Dexamethasone Represses Signaling through the Mammalian Target of Rapamycin in Muscle Cells by Enhancing Expression of REDD1
Open accessAbstract
The mammalian target of rapamycin (mTOR), a critical modulator of cell growth, acts to integrate signals from hormones, nutrients, and growth-promoting stimuli to downstream effector mechanisms involved in the regulation of protein synthesis. Dexamethasone, a synthetic glucocorticoid that represses protein synthesis, acts to inhibit mTOR signaling as assessed by reduced phosphorylation of the downstream targets S6K1 and 4E-BP1. Dexamethasone has also been shown in one study to up-regulate the expression of REDD1 (also referred to RTP801, a novel stress-induced gene linked to repression of mTOR signaling) in lymphoid, but not nonlymphoid, cells. In contrast to the findings of that study, here we demonstrate that REDD1, but not REDD2, mRNA expression is dramatically induced following acute dexamethasone treatment both in rat skeletal muscle in vivo and in L6 myoblasts in culture. In L6 myoblasts, the effect of the drug on mTOR signaling is efficiently blunted in the presence of REDD1 RNA interference oligonucleotides. Moreover, the dexamethasone-induced assembly of the mTOR regulatory complex Tuberin. Hamartin is disrupted in L6 myoblasts following small interfering RNA-mediated repression of REDD1 expression. Finally, overexpression of Rheb, a downstream target of Tuberin function and a positive upstream effector of mTOR, reverses the effect of dexamethasone on phosphorylation of mTOR substrates. Overall, the data support the conclusion that REDD1 functions upstream of Tuberin and Rheb to down-regulate mTOR signaling in response to dexamethasone.
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Redd1 is a new stress-induced protein and a negative regulator of mTOR through the TSC1/TSC2 complex.
“Redd1 is a new stress-induced protein and is known as a negative regulator of mTOR through TSC1/TSC2 complex [106–115].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [115]
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- Authors
- Wang, H., Kubica, N., Ellisen, L. W., Jefferson, L. S., & Kimball, S. R.
- Affiliations
- Pennsylvania State University (US)
- Harvard University (US)
- Corresponding author
- Kimball, Scot R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-12
- Volume
- 281
- Issue
- 51
- Pages
- 39128-39134
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2080447685
- Cited by
- 262
- References
- 4
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 9 · 2023: 10 · 2022: 8 · 2021: 17 · 2020: 14 · 2019: 15 · 2018: 12 · 2017: 11 · 2016: 15 · 2015: 17 · 2014: 13 · 2013: 17 · 2012: 22
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Pennsylvania Department of Health
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-15658, R01DK015658)
- 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 › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- dexamethasone, mTOR signaling, REDD1, skeletal muscle, L6 myoblasts, Rheb, S6K1, 4E-BP1, protein synthesis regulation, glucocorticoids, RNA interference
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Dexamethasone, DNA-Binding Proteins, Gene Expression Regulation, Glucocorticoids, Male, Neuropeptides, Protein Kinases, Repressor Proteins, RNA, Messenger, Transcription Factors, Signal Transduction, Rats, Sprague-Dawley, Muscle, Skeletal, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Rats, TOR Serine-Threonine Kinases
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