Glucocorticoid elevation of dexamethasone-induced gene 2 (Dig2/RTP801/REDD1) protein mediates autophagy in lymphocytes.

Molitoris, Jason K.; McColl, Karen; Swerdlow, Sarah; Matsuyama, Mieko; Lam, Minh; Finkel, Terri H.; Matsuyama, Shigemi; Distelhorst, Clark W.

doi:10.1074/jbc.a111.245423

Cited by 16 publications

(21 citation statements)

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“…We observed a decrease in the mTORC1-dependent ULK1 phosphorylation together with an increase in LC3 activation after DEX treatment only in WT mice. In accord with our data, Molitoris et al (29) reported that DEX-induced REDD1 expression promotes LC3 lipidation and autophagosome formation in lymphocytes. Taken together, these results suggest that REDD1 is required to induce the ULK1-dependent LC3 activation following DEX administration.…”

Section: Proteolytic Systems Activationsupporting

confidence: 93%

“…Indeed, ULK1 complex inhibition partially represses the activation of LC3 following carbonyl cyanide m-chlorophenylhydrazione treatment (11). Interestingly, Molitoris et al (29) showed that REDD1 promoted LC3 activation and autophagosome formation in lymphocytes following administration of the synthetic GC dexamethasone (DEX). However, this mechanism needs to be confirmed in skeletal muscle since REDD1 function seems to be tissue dependent (40).…”

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confidence: 99%

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REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

Britto

Begue

Rossano

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Ferry A, Bonnieu A, Ollendorff V, Favier FB. REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy. Am J Physiol Endocrinol Metab 307: E983-E993, 2014. First published October 14, 2014 doi:10.1152/ajpendo.00234.2014.-REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wildtype (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoidinduced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy. regulated in development and DNA damage response 1; protein synthesis; mechanistic target of rapamycin; autophagy; glucocorticoids; proline-rich Akt substrate of 40 kDa

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Section: Proteolytic Systems Activationsupporting

confidence: 93%

mentioning

confidence: 99%

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

Britto

Begue

Rossano

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Induction of REDD1 is an important mechanism to overcome stress-induced impairment of cellular functions. REDD1 expression enables stress-induced autophagy by inhibition of mTOR signalling [11,47]. Autophagy contributes to stress-clearance by controlled elimination of damaged or harmful cellular components [48].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Jessica

Bongartz

Klepsch

et al. 2016

Cellular Signalling

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Abstract:Interleukin 6 is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by interleukin 6 (IL-6) is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity.

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“…Glucocorticoids may also inhibit tumor growth through suppression of the mTOR signal pathway [49,50]. REDD1 (RTP801, an mTOR complex 1, mTORC1, repressor) is a novel stress-induced gene linked to regression of mTOR signaling and is induced by glucocorticoids [51][52][53]. Recently, we generated Apc+/min mice with selective deletion of 11ßHSD2 in intestinal epithelial cells, and intestinal tumorigenesis is inhibited in these mice.…”

Section: Cyclooxygenase-2 and Glucocorticoids In Tumorigenesismentioning

confidence: 99%

11β-hydroxysteroid dehydrogenase type II: a Potential target for prevention of colonic tumorigenesis

Wang¹,

Harris²,

Zhang³

2016

Integr Cancer Sci Therap

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Cancer is the second most common cause of death in the world, and primary prevention remains the best approach to reducing overall morbidity and mortality. There is a molecular link between cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) production and colonic tumorigenesis. Selective COX-2 inhibitors as well as non-steroidal anti-inflammatory drugs (NSAIDs) reduce the number and sizes of colonic adenomas; however, increased cardiovascular risks of selective COX-2 inhibitors and increased gastrointestinal side-effects of NSAIDs limit their use. Glucocorticoids induce cancer cell apoptosis and are endogenous, potent COX-2 inhibitors. In tissues, glucocorticoid actions are down-regulated by type 2 11ß-hydroxysteroid dehydrogenase (11ßHSD2), and inhibition of 11ßHSD2 activity will elevate intracellular active glucocorticoids to levels that effectively suppress COX-2 expression. Both COX-2 and 11ßHSD2 increase in Apc+/min mouse intestinal adenomas and human colonic adenomas, and either pharmacologic or genetic 11βHSD2 inhibition leads to decreases in COX-2-mediated PGE2 production in tumors and prevents adenoma formation, tumor growth, and metastasis. 11ßHSD2 inhibition may represent a novel approach for CRC chemoprevention by increasing tumor cell intracellular glucocorticoid activity, which in turn inhibits tumor growth by suppressing the COX-2-derived PGE2 pathway, as well as other pathways, without potential side-effects relating to chronic application of COX-2 inhibitors, NSAIDs and glucocorticoids.

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Glucocorticoid elevation of dexamethasone-induced gene 2 (Dig2/RTP801/REDD1) protein mediates autophagy in lymphocytes.

Cited by 16 publications

References 0 publications

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

11β-hydroxysteroid dehydrogenase type II: a Potential target for prevention of colonic tumorigenesis

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