Dexamethasone represses signaling through the mammalian target of rapamycin in muscle cells by enhancing expression of REDD1.
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.
Wang
Hongmei
H
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Kubica
Neil
N
Ellisen
Leif W
LW
Jefferson
Leonard S
LS
Kimball
Scot R
SR
D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis; D018482:Muscle, Skeletal / Q000378:metabolism; D009479:Neuropeptides / Q000096:biosynthesis; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
D004268:DNA-Binding Proteins; C000632146:Ddit4 protein, rat; D005938:Glucocorticoids; D009479:Neuropeptides; D012333:RNA, Messenger; D000076205:Ras Homolog Enriched in Brain Protein; D012097:Repressor Proteins; C087693:Rheb protein, rat; D014157:Transcription Factors; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins