TY - JOUR
T1 - pVHL suppresses Akt/β-catenin-mediated cell proliferation by inhibiting 14-3-3ζ expression
AU - Castañeda, Azucena
AU - Serrano, Carolina
AU - Hernández-Trejo, José Antonio
AU - Gutiérrez-Martínez, Itzel Zenidel
AU - Montejo-López, Wilber
AU - Gómez-Suárez, Mauricio
AU - Hernández-Ruiz, Marcela
AU - Betanzos, Abigail
AU - Candelario-Martínez, Aurora
AU - Romo-Parra, Hector
AU - Arias-Montaño, José Antonio
AU - Schnoor, Michael
AU - Meraz Ríos, Marco Antonio
AU - Gutierrez-Castillo, Maria Eugenia
AU - Martínez-Dávila, Irma Alicia
AU - Villegas-Sepúlveda, Nicolás
AU - Martinez-Fong, Daniel
AU - Nava, Porfirio
N1 - Publisher Copyright:
© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.
PY - 2017/8/15
Y1 - 2017/8/15
N2 - 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 14-3-3ζ 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.
AB - 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 14-3-3ζ 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.
UR - http://www.scopus.com/inward/record.url?scp=85026695224&partnerID=8YFLogxK
U2 - 10.1042/BCJ20161097
DO - 10.1042/BCJ20161097
M3 - Artículo
SN - 0264-6021
VL - 474
SP - 2679
EP - 2689
JO - Biochemical Journal
JF - Biochemical Journal
IS - 16
ER -