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tumor progression and 14-3-3

14-3-3σ is expressed only in cells of epithelial origin and loss of 14-3-3σ has been observed in multiple solid tumors suggesting that it functions as a tumor suppressor. However, the mechanisms by which 14-3-3σ loss leads to tumor progression are not understood. The experiments in this report demonstrate that loss of 14-3-3σ leads to an induction of the epithelial to mesenchymal transition (EMT). The EMT was accompanied by an increase in epithelial markers, a decrease in mesenchymal markers and an increase in migration and invasion were observed in the 14-3-3σ -/- cells. 14-3-3σ-/- cells show increased stabilization of c-Jun resulting in an increase in the expression of the EMT transcription factor, Slug. High levels of Slug and c-Jun in multiple tumor types are inversely correlated with the levels of 14-3-3σ. 14-3-3σ induces the ubiquitination and degradation of c-Jun in an FBW7 dependent manner and the degradation requires the 14-3-3σ mediated nuclear export of c-Jun. Our results have identified a novel mechanism by which 14-3-3σ maintains the epithelial phenotype by inhibiting the epithelial mesenchymal transition and that this property of 14-3-3σ might inhibit tumor progression. We are currently determining the mechanisms by which loss of 14-3-3σ might affect tumor progression and metastasis.

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