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dc.contributor.author
Wittenberg, Avigail Dreazen
dc.contributor.author
Azar, Shahar
dc.contributor.author
Klochendler, Agnes
dc.contributor.author
Stolovich-Rain, Miri
dc.contributor.author
Avraham, Shlomit
dc.contributor.author
Birnbaum, Lea
dc.contributor.author
Binder Gallimidi, Adi
dc.contributor.author
Katz, Maximiliano Javier
dc.contributor.author
Dor, Yuval
dc.contributor.author
Meyuhas, Oded
dc.date.available
2017-06-16T19:52:42Z
dc.date.issued
2016-02
dc.identifier.citation
Wittenberg, Avigail Dreazen; Azar, Shahar; Klochendler, Agnes; Stolovich-Rain, Miri; Avraham, Shlomit; et al.; Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells; Public Library Of Science; Plos One; 11; 2; 2-2016; 1-25; e0149995
dc.identifier.uri
http://hdl.handle.net/11336/18350
dc.description.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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Public Library Of Science
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
Rps6
dc.subject.classification
Biología Celular, Microbiología
dc.subject.classification
Ciencias Biológicas
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
dc.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
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-06-12T21:00:25Z
dc.identifier.eissn
1932-6203
dc.journal.volume
11
dc.journal.number
2
dc.journal.pagination
1-25; e0149995
dc.journal.pais
Estados Unidos
dc.journal.ciudad
San Francisco
dc.description.fil
Fil: Wittenberg, Avigail Dreazen. The Hebrew University Of Jerusalem; Israel
dc.description.fil
Fil: Azar, Shahar. The Hebrew University Of Jerusalem; Israel
dc.description.fil
Fil: Klochendler, Agnes. The Hebrew University Of Jerusalem; Israel
dc.description.fil
Fil: Stolovich-Rain, Miri. The Hebrew University Of Jerusalem; Israel
dc.description.fil
Fil: Avraham, Shlomit. The Hebrew University Of Jerusalem; Israel
dc.description.fil
Fil: Birnbaum, Lea. The Hebrew University Of Jerusalem; Israel
dc.description.fil
Fil: Binder Gallimidi, Adi. The Hebrew University Of Jerusalem; Israel
dc.description.fil
Fil: Katz, Maximiliano Javier. The Hebrew University Of Jerusalem; Israel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
dc.description.fil
Fil: Dor, Yuval. The Hebrew University Of Jerusalem; Israel
dc.description.fil
Fil: Meyuhas, Oded. The Hebrew University Of Jerusalem; Israel
dc.journal.title
Plos One
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149995
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://dx.doi.org/10.1371/journal.pone.0149995
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