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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. 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. In contrast to the anabolic actions of growth-promoting hormones such as insulin and insulin-like growth factor 1, glucocorticoids act to repress protein synthesis in skeletal muscle of animals in vivo (1Rannels D.E. Rannels S.R. Li J.B. Pegg A.E. Morgan H.E. Jefferson L.S. Advances in Myocardiology. University Park Press, Baltimore1980: 493-501Google Scholar), in perfused hind limb preparations (2Rannels S.R. Rannels D.E. Pegg A. Jefferson L.S. Am. J. Physiol. 1978; 235: E134-E139Crossref PubMed Google Scholar, 3Rannels S.R. Jefferson L.S. Am. J. 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In part, the repression of protein synthesis in response to glucocorticoids is a result of decreased signaling through a protein kinase referred to as the mammalian target of rapamycin (mTOR). 2The abbreviations used are: mTOR, mammalian target of rapamycin; siRNA, short interfering RNA; eIF, eukaryotic initiation factor; 4E-BP1, eukaryotic initiation factor 4E-binding protein 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RT, reverse transcription; S6K1, ribosomal protein S6 kinase 1; GAP, GTPase-activating protein; CHAPS, 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acid; PKB, protein kinase B; ERK, extracellular-signal regulated kinase; AMPK, AMP-activated protein kinase. mTOR phosphorylates at least two proteins involved in the regulation of mRNA translation, the eukaryotic initiation factor (eIF)-4E-binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase 1 (S6K1) (6Richardson C.J. Schalm S.S. Blenis J. Semin. Cell Dev. Biol. 2004; 15: 147-159Crossref PubMed Scopus (117) Google Scholar). 4E-BP1 acts to repress mRNA translation by sequestering the mRNA cap-binding protein eIF4E into an inactive complex (7Lin T.-A. Kong X. Haystead T.A.J. Pause A. Belsham G. Sonenberg N. Lawrence J.C. Science. 1994; 266: 653-656Crossref PubMed Scopus (602) Google Scholar, 8Pause A. Belsham G.J. Gingras A.-C. Donze O. Lin T.-A. Lawrence J.C. Sonenberg N. Nature. 1994; 371: 762-767Crossref PubMed Scopus (1063) Google Scholar). Phosphorylation of 4E-BP1 by mTOR initiates a series of phosphorylation events that ultimately result in the release of eIF4E from the inactive 4E-BP1·eIF4E complex, allowing it to bind to eIF4G to form the active eIF4F complex. Phosphorylation of S6K1 by mTOR generates a docking site for a second protein kinase, phosphoinositide-dependent protein kinase 1 (PDK1), allowing PDK1 to phosphorylate and activate S6K1 (9Alessi D.R. Kozlowski M.T. Weng Q.-P. Morrice N. Avruch J. Curr. 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Thus, repression of mTOR signaling results in a reduction in both the initiation and elongation phases of mRNA translation, resulting in a down-regulation of protein synthesis. Previous studies have shown that the down-regulation of protein synthesis caused by dexamethasone administration to rats in vivo (15Shah O.J. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 278: E76-E82Crossref PubMed Google Scholar) or the addition of the drug to the culture medium of L6 myoblasts (16Shah O.J. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 279: E74-E82Crossref PubMed Google Scholar, 17Shah O.J. Kimball S.R. Jefferson L.S. Biochem. J. 2000; 347: 389-397Crossref PubMed Scopus (63) Google Scholar) temporally correlates with reduced phosphorylation of the mTOR substrates 4E-BP1 and S6K1, suggesting that glucocorticoids might decrease protein synthesis through repression of mTOR. The dexamethasone-induced reduction in 4E-BP1 and S6K1 phosphorylation is attenuated both by inhibitors of glucocorticoid receptor function and inhibitors of transcription and translation (16Shah O.J. