The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
Hypoxia regulates TSC1/2–mTOR signaling and tumor suppression through REDD1-mediated 14–3–3 shuttling
Open accessAbstract
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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“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]
In the citing paper
“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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Cites
Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083
Defining the role of mTOR in cancer
Guertin, D. A., & Sabatini, D. M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.05.008 · Cited by 2,833
Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Inoki, K., Li, Y., Xu, T., & Guan, K.-L. (2003) · Genes & Development · doi:10.1101/gad.1110003 · Cited by 1,911
Shaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A., & Cantley, L. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308061100 · Cited by 1,797
The Tuberous Sclerosis Complex
Crino, P. B., Nathanson, K. L., & Henske, E. P. (2006) · New England Journal of Medicine · doi:10.1056/nejmra055323 · Cited by 1,793
Growing roles for the mTOR pathway
Sarbassov, D. D., Ali, S. M., & Sabatini, D. M. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.09.009 · Cited by 1,590
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00568-3 · Cited by 1,555
Brugarolas, J., Lei, K., Hurley, R. L., Manning, B. D., Reiling, J. H., Hafen, E., Witters, L. A., Ellisen, L. W., & Kaelin, W. G. (2004) · Genes & Development · doi:10.1101/gad.1256804 · Cited by 1,384
Self-citationGene expression profiling identifies clinically relevant subtypes of prostate cancer
Lapointe, J., Li, C., Higgins, J., van de Rijn, M., Bair, E., Montgomery, K. D., Ferrari, M. K., Egevad, L., Rayford, W., Bergerheim, U. S. R., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0304146101 · Cited by 1,282
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Sureshkumar, S., Espitia, C. M., Bi, F., Xiong, R., Gamble, M. E., Hakim, N. L., Kelly, K. R., Carew, J. S., & Nawrocki, S. T. (2026) · Cancers · doi:10.3390/cancers18203358
Inhibition of Mammalian Target of Rapamycin (mTOR) in Epidermis
Sully, K. (2012)
Novel Regulation of mTOR Complex 1 Signaling by Site-Specific mTOR Phosphorylation.
Üstünel, B. E. (2012) · Deep Blue (University of Michigan)
Metadata
- Authors
- DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D., & Ellisen, L. W.
- Affiliations
- Harvard University (US)
- 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
- 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 › Genetics (clinical) › 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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