REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A–DDB1 ubiquitin ligase
Open accessAbstract
The cellular response to hypoxia involves several signalling pathways that mediate adaptation and survival. REDD1 (regulated in development and DNA damage responses 1), a hypoxia-inducible factor-1 target gene, has a crucial role in inhibiting mammalian target of rapamycin complex 1 (mTORC1) signalling during hypoxic stress. However, little is known about the signalling pathways and post-translational modifications that regulate REDD1 function. Here, we show that REDD1 is subject to ubiquitin-mediated degradation mediated by the CUL4A-DDB1-ROC1-beta-TRCP E3 ligase complex and through the activity of glycogen synthase kinase 3beta. Furthermore, REDD1 degradation is crucially required for the restoration of mTOR signalling as cells recover from hypoxic stress. Our findings define a mechanism underlying REDD1 degradation and its importance for regulating mTOR signalling.
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Hypoxia increases REDD1 expression.
“For example, hypoxia increases REDD1 expression105 and also induces spine loss in PFC and impaired PFC cognitive function106.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [105]
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References 23 · Cited by 150
- Authors
- Katiyar, S., Liu, E., Knutzen, C. A., Lang, E. S., Lombardo, C. R., Sankar, S., Toth, J. I., Petroski, M. D., Ronai, Z., & Chiang, G. G.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Venue
- The EMBO Reports
- Published
- 2009-06-26
- Volume
- 10
- Issue
- 8
- Pages
- 866-872
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC2726664
- OpenAlex
- W2030857424
- Cited by
- 150
- References
- 23
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 3 · 2022: 11 · 2021: 8 · 2020: 7 · 2019: 11 · 2018: 10 · 2017: 12 · 2016: 12 · 2015: 11 · 2014: 16 · 2013: 11 · 2012: 8
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- EMBO Reports (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Celgene
- National Institutes of Health
- National Cancer Institute (CA76193, U01CA052995, CA-52995, R01CA076193, R01CA111515, U19CA052995)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- REDD1, mTOR signaling, mTORC1, hypoxia, ubiquitin-mediated proteolysis, glycogen synthase kinase-3β, ROC1, β-TrCP, post-translational modification, HIF-1, protein stability
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Carrier Proteins, Cell Line, Cycloheximide, DNA-Binding Proteins, Humans, Phosphorylation, Protein Kinases, Protein Synthesis Inhibitors, Transcription Factors, Immunoblotting, Signal Transduction, Cell Hypoxia, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Glycogen Synthase Kinase 3, Ubiquitin-Protein Ligases, Cullin Proteins, beta-Transducin Repeat-Containing Proteins, Cell Line, Tumor, Protein Stability, TOR Serine-Threonine Kinases
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