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Glucocorticoid Elevation of Dexamethasone-induced Gene 2 (Dig2/RTP801/REDD1) Protein Mediates Autophagy in Lymphocytes
Open accessAbstract
Glucocorticoid hormones, including dexamethasone, induce apoptosis in lymphocytes and consequently are used clinically as chemotherapeutic agents in many hematologic malignancies. Dexamethasone also induces autophagy in lymphocytes, although the mechanism is not fully elucidated. Through gene expression analysis, we found that dexamethasone induces the expression of a gene encoding a stress response protein variously referred to as Dig2, RTP801, or REDD1. This protein is reported to inhibit mammalian target of rapamycin (mTOR) signaling. Because autophagy is one outcome of mTOR inhibition, we investigated the hypothesis that Dig2/RTP801/REDD1 elevation contributes to autophagy induction in dexamethasone-treated lymphocytes. In support of this hypothesis, RNAi-mediated suppression of Dig2/RTP801/REDD1 reduces mTOR inhibition and autophagy in glucocorticoid-treated lymphocytes. We observed similar results in Dig2/Rtp801/Redd1 knock-out murine thymocytes treated with dexamethasone. Dig2/RTP801/REDD1 knockdown also leads to increased levels of dexamethasone-induced cell death, suggesting that Dig2/RTP801/REDD1-mediated autophagy promotes cell survival. Collectively, these findings demonstrate for the first time that elevation of Dig2/RTP801/REDD1 contributes to the induction of autophagy.
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Glucocorticoids reduce circulating T cells by enhancing their migration to bone marrow and secondary lymphoid organs and trigger T cell apoptosis through up-regulation of BIM.
“In contrast to neutrophils, GCs reduce the levels of circulating T cells by enhancing their migration back to the bone-marrow and secondary lymphoid organs (47, 48). GCs also trigger T cells apoptosis, notably through the up-regulation of BIM (49, 50).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [49]
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Metadata
- Authors
- Molitoris, J. K., McColl, K. S., Swerdlow, S., Matsuyama, M., Lam, M., Finkel, T. H., Matsuyama, S., & Distelhorst, C. W.
- Affiliations
- University Hospitals of Cleveland (US)
- University of Pennsylvania (US)
- Corresponding author
- Distelhorst, Clark W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 286
- Issue
- 34
- Pages
- 30181-30189
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3191057
- OpenAlex
- W1995383659
- Cited by
- 96
- References
- 53
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 12 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 12 · 2013: 9 · 2012: 4
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM007250)
- National Institute on Aging (R01AG031903)
- National Heart, Lung, and Blood Institute (T32HL007147)
- National Cancer Institute (CA85804, R01 CA42755, R01CA042755, R01CA085804)
- National Institute of General Medical Sciences (T32GM007250)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- dexamethasone, autophagy, lymphocytes, glucocorticoids, mTOR inhibition, stress proteins, apoptosis, thymocytes, cell survival, hematologic malignancies
- MeSH terms
- Animals, Anti-Inflammatory Agents, Autophagy, Cell Line, Cell Survival, Dexamethasone, Lymphocytes, Transcription Factors, Mice, Knockout, Mice, TOR Serine-Threonine Kinases
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