates a Novel Mechanism for Up-Regulation of the Proto-Oncogene c-Jun

Revital Knirsh^*, Iris Ben-Dror^*, Barbara Spangler, Gideon D. Matthews^*, Silke Kuphal, Anja K. Bosserhoff, and Lily Vardimon^*

*Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel; and Institute of Pathology, University of Regensburg, D-93053 Regensburg, Germany

Submitted December 12, 2008; Accepted January 23, 2009
Monitoring Editor: Carl-Henrik Heldin

InCytes from MBC

Loss of E-cadherin–mediated cell–cell contacts can elicit a signaling pathway that leads to acquisition of an invasive phenotype. Here, we show that at the receiving end of this pathway is the proto-oncogene c-Jun, a member of the activator protein-1 family of transcription factors that play a key role in stimulation of cell proliferation and tumor promotion. Cell separation or abrogation of E-cadherin–mediated cell–cell contacts both cause a dramatic increase in accumulation of the c-Jun protein. Unlike growth factors that enhance the expression of c-Jun by activating the transcription of the c-jun gene, the cell contact-dependent increase in c-Jun accumulation is not accompanied by a corresponding increase in c-Jun mRNA or c-Jun protein stability but rather in the translatability of the c-Jun transcript. Consistently, the increase in c-Jun accumulation is not dependent on activation of the mitogen-activated protein kinase or β-catenin pathways but is mediated by signals triggered by the restructured cytoskeleton. Depolymerization of the cytoskeleton can mimic the effect of cell separation and cause a dramatic increase in c-Jun accumulation, whereas Taxol inhibits the cell contact-dependent increase. This novel mechanism of c-Jun regulation seems to underlie the robust overexpression of c-Jun in tumor cells of patients with colon carcinoma.

Address correspondence to: Lily Vardimon (vardi{at}post.tau.ac.il)