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PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma

Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often und...

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Detalles Bibliográficos
Autores principales: Shin, Yong Jae, Sa, Jason K., Lee, Yeri, Kim, Donggeon, Chang, Nakho, Cho, Hee Jin, Son, Miseol, Oh, Michael Y.T., Shin, Kayoung, Lee, Jin-Ku, Park, Jiwon, Jo, Yoon Kyung, Kim, Misuk, Paddison, Patrick J., Tergaonkar, Vinay, Lee, Jeongwu, Nam, Do-Hyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504209/
https://www.ncbi.nlm.nih.gov/pubmed/30898893
http://dx.doi.org/10.1084/jem.20172170
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author Shin, Yong Jae
Sa, Jason K.
Lee, Yeri
Kim, Donggeon
Chang, Nakho
Cho, Hee Jin
Son, Miseol
Oh, Michael Y.T.
Shin, Kayoung
Lee, Jin-Ku
Park, Jiwon
Jo, Yoon Kyung
Kim, Misuk
Paddison, Patrick J.
Tergaonkar, Vinay
Lee, Jeongwu
Nam, Do-Hyun
author_facet Shin, Yong Jae
Sa, Jason K.
Lee, Yeri
Kim, Donggeon
Chang, Nakho
Cho, Hee Jin
Son, Miseol
Oh, Michael Y.T.
Shin, Kayoung
Lee, Jin-Ku
Park, Jiwon
Jo, Yoon Kyung
Kim, Misuk
Paddison, Patrick J.
Tergaonkar, Vinay
Lee, Jeongwu
Nam, Do-Hyun
author_sort Shin, Yong Jae
collection PubMed
description Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen.
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spelling pubmed-65042092019-05-20 PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma Shin, Yong Jae Sa, Jason K. Lee, Yeri Kim, Donggeon Chang, Nakho Cho, Hee Jin Son, Miseol Oh, Michael Y.T. Shin, Kayoung Lee, Jin-Ku Park, Jiwon Jo, Yoon Kyung Kim, Misuk Paddison, Patrick J. Tergaonkar, Vinay Lee, Jeongwu Nam, Do-Hyun J Exp Med Research Articles Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen. Rockefeller University Press 2019-05-06 2019-03-21 /pmc/articles/PMC6504209/ /pubmed/30898893 http://dx.doi.org/10.1084/jem.20172170 Text en © 2019 Shin et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Shin, Yong Jae
Sa, Jason K.
Lee, Yeri
Kim, Donggeon
Chang, Nakho
Cho, Hee Jin
Son, Miseol
Oh, Michael Y.T.
Shin, Kayoung
Lee, Jin-Ku
Park, Jiwon
Jo, Yoon Kyung
Kim, Misuk
Paddison, Patrick J.
Tergaonkar, Vinay
Lee, Jeongwu
Nam, Do-Hyun
PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma
title PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma
title_full PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma
title_fullStr PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma
title_full_unstemmed PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma
title_short PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma
title_sort pip4k2a as a negative regulator of pi3k in pten-deficient glioblastoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504209/
https://www.ncbi.nlm.nih.gov/pubmed/30898893
http://dx.doi.org/10.1084/jem.20172170
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