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Dexamethasone represses signaling through mammalian target of rapamycin (mTOR) in muscle cells by enhancing expression of REDD1
Author(s) -
Kimball Scot R,
Wang Hongmei,
Kubica Neil,
Ellisen Leif W,
Jefferson Leonard S
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a651-a
Subject(s) - pi3k/akt/mtor pathway , rheb , rptor , microbiology and biotechnology , effector , phosphorylation , chemistry , dexamethasone , downregulation and upregulation , signal transduction , biology , endocrinology , mtorc1 , biochemistry , gene
The protein kinase mTOR 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. Dexamethasone has also been shown in one study to upregulate the expression of REDD1 (a.k.a. RTP801, a novel stress‐induced gene linked to repression of mTOR signaling) in lymphoid, but not non‐lymphoid, cells. In contrast to the findings of that study, 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 dexamethasone on mTOR signaling is efficiently blunted in the presence of REDD1 RNAi oligonucleotides. Moreover, the dexamethasone‐induced assembly of the mTOR regulatory complex TSC2·TSC1 is disrupted in L6 myoblasts following siRNA‐mediated repression of REDD1 expression. Finally, overexpression of Rheb, a downstream target of TSC2 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 TSC2 and Rheb to downregulate mTOR signaling in response to dexamethasone. (supported by NIH grant DK15658)