pVHL suppresses Akt/β-catenin-mediated cell proliferation by inhibiting 14-3-3ζ expression.

The mechanisms controlling degradation of cytosolic beta-catenin are important for regulating beta-catenin co-transcriptional activity. Loss of von Hippel-Lindau protein (pVHL) has been shown to stabilize beta-catenin, increasing beta-catenin transactivation and beta-cateninmediated cell proliferation. However, the role of phosphoinositide 3-kinase (PI3K)/Akt in the regulation of beta-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 beta-catenin. PI3K/Akt hyperactivation is facilitated by the up-regulation of 14-3-3 zeta. and the down-regulation of 14-3-3 epsilon, 14-3-3 eta. and 14-3-3 theta.Up-regulation of 14-3-3 zeta. in response to pVHL is important for the recruitment of PI3K to the cell membrane and for stabilization of soluble beta-catenin. In contrast, 14-3-3 epsilon and 14-3-3 eta. enhanced PI3K/Akt signaling by inhibiting PI3K and PDK1, respectively. Thus, our results demonstrated that 14-3- 3 family members enhance PI3K/Akt/ beta-catenin signaling in order to increase proliferation. Inhibition of Akt activation and/ or 14-3-3 function strongly reduces beta-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 beta-catenin signaling due to pVHL loss.