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FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction

TORC1, a central regulator of cell survival, growth, and metabolism, is activated in a variety of cancers. Loss of the tumor suppressors PTEN and Tsc1/2 results in hyperactivation of TORC1. Tumors caused by the loss of PTEN, but not Tsc1/2, are often malignant and have been shown to be insensitive t...

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Autores principales: Nowak, Katarzyna, Gupta, Avantika, Stocker, Hugo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931687/
https://www.ncbi.nlm.nih.gov/pubmed/29677182
http://dx.doi.org/10.1371/journal.pgen.1007347
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author Nowak, Katarzyna
Gupta, Avantika
Stocker, Hugo
author_facet Nowak, Katarzyna
Gupta, Avantika
Stocker, Hugo
author_sort Nowak, Katarzyna
collection PubMed
description TORC1, a central regulator of cell survival, growth, and metabolism, is activated in a variety of cancers. Loss of the tumor suppressors PTEN and Tsc1/2 results in hyperactivation of TORC1. Tumors caused by the loss of PTEN, but not Tsc1/2, are often malignant and have been shown to be insensitive to nutrient restriction (NR). In Drosophila, loss of PTEN or Tsc1 results in hypertrophic overgrowth of epithelial tissues under normal nutritional conditions, and an enhanced TORC1-dependent hyperplastic overgrowth of PTEN mutant tissue under NR. Here we demonstrate that epithelial cells lacking Tsc1 or Tsc2 also acquire a growth advantage under NR. The overgrowth correlates with high TORC1 activity, and activating TORC1 downstream of Tsc1 by overexpression of Rheb is sufficient to enhance tissue growth. In contrast to cells lacking PTEN, Tsc1 mutant cells show decreased PKB activity, and the extent of Tsc1 mutant overgrowth is dependent on the loss of PKB-mediated inhibition of the transcription factor FoxO. Removal of FoxO function from Tsc1 mutant tissue induces massive hyperplasia, precocious differentiation, and morphological defects specifically under NR, demonstrating that FoxO activation is responsible for restricting overgrowth of Tsc1 mutant tissue. The activation status of FoxO may thus explain why tumors caused by the loss of Tsc1–in contrast to PTEN–rarely become malignant.
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spelling pubmed-59316872018-05-11 FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction Nowak, Katarzyna Gupta, Avantika Stocker, Hugo PLoS Genet Research Article TORC1, a central regulator of cell survival, growth, and metabolism, is activated in a variety of cancers. Loss of the tumor suppressors PTEN and Tsc1/2 results in hyperactivation of TORC1. Tumors caused by the loss of PTEN, but not Tsc1/2, are often malignant and have been shown to be insensitive to nutrient restriction (NR). In Drosophila, loss of PTEN or Tsc1 results in hypertrophic overgrowth of epithelial tissues under normal nutritional conditions, and an enhanced TORC1-dependent hyperplastic overgrowth of PTEN mutant tissue under NR. Here we demonstrate that epithelial cells lacking Tsc1 or Tsc2 also acquire a growth advantage under NR. The overgrowth correlates with high TORC1 activity, and activating TORC1 downstream of Tsc1 by overexpression of Rheb is sufficient to enhance tissue growth. In contrast to cells lacking PTEN, Tsc1 mutant cells show decreased PKB activity, and the extent of Tsc1 mutant overgrowth is dependent on the loss of PKB-mediated inhibition of the transcription factor FoxO. Removal of FoxO function from Tsc1 mutant tissue induces massive hyperplasia, precocious differentiation, and morphological defects specifically under NR, demonstrating that FoxO activation is responsible for restricting overgrowth of Tsc1 mutant tissue. The activation status of FoxO may thus explain why tumors caused by the loss of Tsc1–in contrast to PTEN–rarely become malignant. Public Library of Science 2018-04-20 /pmc/articles/PMC5931687/ /pubmed/29677182 http://dx.doi.org/10.1371/journal.pgen.1007347 Text en © 2018 Nowak 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
Nowak, Katarzyna
Gupta, Avantika
Stocker, Hugo
FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction
title FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction
title_full FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction
title_fullStr FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction
title_full_unstemmed FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction
title_short FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction
title_sort foxo restricts growth and differentiation of cells with elevated torc1 activity under nutrient restriction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931687/
https://www.ncbi.nlm.nih.gov/pubmed/29677182
http://dx.doi.org/10.1371/journal.pgen.1007347
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AT stockerhugo foxorestrictsgrowthanddifferentiationofcellswithelevatedtorc1activityundernutrientrestriction