Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation

The INK4a/ARF locus on the short arm of chromosome 9 is one of the most frequently altered loci in human cancer. It is generally accepted that ARF is involved in oncogenic checkpoint pathways by sensitizing incipient cancer cells to undergo growth arrest or apoptosis through both p53-dependent and i...

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Autores principales: Vivo, Maria, Ranieri, Michela, Sansone, Federica, Santoriello, Cristina, Calogero, Raffaele A., Calabrò, Viola, Pollice, Alessandra, La Mantia, Girolama
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538741/
https://www.ncbi.nlm.nih.gov/pubmed/23308265
http://dx.doi.org/10.1371/journal.pone.0053631
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author Vivo, Maria
Ranieri, Michela
Sansone, Federica
Santoriello, Cristina
Calogero, Raffaele A.
Calabrò, Viola
Pollice, Alessandra
La Mantia, Girolama
author_facet Vivo, Maria
Ranieri, Michela
Sansone, Federica
Santoriello, Cristina
Calogero, Raffaele A.
Calabrò, Viola
Pollice, Alessandra
La Mantia, Girolama
author_sort Vivo, Maria
collection PubMed
description The INK4a/ARF locus on the short arm of chromosome 9 is one of the most frequently altered loci in human cancer. It is generally accepted that ARF is involved in oncogenic checkpoint pathways by sensitizing incipient cancer cells to undergo growth arrest or apoptosis through both p53-dependent and independent pathways. While intensive studies have been focused on ARF activation at the transcriptional level, only recently mechanisms governing ARF turnover have been identified. Here, we show for the first time that p14ARF is a PKC target. Prediction analysis showed many potential phosphorylation sites in PKC consensus sequences within ARF protein, and, among them, the threonine at position 8 was the most conserved. Substitution of this threonine influences both ARF stability and localization. Furthermore, a phosphomimetic ARF mutation reduces the ability to arrest cell growth although the ability to bind MDM2 and stabilize p53 result unaffected. Thus we propose that phosphorylation of ARF in both immortalized and tumor cell lines could be a mechanism to escape ARF surveillance following proliferative and oncogenic stress.
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spelling pubmed-35387412013-01-10 Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation Vivo, Maria Ranieri, Michela Sansone, Federica Santoriello, Cristina Calogero, Raffaele A. Calabrò, Viola Pollice, Alessandra La Mantia, Girolama PLoS One Research Article The INK4a/ARF locus on the short arm of chromosome 9 is one of the most frequently altered loci in human cancer. It is generally accepted that ARF is involved in oncogenic checkpoint pathways by sensitizing incipient cancer cells to undergo growth arrest or apoptosis through both p53-dependent and independent pathways. While intensive studies have been focused on ARF activation at the transcriptional level, only recently mechanisms governing ARF turnover have been identified. Here, we show for the first time that p14ARF is a PKC target. Prediction analysis showed many potential phosphorylation sites in PKC consensus sequences within ARF protein, and, among them, the threonine at position 8 was the most conserved. Substitution of this threonine influences both ARF stability and localization. Furthermore, a phosphomimetic ARF mutation reduces the ability to arrest cell growth although the ability to bind MDM2 and stabilize p53 result unaffected. Thus we propose that phosphorylation of ARF in both immortalized and tumor cell lines could be a mechanism to escape ARF surveillance following proliferative and oncogenic stress. Public Library of Science 2013-01-07 /pmc/articles/PMC3538741/ /pubmed/23308265 http://dx.doi.org/10.1371/journal.pone.0053631 Text en © 2013 Vivo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Vivo, Maria
Ranieri, Michela
Sansone, Federica
Santoriello, Cristina
Calogero, Raffaele A.
Calabrò, Viola
Pollice, Alessandra
La Mantia, Girolama
Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation
title Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation
title_full Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation
title_fullStr Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation
title_full_unstemmed Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation
title_short Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation
title_sort mimicking p14arf phosphorylation influences its ability to restrain cell proliferation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538741/
https://www.ncbi.nlm.nih.gov/pubmed/23308265
http://dx.doi.org/10.1371/journal.pone.0053631
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