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 279: E74-E82Crossref PubMed Google Scholar). Moreover, the glucocorticoid receptor is both necessary and sufficient for the dexamethasone-induced dephosphorylation of S6K1 (18Shah O.J. Iniguez-Lluhi J.A. Romanelli A. Kimball S.R. Jefferson L.S. J. Biol. Chem. 2002; 277: 2525-2533Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Mutational analysis of the glucocorticoid receptor reveals that the DNA binding and transcriptional activation functions, but not the transcriptional repression function, of the receptor are required for S6K1 regulation (18Shah O.J. Iniguez-Lluhi J.A. Romanelli A. Kimball S.R. Jefferson L.S. J. Biol. Chem. 2002; 277: 2525-2533Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Overall, the available evidence strongly suggests that the repression of mTOR signaling in response to glucocorticoids is a result of enhanced transcription of a gene that encodes a repressor of mTOR signaling. However, the identity of the putative mTOR repressor is unknown. Recent studies have identified two novel repressors of mTOR signaling; proteins referred to as REDD1 and REDD2 (regulated in development and DNA damage responses; also known as RTP801 and RTP801l, respectively). REDD1 and REDD2 were originally identified as genes that are transcriptionally up-regulated in response to a variety of cellular stresses, including hypoxia (19Brugarolas J. Lei K. Hurley R.L. Manning B.D. Reiling J.H. Hafen E. Witters L.A. Ellisen L.W. Kaelin Jr., W.G. Genes Dev. 2004; 18: 2893-2904Crossref PubMed Scopus (1078) Google Scholar, 20Reiling J.H. Hafen E. Genes Dev. 2004; 18: 2879-2892Crossref PubMed Scopus (252) Google Scholar, 21Schwarzer R. Tondera D. Arnold W. Giese K. Klippel A. Kaufmann J. Oncogene. 2004; 24: 1138-1149Crossref Scopus (107) Google Scholar, 22Shoshani T. Faerman A. Mett I. Zelin E. Tenne T. Gorodin S. Moshel Y. Elbaz S. Budanov A. Chajut A. Kalinski H. Kamer I. Rozen A. Mor O. Keshet E. Leshkowitz D. Einat P. Skaliter R. Feinstein E. Mol. Cell. Biol. 2002; 22: 2283-2293Crossref PubMed Scopus (479) Google Scholar) and exposure to arsenite (23Lin L. Stringfield T.M. Shi X. Chen Y. Biochem. J. 2005; 392: 93-102Crossref PubMed Scopus (55) Google Scholar), or by agents that cause DNA damage (24Lin L. Qian Y. Shi X. Chen Y. Biochemistry. 2005; 44: 3909-3914Crossref PubMed Scopus (28) Google Scholar). More recent studies show that REDD1-induced repression of mTOR signaling requires Tuberin, the product of the TSC2 gene (19Brugarolas J. Lei K. Hurley R.L. Manning B.D. Reiling J.H. Hafen E. Witters L.A. Ellisen L.W. Kaelin Jr., W.G. Genes Dev. 2004; 18: 2893-2904Crossref PubMed Scopus (1078) Google Scholar, 20Reiling J.H. Hafen E. Genes Dev. 2004; 18: 2879-2892Crossref PubMed Scopus (252) Google Scholar, 25Sofer A. Lei K. Johannessen C.M. Ellisen L.W. Mol. Cell. Biol. 2005; 25: 5834-5845Crossref PubMed Scopus (354) Google Scholar). Tuberin in a complex with Hamartin, the product of the TSC1 gene, functions as a GTPase-activating protein (GAP) toward a small G protein referred to as Rheb (Ras homologue enriched in brain), a positive upstream effector of mTOR (26Li Y. Corradetti M.N. Inoki K. Guan K.-L. Trends Biochem. Sci. 2004; 29: 32-38Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar). Binding of Rheb·GTP to mTOR enhances, whereas binding of Rheb·GDP inhibits, mTOR activity (27Long X. Lin Y. Ortiz-Vega S. Yonezawa K. Avruch J. Curr. Biol. 2005; 15: 702Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar, 28Smith E.M. Finn S.G. Tee A.R. Browne G.J. Proud C.G. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, activation of Tuberin mTOR signaling by Rheb resulting in an in the of Rheb in an complex with A. J. G. L. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar, A. F. T. M. M. H. S. Hafen E. J. Thomas G. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, X. Li L. D. B.A. Cell Biol. PubMed Scopus Google Scholar, H. T. B. F. P. P. S. Thomas G. Hafen E. Cell Biol. PubMed Scopus Google Scholar). However, it is that REDD1 requires Tuberin to repress mTOR the through REDD1 might act to Tuberin function is as recent study F. F. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar) that dexamethasone the expression of a gene referred to as of the mRNA that it is to REDD1 F. F. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar), suggesting a of expression and repression of signaling through mTOR. However, in that study, dexamethasone to REDD1 expression in and not in into the of REDD1 in the actions of glucocorticoids on mTOR signaling in of or In the study, the that glucocorticoids repress mTOR signaling in skeletal muscle through of REDD1 REDD2 In contrast to an study F. F. