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Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit

The ubiquitously expressed 14-3-3 proteins regulate many pathways involved in transformation. Previously, we found that 14-3-3ζ overexpression increased Akt phosphorylation in human mammary epithelial cells. Here, we investigated the clinical relevance and molecular mechanism of 14-3-3ζ overexpressi...

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Autores principales: Neal, Christopher L., Xu, Jia, Li, Ping, Mori, Seiji, Yang, Jun, Neal, Nina N., Zhou, Xiaoyan, Wyszomierski, Shannon L., Yu, Dihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193867/
https://www.ncbi.nlm.nih.gov/pubmed/21743495
http://dx.doi.org/10.1038/onc.2011.284
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author Neal, Christopher L.
Xu, Jia
Li, Ping
Mori, Seiji
Yang, Jun
Neal, Nina N.
Zhou, Xiaoyan
Wyszomierski, Shannon L.
Yu, Dihua
author_facet Neal, Christopher L.
Xu, Jia
Li, Ping
Mori, Seiji
Yang, Jun
Neal, Nina N.
Zhou, Xiaoyan
Wyszomierski, Shannon L.
Yu, Dihua
author_sort Neal, Christopher L.
collection PubMed
description The ubiquitously expressed 14-3-3 proteins regulate many pathways involved in transformation. Previously, we found that 14-3-3ζ overexpression increased Akt phosphorylation in human mammary epithelial cells. Here, we investigated the clinical relevance and molecular mechanism of 14-3-3ζ overexpression-mediated Akt phosphorylation and the potential impact on breast cancer progression. We found that 14-3-3ζ overexpression was significantly (P = 0.005) associated with increased Akt phosphorylation in human breast tumors. Additionally, 14-3-3ζ overexpression combined with strong Akt phosphorylation was significantly (P=0.01) associated with increased cancer recurrence in patients. In contrast, knockdown of 14-3-3ζ expression by siRNA in cancer cell lines and tumor xenografts reduced Akt phosphorylation. Furthermore, 14-3-3ζ enhanced Akt phosphorylation through activation of PI3K. Mechanistically, 14-3-3ζ bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane. A single 14-3-3 binding motif encompassing serine 83 on p85 is largely responsible for 14-3-3ζ-mediated p85 binding and PI3K/Akt activation. Mutation of serine 83 to alanine on p85 inhibited 14-3-3ζ binding to the p85 subunit of PI3K, reduced PI3K membrane localization and activation, impeded anchorage independent growth and enhanced stress induced apoptosis. These findings revealed a novel mechanism by which 14-3-3ζ overexpression activates PI3K, a key node in the mitogenic signaling network known to promote malignancies in many cell types.
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spelling pubmed-31938672012-08-16 Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit Neal, Christopher L. Xu, Jia Li, Ping Mori, Seiji Yang, Jun Neal, Nina N. Zhou, Xiaoyan Wyszomierski, Shannon L. Yu, Dihua Oncogene Article The ubiquitously expressed 14-3-3 proteins regulate many pathways involved in transformation. Previously, we found that 14-3-3ζ overexpression increased Akt phosphorylation in human mammary epithelial cells. Here, we investigated the clinical relevance and molecular mechanism of 14-3-3ζ overexpression-mediated Akt phosphorylation and the potential impact on breast cancer progression. We found that 14-3-3ζ overexpression was significantly (P = 0.005) associated with increased Akt phosphorylation in human breast tumors. Additionally, 14-3-3ζ overexpression combined with strong Akt phosphorylation was significantly (P=0.01) associated with increased cancer recurrence in patients. In contrast, knockdown of 14-3-3ζ expression by siRNA in cancer cell lines and tumor xenografts reduced Akt phosphorylation. Furthermore, 14-3-3ζ enhanced Akt phosphorylation through activation of PI3K. Mechanistically, 14-3-3ζ bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane. A single 14-3-3 binding motif encompassing serine 83 on p85 is largely responsible for 14-3-3ζ-mediated p85 binding and PI3K/Akt activation. Mutation of serine 83 to alanine on p85 inhibited 14-3-3ζ binding to the p85 subunit of PI3K, reduced PI3K membrane localization and activation, impeded anchorage independent growth and enhanced stress induced apoptosis. These findings revealed a novel mechanism by which 14-3-3ζ overexpression activates PI3K, a key node in the mitogenic signaling network known to promote malignancies in many cell types. 2011-07-11 2012-02-16 /pmc/articles/PMC3193867/ /pubmed/21743495 http://dx.doi.org/10.1038/onc.2011.284 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Neal, Christopher L.
Xu, Jia
Li, Ping
Mori, Seiji
Yang, Jun
Neal, Nina N.
Zhou, Xiaoyan
Wyszomierski, Shannon L.
Yu, Dihua
Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit
title Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit
title_full Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit
title_fullStr Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit
title_full_unstemmed Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit
title_short Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit
title_sort overexpression of 14-3-3ζ in cancer cells activates pi3k via binding the p85 regulatory subunit
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193867/
https://www.ncbi.nlm.nih.gov/pubmed/21743495
http://dx.doi.org/10.1038/onc.2011.284
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