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

Abstract

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.

Aberrant expression of c-Jun in glioblastoma by internal ribosome entry site (IRES)-mediated translational activation

“…Total RNA was isolated from tissue samples using the RNAeasy Mini Kit (Qiagen) and from cell cultures using the EZ-RNA reagent (Biological Industries) according to the manufacturers' instructions. RNA was analyzed by Northern blot and quantitative RT-PCR as previously described (18). The detailed protocol is included in SI Materials and Methods.…”

“…Although expression of c-Jun is known to be mainly activated by the MAPK pathway, recent studies have shown that c-Jun expression can also be activated by a cytoskeleton-dependent pathway (18,22,23). This latter pathway does not affect the transcription of the c-Jun gene or the stability of the c-Jun protein but, rather, the translatability of its transcript (22).…”

“…In addition to external stimuli, expression of c-Jun can be regulated by cell-cell contacts (17)(18)(19)(20). Recent studies have shown that loss of cell-cell contacts, by means of cell separation or functional inhibition of the adhesion molecule E-cadherin, causes a marked and sustained increase in c-Jun protein accumulation and that this increase is not transcriptionally but rather translationally controlled (18).…”

“…Recent studies have shown that loss of cell-cell contacts, by means of cell separation or functional inhibition of the adhesion molecule E-cadherin, causes a marked and sustained increase in c-Jun protein accumulation and that this increase is not transcriptionally but rather translationally controlled (18). Cell contact control of c-Jun translation appears to be mediated by the cytoskeletal network: Depolymerization of the cytoskeleton by overexpression of cofilin 1 (21) or addition of cytoskeleton disrupting agents (18,22,23) mimics the effect of cell separation and causes a dramatic increase in c-Jun accumulation, whereas Taxol inhibits the cell contact-dependent increase (18). As in the case of cell contacts, the cytoskeletal-dependent increase is not accompanied by an increase in c-Jun mRNA or in the half-life of the c-Jun protein.…”

E-cadherin in canine mast cell tumors: Decreased expression and altered subcellular localization in Grade 3 tumors

“…More recent studies have shown that a decrease in E-cadherin expression or its translocation from the plasma membrane to the cytoplasm and/or nucleus can be crucial events in adherent junction destabilization (Gloushankova, 2008;Salahshor et al, 2008;Elston et al, 2009;Knirsh et al, 2009). In addition, it has been shown that E-cadherin is expressed in not only canine cutaneous histiocytomas, but also multiple other canine round cell tumors, including MCTs, plasma cell tumors, histiocytic sarcomas and epitheliotropic lymphomas .…”