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

DeYoung, Maurice Phillip; Horak, Peter; Sofer, Avi; Sgroi, Dennis; Ellisen, Leif W.

doi:10.1101/gad.1617608

PreprintCited by 710PI3K/AKT/mTOR signaling in cancerCancer, Hypoxia, and MetabolismTuberous Sclerosis Complex Research

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

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DeYoung, Maurice Phillip, Horak, Peter, Sofer, Avi, Sgroi, Dennis, Ellisen, Leif W.·2008·Genes & Development

DOI 10.1101/gad.1617608PMC PMC2192757

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Abstract

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. Here, we demonstrate that hypoxia and REDD1 suppress mammalian TORC1 (mTORC1) activity by releasing TSC2 from its growth factor-induced association with inhibitory 14–3–3 proteins. Endogenous REDD1 is required for both dissociation of endogenous TSC2/14–3–3 and inhibition of mTORC1 in response to hypoxia. REDD1 mutants that fail to bind 14–3–3 are defective in eliciting TSC2/14–3–3 dissociation and mTORC1 inhibition, while TSC2 mutants that do not bind 14-3-3 are inactive in hypoxia signaling to mTORC1. In vitro, loss of REDD1 signaling promotes proliferation and anchorage-independent growth under hypoxia through mTORC1 dysregulation. In vivo, REDD1 loss elicits tumorigenesis in a mouse model, and down-regulation of REDD1 is observed in a subset of human cancers. Together, these findings define a molecular mechanism of signal integration by TSC1/2 that provides insight into the ability of REDD1 to function in a hypoxia-dependent tumor suppressor pathway.

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Endogenous Redd1 is required for both dissociation of endogenous TSC2/14-3-3 proteins and inhibition of mTOR in response to hypoxia.
“A recent study showed that endogenous Redd1 is required for both dissociation of endogenous TSC2/14–3-3 proteins and inhibition of mTOR in response to hypoxia [127].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [127]
Hypoxia-dependent regulation through REDD1 disrupts cytosolic 14-3-3-bound TSC2 and enables subsequent TSC2 localization to the lysosome where it can inhibit Rheb.
“Another example of this localization dependency includes hypoxia-dependent regulation through REDD1 (Brugarolas et al., 2004), which disrupts cytosolic 14-3-3-bound TSC2 and enables subsequent TSC2 localization to the lysosome where it can inhibit Rheb (DeYoung et al., 2008).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as DeYoung et al., 2008

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Authors: DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D., & Ellisen, L. W.
Affiliations: Harvard University (US)
ORCID: DeYoung, Maurice Phillip
Horak, Peter
Sgroi, Dennis
Ellisen, Leif W.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2008-01-15
Volume: 22
Issue: 2
Pages: 239-251
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.1617608
PMC: PMC2192757
OpenAlex: W2130396048
Cited by: 710
References: 41
Citations by year: 2026: 24 · 2025: 26 · 2024: 17 · 2023: 32 · 2022: 37 · 2021: 43 · 2020: 34 · 2019: 38 · 2018: 41 · 2017: 42 · 2016: 44 · 2015: 42 · 2014: 48 · 2013: 45 · 2012: 47
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01CA122589)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
Keywords: hypoxia, TSC1/2, mTORC1, REDD1, 14-3-3 proteins, TORC1 inhibition, tumor suppression, anchorage-independent growth, carcinogenesis, cellular metabolism, signal integration
MeSH terms: Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Breast Neoplasms, Cells, Cultured, Humans, Mice, Nude, Models, Biological, Neoplasm Transplantation, Protein Kinases, Transcription Factors, Signal Transduction, Cell Hypoxia, Tumor Suppressor Proteins, Mice, TOR Serine-Threonine Kinases

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

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