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Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells

Constitutive expression of active Akt (Akt(tg)) drives hyperplasia and hypertrophy of pancreatic β-cells, concomitantly with increased insulin secretion and improved glucose tolerance, and at a later stage the development of insulinoma. To determine which functions of Akt are mediated by ribosomal p...

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Autores principales: Wittenberg, Avigail Dreazen, Azar, Shahar, Klochendler, Agnes, Stolovich-Rain, Miri, Avraham, Shlomit, Birnbaum, Lea, Binder Gallimidi, Adi, Katz, Maximiliano, Dor, Yuval, Meyuhas, Oded
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769037/
https://www.ncbi.nlm.nih.gov/pubmed/26919188
http://dx.doi.org/10.1371/journal.pone.0149995
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author Wittenberg, Avigail Dreazen
Azar, Shahar
Klochendler, Agnes
Stolovich-Rain, Miri
Avraham, Shlomit
Birnbaum, Lea
Binder Gallimidi, Adi
Katz, Maximiliano
Dor, Yuval
Meyuhas, Oded
author_facet Wittenberg, Avigail Dreazen
Azar, Shahar
Klochendler, Agnes
Stolovich-Rain, Miri
Avraham, Shlomit
Birnbaum, Lea
Binder Gallimidi, Adi
Katz, Maximiliano
Dor, Yuval
Meyuhas, Oded
author_sort Wittenberg, Avigail Dreazen
collection PubMed
description Constitutive expression of active Akt (Akt(tg)) drives hyperplasia and hypertrophy of pancreatic β-cells, concomitantly with increased insulin secretion and improved glucose tolerance, and at a later stage the development of insulinoma. To determine which functions of Akt are mediated by ribosomal protein S6 (rpS6), an Akt effector, we generated mice that express constitutive Akt in β-cells in the background of unphosphorylatable ribosomal protein S6 (rpS6(P-/-)). rpS6 phosphorylation deficiency failed to block Akt(tg)-induced hypertrophy and aneuploidy in β-cells, as well as the improved glucose homeostasis, indicating that Akt carries out these functions independently of rpS6 phosphorylation. In contrast, rpS6 phosphorylation deficiency efficiently restrained the reduction in nuclear localization of the cell cycle inhibitor p27, as well as the development of Akt(tg)-driven hyperplasia and tumor formation in β-cells. In vitro experiments with Akt(tg) and rpS6(P-/-);Akt(tg) fibroblasts demonstrated that rpS6 phosphorylation deficiency leads to reduced translation fidelity, which might underlie its anti-tumorigenic effect in the pancreas. However, the role of translation infidelity in tumor suppression cannot simply be inferred from this heterologous experimental model, as rpS6 phosphorylation deficiency unexpectedly elevated the resistance of Akt(tg) fibroblasts to proteotoxic, genotoxic as well as autophagic stresses. In contrast, rpS6(P-/-) fibroblasts exhibited a higher sensitivity to these stresses upon constitutive expression of oncogenic Kras. The latter result provides a possible mechanistic explanation for the ability of rpS6 phosphorylation deficiency to enhance DNA damage and protect mice from Kras-induced neoplastic transformation in the exocrine pancreas. We propose that Akt1 and Kras exert their oncogenic properties through distinct mechanisms, even though both show addiction to rpS6 phosphorylation.
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spelling pubmed-47690372016-03-09 Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells Wittenberg, Avigail Dreazen Azar, Shahar Klochendler, Agnes Stolovich-Rain, Miri Avraham, Shlomit Birnbaum, Lea Binder Gallimidi, Adi Katz, Maximiliano Dor, Yuval Meyuhas, Oded PLoS One Research Article Constitutive expression of active Akt (Akt(tg)) drives hyperplasia and hypertrophy of pancreatic β-cells, concomitantly with increased insulin secretion and improved glucose tolerance, and at a later stage the development of insulinoma. To determine which functions of Akt are mediated by ribosomal protein S6 (rpS6), an Akt effector, we generated mice that express constitutive Akt in β-cells in the background of unphosphorylatable ribosomal protein S6 (rpS6(P-/-)). rpS6 phosphorylation deficiency failed to block Akt(tg)-induced hypertrophy and aneuploidy in β-cells, as well as the improved glucose homeostasis, indicating that Akt carries out these functions independently of rpS6 phosphorylation. In contrast, rpS6 phosphorylation deficiency efficiently restrained the reduction in nuclear localization of the cell cycle inhibitor p27, as well as the development of Akt(tg)-driven hyperplasia and tumor formation in β-cells. In vitro experiments with Akt(tg) and rpS6(P-/-);Akt(tg) fibroblasts demonstrated that rpS6 phosphorylation deficiency leads to reduced translation fidelity, which might underlie its anti-tumorigenic effect in the pancreas. However, the role of translation infidelity in tumor suppression cannot simply be inferred from this heterologous experimental model, as rpS6 phosphorylation deficiency unexpectedly elevated the resistance of Akt(tg) fibroblasts to proteotoxic, genotoxic as well as autophagic stresses. In contrast, rpS6(P-/-) fibroblasts exhibited a higher sensitivity to these stresses upon constitutive expression of oncogenic Kras. The latter result provides a possible mechanistic explanation for the ability of rpS6 phosphorylation deficiency to enhance DNA damage and protect mice from Kras-induced neoplastic transformation in the exocrine pancreas. We propose that Akt1 and Kras exert their oncogenic properties through distinct mechanisms, even though both show addiction to rpS6 phosphorylation. Public Library of Science 2016-02-26 /pmc/articles/PMC4769037/ /pubmed/26919188 http://dx.doi.org/10.1371/journal.pone.0149995 Text en © 2016 Wittenberg 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wittenberg, Avigail Dreazen
Azar, Shahar
Klochendler, Agnes
Stolovich-Rain, Miri
Avraham, Shlomit
Birnbaum, Lea
Binder Gallimidi, Adi
Katz, Maximiliano
Dor, Yuval
Meyuhas, Oded
Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells
title Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells
title_full Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells
title_fullStr Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells
title_full_unstemmed Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells
title_short Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells
title_sort phosphorylated ribosomal protein s6 is required for akt-driven hyperplasia and malignant transformation, but not for hypertrophy, aneuploidy and hyperfunction of pancreatic β-cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769037/
https://www.ncbi.nlm.nih.gov/pubmed/26919188
http://dx.doi.org/10.1371/journal.pone.0149995
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