Overexpression of the transcriptional coregulator Cited2 protects against glucocorticoid-induced atrophy of C2C12 myotubes.
In patients with various catabolic conditions, glucocorticoid excess induces skeletal muscle wasting by accelerating protein degradation via the ubiquitin-proteasome pathway. Although the transcriptional coactivator p300 has been implicated in this pathological process, regulatory mechanisms and molecular targets of its action remain unclear. Here we show that CREB-binding protein (CBP)/p300-interacting transactivator with ED-rich tail 2 (Cited2), which binds to the cysteine-histidine-rich region 1 of p300 and CBP, regulates muscle mass in vitro. Adenovirus-mediated overexpression of wild-type Cited2 significantly blocked morphological alterations of C2C12 myotubes with a concomitant decrease in myosin heavy chain protein in response to synthetic glucocorticoid dexamethasone, which were attributable to the reduced induction of atrophy-related ubiquitin ligases MuRF1 and MAFbx. These myotube-sparing effects were less pronounced, however, with a carboxyl-terminally truncated mutant of Cited2 that lacked the ability to bind p300. These results suggest that the gain of Cited2 function counteracts glucocorticoid-induced muscle atrophy through inhibition of proteolysis mediated by p300-dependent gene transcription.
Tobimatsu
Kazutoshi
K
Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Noguchi
Tetsuya
T
Hosooka
Tetsuya
T
Sakai
Mashito
M
Inagaki
Kenjiro
K
Matsuki
Yasushi
Y
Hiramatsu
Ryuji
R
Kasuga
Masato
M
D000818:Animals; D003907:Dexamethasone / Q000633:toxicity*; D005938:Glucocorticoids / Q000633:toxicity; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D044843:SKP Cullin F-Box Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
C110087:Cited2 protein, mouse; D005938:Glucocorticoids; D009124:Muscle Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D000070584:Tripartite Motif Proteins; D003907:Dexamethasone; D050880:p300-CBP Transcription Factors; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases