Rapid Turnover of the mTOR Complex 1 (mTORC1) Repressor REDD1 and Activation of mTORC1 Signaling following Inhibition of Protein Synthesis

Kimball, Scot R.; Dang, An; Kutzler, Lydia; Cavener, Douglas R.; Jefferson, Leonard S.

doi:10.1074/jbc.m706643200

Cited by 95 publications

(90 citation statements)

References 60 publications

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“…Endogenous as well as exogenous REDD1 protein is rapidly degraded within less than 15 min (Fig.2 C and D) as it has also been shown by Kimball et al [29]. Katiyar et al describe ubiquitinationdependent proteasomal degradation of REDD1 [20].…”

Section: Discussionsupporting

confidence: 49%

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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Section: Discussionsupporting

confidence: 49%

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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“…In skeletal muscle, REDD1 has been shown to inhibit mTOR signaling and protein synthesis in response to dexamethasone and alcohol intoxication (67,105). In addition, Kimball et al (65) found that rapid degradation of REDD1 in muscle was associated with enhanced mTOR signaling. Recent studies in human skeletal muscle have also suggested that expression of REDD1 and REDD2 plays a role in regulating mTOR activity and protein synthesis (26,27).…”

Section: Stress Response Genes Redd1/redd2 and Mtor Signalingmentioning

confidence: 99%

Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals

Miyazaki

Esser²

2009

Journal of Applied Physiology

164

142

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Miyazaki M, Esser KA. Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals. J Appl Physiol 106: 1367-1373, 2009; doi:10.1152/japplphysiol.91355.2008.-Growth and maintenance of skeletal muscle mass is critical for long-term health and quality of life. Skeletal muscle is a highly adaptable tissue with well-known sensitivities to environmental cues such as growth factors, cytokines, nutrients, and mechanical loading. All of these factors act at the level of the cell and signal through pathways that lead to changes in phenotype through multiple mechanisms. In this review, we discuss the animal and cell culture models used and the signaling mechanisms identified in understanding regulation of protein synthesis in response to mechanical loading/resistance exercise. Particular emphasis has been placed on 1) alterations in mechanical loading and regulation of protein synthesis in both in vivo animal studies and in vitro cell culture studies and 2) upstream mediators regulating mammalian target of rapamycin signaling and protein synthesis during skeletal muscle hypertrophy. mechanical stretch; REDD2; overload; IGF-1; amino acids IT IS WIDELY ACCEPTED that repeated bouts of resistance exercise/ high-force contractions produce compensatory growth of skeletal muscle (35,42,47,95). The increase in skeletal muscle mass results from rates of protein synthesis increased more than changes in protein degradation with the net result being an accumulation of protein and increased fiber area (66,96). While the effect of resistance exercise/contraction on muscle mass has long been recognized, the mechanisms underlying the link between high resistance contractions and muscle growth are, to date, not fully understood.One of the important variables contributing to the growth response in skeletal muscle is the application of mechanical loading. For this review we use mechanical loading very generally as the application of force on the muscle or muscle cell. This force on the muscle can occur via active cross-bridge interactions (such as during concentric, isometric, or eccentric contractions) in a gravity-based environment or via external application of force such as passive stretching. The most established animal model for studying skeletal muscle hypertrophy in response to mechanical loading was described by Dr. A. L. Goldberg (38) and was referred to as work-induced muscle growth. This model is now commonly known as the synergist ablation/mechanical overload model and is a surgical model that involves cutting of the tendon and removal of the gastrocnemius muscle, resulting in loading and compensatory growth of the remaining plantar flexors, the plantaris, and soleus muscles. These muscles are involved in maintenance of posture and walking so are loaded by the body weight of the animal. Muscle mass changes are fairly rapid and the growth is robust, ranging from 40 to 200% depending on the muscle and species studied (7,37,38,53,56). Many labs use this model in their research programs to study mole...

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“…Because of the extent to which cycloheximide augmented p70S6K phosphorylation, we examined the possibility that the mTORC1 repressor, DNA damage response 1 (REDD1) (61) was affected by the inhibition of protein synthesis as previously described (62). However, in rat hepatocytes the expression level of REDD1 was not down-regulated by cycloheximide (Fig.…”

Section: Proteomic Analysis Of Rat Livermentioning

confidence: 99%

Epidermal Growth Factor-induced Vacuolar (H+)-ATPase Assembly

Parmar

Roux

et al. 2012

Journal of Biological Chemistry

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Background: EGF-induced activation of mTORC1 in hepatocytes is essential for cell proliferation. Results: Blocking EGF-induced vacuolar acidification reduced intracellular essential amino acid levels and inhibited mTORC1 signaling without affecting Akt/Erk activation. Conclusion: EGF-induced mTORC1 signaling depends on sustaining intracellular amino acid levels. Significance: Our results support a role for vacuolar acidification in growth factor signaling.

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Rapid Turnover of the mTOR Complex 1 (mTORC1) Repressor REDD1 and Activation of mTORC1 Signaling following Inhibition of Protein Synthesis

Cited by 95 publications

References 60 publications

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

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

Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals

Epidermal Growth Factor-induced Vacuolar (H+)-ATPase Assembly

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