Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling

DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW · 2008 · Genes & Development · Atlas ID DEY2008

What this study shows

Explains how low oxygen turns mTORC1 off. Growth factors keep TSC2 bound to inhibitory 14-3-3 proteins; under hypoxia REDD1 releases TSC2 from 14-3-3, which frees TSC2 to inhibit mTORC1. REDD1-null cells failed to release TSC2 or to switch mTORC1 off in hypoxia, and REDD1 mutants that cannot bind 14-3-3, or TSC2 mutants that cannot bind it, broke the signal. REDD1-null cells grew into far larger tumours in mice, and REDD1 was low in a subset of human breast carcinomas (8 of 27). Boundary: cell lines and mouse xenografts under acute hypoxia (hours); the human data are expression correlations only.

Abstract

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Hypoxia induces rapid and dramatic changes in cellular metabolism, in part through inhibition of target of rapamycin (TOR) kinase complex 1 (TORC1) activity. Genetic studies have shown the tuberous sclerosis tumor suppressors TSC1/2 and the REDD1 protein to be essential for hypoxia regulation of TORC1 activity in Drosophila and in mammalian cells. The molecular mechanism and physiologic significance of this effect of hypoxia remain unknown.

Read the full abstract on PubMed →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: REDD1-/- and TSC2-/- mouse embryonic fibroblasts, human cell lines in 1% O2; xenografts in nude mice; human breast carcinoma samples) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	REDD1-/- and TSC2-/- mouse embryonic fibroblasts, human cell lines in 1% O2; xenografts in nude mice; human breast carcinoma samples
Journal	Genes & Development
Year	2008
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1101/gad.1617608 · PMID 18198340 · Free full text (PMC2192757)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Hypoxia (1% O2); REDD1 and TSC2 knockout and 14-3-3-binding mutants
Target	REDD1 -> TSC2/14-3-3 -> mTORC1
Model	Mouse embryonic fibroblasts, human cell lines, nude-mouse xenografts, human tumour samples
Effect	Hypoxia inhibits mTORC1 by REDD1-driven release of TSC2 from 14-3-3; REDD1 loss promotes tumour growth

In the Atlas

Links in the pathway map

Supports REDD1 (DDIT4) activates TSC1/TSC2
Supports TSC1/TSC2 inhibits mTORC1

Cite this paper

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DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D., & Ellisen, L. W. (2008). Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes & Development. https://doi.org/10.1101/gad.1617608

@article{DEY2008,
  author       = {DeYoung, M. P. and Horak, P. and Sofer, A. and Sgroi, D. and Ellisen, L. W.},
  title        = {{Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling}},
  journal      = {Genes & Development},
  year         = {2008},
  doi          = {10.1101/gad.1617608},
  note         = {PMID: 18198340},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record DEY2008) [Data set]. https://mtor-atlas.org/study/DEY2008/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_DEY2008,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record DEY2008},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/DEY2008/},
  doi          = {10.5281/zenodo.22059963}
}

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