학술논문
pVHL suppresses Akt/β-catenin-mediated cell proliferation by inhibiting 14-3-3ζ expression.
Document Type
Article
Author
Castañeda, Azucena; Serrano, Carolina; Hernández-Trejo, José Antonio; Gutiérrez-Martínez, Itzel Zenidel; Montejo-López, Wilber; Gómez-Suárez, Mauricio; Hernández-Ruiz, Marcela; Betanzos, Abigail; Candelario-Martínez, Aurora; Romo-Parra, Hector; Arias-Montaño, José Antonio; Schnoor, Michael; Meraz Ríos, Marco Antonio; Gutierrez-Castillo, Maria Eugenia; Martínez-Dávila, Irma Alicia; Villegas-Sepúlveda, Nicolás; Martinez-Fong, Daniel; Nava, Porfirio
Source
Subject
*CATENINS
*CELL proliferation
*VON Hippel-Lindau disease
*PHOSPHOINOSITIDES
*CELL membranes
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Language
ISSN
0264-6021
Abstract
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-cateninmediated 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 14-3-3ζ and the down-regulation of 14-3-3ε, 14-3-3η and 14-3-3θ. Up-regulation of 14-3-3ζ in response to pVHL is important for the recruitment of PI3K to the cell membrane and for stabilization of soluble β-catenin. In contrast, 14-3-3ε and 14-3-3η 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. [ABSTRACT FROM AUTHOR]