pVHL suppresses Akt/{beta}-catenin-mediated cell proliferation by inhibiting 14-3-3{zeta} expression

The mechanisms controlling degradation of cytosolic β-catenin are important for regulating β-catenin co-transcriptional activity. Loss of von Hippel–Lindau protein (pVHL) has been shown to stabilize β-catenin, increasing β-catenin transactivation and β-catenin-mediated cell proliferation. However, the role of phosphoinositide 3-kinase (PI3K)/Akt in the regulation of β-catenin signaling downstream from pVHL has never been addressed. Here, we report that hyperactivation of PI3K/Akt in cells lacking pVHL contributes to the stabilization and nuclear accumulation of active β-catenin. PI3K/Akt hyperactivation is facilitated by the up-regulation of 14-3-3 and the down-regulation of 14-3-3, 14-3-3 and 14-3-3. Up-regulation of 14-3-3 in response to pVHL is important for the recruitment of PI3K to the cell membrane and for stabilization of soluble β-catenin. In contrast, 14-3-3 and 14-3-3 enhanced PI3K/Akt signaling by inhibiting PI3K and PDK1, respectively. Thus, our results demonstrated that 14-3-3 family members enhance PI3K/Akt/β-catenin signaling in order to increase proliferation. Inhibition of Akt activation and/or 14-3-3 function strongly reduces β-catenin signaling and decreases cell proliferation. Thus, inhibition of Akt and 14-3-3 function efficiently reduces cell proliferation in 786-0 cells characterized by hyperactivation of β-catenin signaling due to pVHL loss.

Source: Biochemical Journal - July 27, 2017 Category: Biochemistry Authors: Castaneda, A., Serrano, C., Hernandez-Trejo, J. A., Gutierrez-Martinez, I. Z., Montejo-Lopez, W., Gomez-Suarez, M., Hernandez-Ruiz, M., Betanzos, A., Candelario-Martinez, A., Romo-Parra, H., Arias-Montano, J. A., Schnoor, M., Meraz Rios, M. A., Gutierrez- Tags: Research Articles Source Type: research