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar) suggesting a of REDD1 by results show that expression of REDD1 is enhanced by dexamethasone both in skeletal muscle in vivo and L6 myoblasts in culture. Moreover, REDD2 expression is by dexamethasone in skeletal muscle and L6 dexamethasone the assembly of the active Tuberin·Hamartin complex, and complex assembly requires REDD1 expression. Finally, overexpression of Rheb the dexamethasone-induced repression of mTOR signaling. Overall, the results are with a dexamethasone REDD1 expression in muscle and REDD1 the Tuberin·Hamartin complex, resulting in repression of mTOR signaling. culture and were from and and were from from and from Cell The to REDD1 from eIF4E by the S.R. H. Jefferson L.S. 1994; PubMed Scopus (55) Google Scholar). and were from were from REDD1 short interfering RNA were from and as the used for the studies and by the and of The University of rats were on a with and were with of in (15Shah O.J. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 278: E76-E82Crossref PubMed Google Scholar). The an of of the animals in were of by J.C. F. Jefferson L.S. Kimball S.R. J. 2000; PubMed Scopus Google Scholar). drug rats were by The and were as a and to the of The were and in of 1 1 and The at for at and the for Cell RNA and myoblasts were in medium and at in a were a in the presence of of and a of at 1 were of for and with dexamethasone for to also were in medium were to the and from muscle and cell were with an of and at for The were to and with as in the were by enhanced a were by of muscle or cell with or by of the The were with 1 CHAPS, 1 1 and and proteins were by in were to analysis as S.R. R.L. Jefferson L.S. Am. J. Physiol. 1998; PubMed Google Scholar, F. Kimball S.R. Jefferson L.S. Biochem. PubMed Scopus Google Scholar). of RNA and from muscle and to the RNA and were assessed a RNA of reverse in a and The of RNA and at for and on were and at for and for The analysis by as of GAPDH, REDD1, and REDD2 an a to the The used were as reverse REDD1 reverse REDD2 reverse were in and reverse at of and of in a of a and to for of expression were and to mRNA expression. data are as analysis of and were used to study O.J. J.C. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 279: Google Scholar) that glucocorticoids repress mTOR signaling in skeletal muscle in rats and that administration to rats reverses the The study the results of the study and that dexamethasone phosphorylation of S6K1 and 4E-BP1 reduced in skeletal muscle not dexamethasone or administration the expression of REDD1 or REDD2, the of the in rat skeletal muscle RNA were by and to the of an mRNA that not in response to dexamethasone or shown in dexamethasone the expression of REDD1 mRNA the In REDD2 mRNA expression reduced in muscle from rats with to or rats effect on the expression of form of that the dexamethasone-induced in REDD1 mRNA result in REDD1 protein the effect of the on REDD1 expression assessed by protein that REDD1 protein in muscle from rats but dramatically in muscle of rats with dexamethasone Thus, the in REDD1 mRNA is with a in protein expression. the regulation of REDD1 and REDD2 mRNA expression and mTOR signaling by the effect of the drug in L6 myoblasts shown in mTOR signaling in L6 myoblasts dexamethasone as assessed by a of both S6K1 and 4E-BP1 into in skeletal muscle from dexamethasone enhanced the expression of REDD1 mRNA and REDD2 mRNA expression in L6 myoblasts Moreover, dexamethasone treatment in a in REDD1 protein with or not the enhanced expression of REDD1 mRNA necessary for repression of mTOR the rat REDD1 mRNA were used to expression in L6 shown in administration of REDD1 caused a reduction in REDD1 mRNA expression to of the in that been a Moreover, administration of REDD1 to dexamethasone dramatically attenuated the expression of the shown in the effect on the dexamethasone-induced decrease in S6K1 However, in with the REDD1 siRNA, dexamethasone or effect on S6K1 suggesting that the drug mTOR signaling through enhanced expression of support for by the that the dexamethasone-induced dephosphorylation of 4E-BP1 also attenuated in with REDD1 through mTOR signaling is regulated the Tuberin·Hamartin complex. shown in dexamethasone enhanced the of with Tuberin in L6 myoblasts with However, the drug effect on assembly of the Tuberin·Hamartin complex in with REDD1 siRNA, suggesting that REDD1 function upstream of Tuberin·Hamartin in mTOR signaling. a for the Tuberin·Hamartin complex in repression of mTOR the effect of expression of Rheb on the dexamethasone-induced repression of mTOR signaling were used Rheb in L6 myoblasts not shown in Rheb expression by at least an of in with the with with the in L6 myoblasts, dexamethasone caused a decrease in phosphorylation of both S6K1 and 4E-BP1 as assessed by decreased In expression of Rheb enhanced both S6K1 and 4E-BP1 phosphorylation in the of dexamethasone. in Rheb, the effect of dexamethasone on S6K1 and 4E-BP1 phosphorylation The results of the study that glucocorticoids repress mTOR signaling in skeletal muscle (15Shah O.J. