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Glucocorticoids Activate Ubiquitin Transcription in Muscle By Suppressing PI3‐Kinase: Implications for Muscle Atrophy
Author(s) -
Price S. Russ,
Zheng Bin
Publication year - 2008
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.22.1_supplement.757.36
Subject(s) - myogenesis , pi3k/akt/mtor pathway , mapk/erk pathway , protein kinase b , transcription factor , muscle atrophy , phosphorylation , endocrinology , glucocorticoid , medicine , phosphoinositide 3 kinase , kinase , signal transduction , biology , protein kinase a , ubiquitin , skeletal muscle , microbiology and biotechnology , gene , biochemistry
Muscle atrophy is a consequence of chronic systemic diseases (e.g., diabetes) that results from muscle‐specific activation of the ubiquitin‐proteasome (UbP) pathway. Glucocorticoids are required for these transcriptional responses. We previously demonstrated that glucocorticoids increased the transcription of the Ubiquitin C (UbC) gene in L6 myotubes by a mechanism involving MEK1 and the Sp1 transcription factor. Presently, we examined how glucocorticoids activate MEK1 and UbC transcription. Dexamethasone (Dex; 100nM) increased UbC promoter‐driven luciferase activity by 205±7% after 24 h and by 310±6% after 48 h (both are P<0.05 vs control). In the time course requiring ≥ 24h, Dex increased MEK/ERK signaling, induced Sp1 phosphorylation and suppressed PI3‐kinase (PI3K)/Akt signaling. To test if inhibition of the PI3K pathway reroutes cell signaling to the MEK/ERK pathway, cells were infected with a PI3K p85 subunit to suppress PI3K activity. MEK1/2 phosphorylation and UbC promoter activity were increased. Thus, we propose that glucocorticoids increase MEK signaling and UbC transcription by an indirect mechanism involving suppression of the PI3K pathway. Our findings underscore the multifaceted role that glucocorticoids play in muscle atrophy due to chronic systemic diseases associated with increased glucocorticoid production, insulin resistance and muscle wasting. Supported by NIH DK61521.