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

Open access
Date
2018-04-20Type
- Journal Article
Citations
Cited 14 times in
Web of Science
Cited 16 times in
Scopus
ETH Bibliography
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Abstract
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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000265109Publication status
publishedExternal links
Journal / series
PLoS GeneticsVolume
Pages / Article No.
Publisher
Public Library of ScienceOrganisational unit
02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology03710 - Hafen, Ernst (emeritus) / Hafen, Ernst (emeritus)
Funding
166680 - Analysis of early tumorigenic stages in Drosophila epithelia (SNF)
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Show all metadata
Citations
Cited 14 times in
Web of Science
Cited 16 times in
Scopus
ETH Bibliography
yes
Altmetrics