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 278: E76-E82Crossref PubMed Google Scholar, O.J. J.C. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 279: Google Scholar) and L6 myoblasts (16Shah O.J. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 279: E74-E82Crossref PubMed Google Scholar). Thus, in both muscle and L6 myoblasts, dexamethasone dephosphorylation of the mTOR substrates S6K1 and 4E-BP1. The study the findings from studies to show that REDD1, but not REDD2, mRNA expression is enhanced in both skeletal muscle and L6 myoblasts in response to dexamethasone In a study F. F. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar), dexamethasone shown to REDD1 expression in but not in the that were mTOR signaling not in the study, the for of REDD1 mRNA by dexamethasone in F. F. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar) that for the repression of mTOR signaling in L6 myoblasts (16Shah O.J. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 279: E74-E82Crossref PubMed Google Scholar). Moreover, both dexamethasone-induced expression of REDD1 mRNA in F. F. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar) and repression of mTOR signaling in L6 myoblasts (18Shah O.J. Iniguez-Lluhi J.A. Romanelli A. Kimball S.R. Jefferson L.S. J. Biol. Chem. 2002; 277: 2525-2533Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar) are by a glucocorticoid that with dexamethasone for binding to the glucocorticoid Overall, the available evidence suggests that dexamethasone might act to repress mTOR signaling through a glucocorticoid in REDD1 expression. is by the results of the study that dexamethasone REDD1 expression not in as F. F. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar), but also in skeletal muscle in vivo as as in L6 myoblasts in culture. of recent studies have a of REDD1 expression and repression of signaling through mTOR. in both J.H. Hafen E. Genes Dev. 2004; 18: 2879-2892Crossref PubMed Scopus (252) Google Scholar) and mammalian M.N. Inoki K. Guan K.-L. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar) show that overexpression of REDD1 or REDD2 represses mTOR whereas decreased expression of protein signaling through mTOR. Moreover, in REDD1, that expression of the protein have effect on the phosphorylation of S6K1 or 4E-BP1 A. Lei K. Johannessen C.M. Ellisen L.W. Mol. Cell. Biol. 2005; 25: 5834-5845Crossref PubMed Scopus (354) Google Scholar). through mTOR is regulated with Rheb to mTOR the of (27Long X. Lin Y. Ortiz-Vega S. Yonezawa K. Avruch J. Curr. Biol. 2005; 15: 702Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar). it is with Rheb acts to mTOR but it is with it is a The in the study, that overexpression of Rheb in L6 myoblasts the down-regulation of mTOR signaling caused by suggests that the drug act to repress mTOR signaling by the of Rheb in the a is also by the that overexpression of Rheb in reverses the effect of expression of REDD1 on mTOR signaling A. Lei K. Johannessen C.M. Ellisen L.W. Mol. Cell. Biol. 2005; 25: 5834-5845Crossref PubMed Scopus (354) Google Scholar). evidence the that dexamethasone act to the of Rheb in the form is the novel that dexamethasone the assembly of the Tuberin·Hamartin complex Moreover, REDD1 dexamethasone-induced assembly of the complex, suggesting that REDD1 acts to repress mTOR by signaling to Tuberin and Tuberin by activity toward Rheb in in of both Tuberin and is required for repression of mTOR signaling in in culture A.R. Manning B.D. Blenis J. Sci. S. A. 2002; PubMed Scopus Google Scholar). Moreover, in Tuberin that with binding to repress the growth of the protein in J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). REDD1 functions through the Tuberin·Hamartin complex to mTOR function is by recent studies that REDD1 signaling to mTOR requires in in Tuberin expression is reduced siRNA, of REDD1 expression has or effect on S6K1 phosphorylation (19Brugarolas J. Lei K. Hurley R.L. Manning B.D. Reiling J.H. Hafen E. Witters L.A. Ellisen L.W. Kaelin Jr., W.G. Genes Dev. 2004; 18: 2893-2904Crossref PubMed Scopus (1078) Google Scholar, M.N. Inoki K. N. Guan K.