Phosphorylated ribosomal protein S6 is required for Akt-driven hyperplasia and malignant transformation, but not for hypertrophy, aneuploidy and hyperfunction of pancreatic β-cells

Avigail Dreazen Wittenberg, Shahar Azar, Agnes Klochendler, Miri Stolovich-Rain, Shlomit Avraham, Lea Birnbaum, Adi Binder Gallimidi, Maximiliano Katz, Yuval Dor, Oded Meyuhas

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18 Scopus citations

Abstract

Constitutive expression of active Akt (Akttg) 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 (rpS6P-/-). rpS6 phosphorylation deficiency failed to block Akttg-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 Akttg-driven hyperplasia and tumor formation in β-cells. In vitro experiments with Akttg and rpS6P-/-;Akttg 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 Akttg fibroblasts to proteotoxic, genotoxic as well as autophagic stresses. In contrast, rpS6P-/- 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.

Original languageAmerican English
Article numbere0149995
JournalPLoS ONE
Volume11
Issue number2
DOIs
StatePublished - Feb 2016

Bibliographical note

Funding Information:
This work was supported by US-Israel Binational Science Foundation (No. 2009054); Israel Cancer Research Fund, and the Otto Stieber Foundation (to O.M.). We thank Dr. Dror Kolodkin-Gal from Hadassah Medical Center for the histochemical analysis of pancreatic slides for cleaved caspase 3, Dr. Morris J. Birnbaum from University of Pennsylvania School of Medicine for providing us with the RIP-myr-Akt1–expressing mice and the pLCNX myr-Akt expression plasmid; Dr. Tamar Ziv from the Smoler Proteomics Center at the Technion-Israel Institute of Technology for conducting the proteomic analysis; Dr. Shu-Bing Qian from Cornell University for the firefly expression vectors [Fluc(WT), Fluc(R218S) and Fluc(Stop)]; Dr. Valery Krizhanovsky from the Weizmann Institute of Science for the pBABE-Kras plasmid; and Dr. Lily Vardimon from Tel Aviv University for the Renilla luciferase expression vector. G12D

Publisher Copyright:
© 2016 Wittenberg et al. 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 credited.

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