-L. Genes Dev. 2004; 18: PubMed Scopus Google Scholar). Moreover, in contrast to expression of REDD1 in Tuberin has effect on S6K1 phosphorylation A. Lei K. Johannessen C.M. Ellisen L.W. Mol. Cell. Biol. 2005; 25: 5834-5845Crossref PubMed Scopus (354) Google Scholar). However, to the effect of expression of REDD1 on assembly of the Tuberin·Hamartin complex has not been the through REDD1 might Tuberin function is one in Tuberin In Tuberin is regulated through phosphorylation by a of protein phosphorylation of Tuberin on by protein kinase also known as is with of activity toward Rheb, resulting in enhanced signaling through mTOR in O.J. T. Cell 2005; PubMed Scopus Google Scholar). However, in mammalian overexpression of REDD1 has effect on phosphorylation M.N. Inoki K. Guan K.-L. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar), and in REDD1 functions downstream of J.H. Hafen E. Genes Dev. 2004; 18: 2879-2892Crossref PubMed Scopus (252) Google Scholar) suggesting that REDD1 not Tuberin through a Tuberin function is also regulated through phosphorylation by the extracellular-signal regulated kinase L. Chen H. P. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), but the that dexamethasone not activate in L6 myoblasts (15Shah O.J. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 278: E76-E82Crossref PubMed Google Scholar) suggests that is not downstream of The AMP-activated protein kinase also phosphorylates Tuberin, and in contrast to phosphorylation by or ERK, phosphorylation by Tuberin resulting in mTOR signaling K. T. Guan K.-L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). However, REDD1 not to repress mTOR signaling (19Brugarolas J. Lei K. Hurley R.L. Manning B.D. Reiling J.H. Hafen E. Witters L.A. Ellisen L.W. Kaelin Jr., W.G. Genes Dev. 2004; 18: 2893-2904Crossref PubMed Scopus (1078) Google Scholar, 25Sofer A. Lei K. Johannessen C.M. Ellisen L.W. Mol. Cell. Biol. 2005; 25: 5834-5845Crossref PubMed Scopus (354) Google Scholar), requires REDD1 to mTOR activity A. Lei K. Johannessen C.M. Ellisen L.W. Mol. Cell. Biol. 2005; 25: 5834-5845Crossref PubMed Scopus (354) Google Scholar). Overall, the available evidence suggests that REDD1 Tuberin·Hamartin assembly through an as to the through REDD1 might Tuberin function is the that administration of to rats has effect on or dexamethasone-induced REDD1 expression. In the of the in 4E-BP1 and S6K1 phosphorylation is by dexamethasone O.J. J.C. Kimball S.R. Jefferson L.S. Am. J. Physiol. 2000; 279: Google Scholar), suggesting that acts downstream of REDD1 to activate mTOR. have E.M. Finn S.G. Tee A.R. Browne G.J. Proud C.G. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Oncogene. 2005; 25: Scopus Google Scholar) or effect X. Ortiz-Vega S. Lin Y. Avruch J. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar) on the of to Moreover, in Tuberin, represses mTOR and the of to phosphorylation of 4E-BP1 and S6K1 E.M. Finn S.G. Tee A.R. Browne G.J. Proud C.G. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Oncogene. 2005; 25: Scopus Google Scholar), suggesting that regulation of mTOR through a the putative signaling regulated by has not been a recent study suggests that the of Rheb with mTOR and mTOR protein kinase activity (27Long X. Lin Y. Ortiz-Vega S. Yonezawa K. Avruch J. Curr. Biol. 2005; 15: 702Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar). in part, the of glucocorticoids on mTOR signaling by the binding of Rheb to mTOR. second is that might the activation of a protein for a Rheb has to activation of such a protein might the effect of Tuberin activation and mTOR signaling. an to in In the a for REDD1 in mTOR function in response to dexamethasone The results of the study, in with support a dexamethasone to the glucocorticoid REDD1 gene an as REDD1 the of with Tuberin J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) resulting in enhanced activity toward The resulting in Rheb with represses mTOR function, to decreased phosphorylation of both S6K1 and 4E-BP1 and in mRNA translation and protein synthesis. for with the
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