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筋萎縮関連ユビキチンリガーゼCbl-bの発現調節における酸化ストレスの重要性
ROS induced Cbl-b expression in rat L6 cells
著者
内田, 貴之 徳島大学大学院栄養生命科学教育部(人間栄養科学専攻) 徳島大学 教育研究者総覧 KAKEN研究者をさがす
Sakashita, Yoshihiro Tokushima University
Kitahata, Kanako Tokushima University
Yamashita, Yui Tokushima University
Tomida, Chisato Tokushima University
Kimori, Yuki Tokushima University
Komatsu, Akio Tokushima University
平坂, 勝也 Tokushima University|Nagasaki University KAKEN研究者をさがす
真板, 綾子 Tokushima University
中尾, 玲子 Tokushima University|National Institute of Advanced Industrial Science and Technology 徳島大学 教育研究者総覧 KAKEN研究者をさがす
Higashitani, Atsushi Tohoku University
東端, 晃 Japan Aerospace Exploration Agency
石岡, 憲昭 Japan Aerospace Exploration Agency
Shimazu, Toru Japan Space Forum
Kobayashi, Takeshi Nagoya University
奥村, 裕司 Tokushima University|Sagami Women’s University KAKEN研究者をさがす
Choi, Inho Yonsei University
Oarada, Motoko Sagami Women’s University
Mills, Edward M. University of Texas
(手嶋)近藤, 茂忠 Tokushima University|Osaka Prefecture University KAKEN研究者をさがす
Takeda, Shin'ichi National Center of Neurology and Psychiatry
Tanaka, Keiji Tokyo Metropolitan Institute of Medical Science
Sokabe, Masahiro Nagoya University
キーワード
Egr
ROS
rat L6 cells
ubquitin ligase Cbl-b
unloading-mediated muscle atrophy
資料タイプ
学位論文
抄録
Unloading-mediated muscle atrophy is associated with increased reactive oxygen species (ROS) production. We previously demonstrated that elevated ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) resulted in the loss of muscle volume (Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, Okumura Y, Nonaka I, Yasutomo K, Baldwin KM, Kominami E, Higashibata A, Nagano K, Tanaka K, Yasui N, Mills EM, Takeda S, Nikawa T. Mol Cell Biol 29: 4798–4811, 2009). However, the pathological role of ROS production associated with unloading-mediated muscle atrophy still remains unknown. Here, we showed that the ROS-mediated signal transduction caused by microgravity or its simulation contributes to Cbl-b expression. In L6 myotubes, the assessment of redox status revealed that oxidized glutathione was increased under microgravity conditions, and simulated microgravity caused a burst of ROS, implicating ROS as a critical upstream mediator linking to downstream atrophic signaling. ROS generation activated the ERK1/2 early-growth response protein (Egr)1/2-Cbl-b signaling pathway, an established contributing pathway to muscle volume loss. Interestingly, antioxidant treatments such as N-acetylcysteine and TEMPOL, but not catalase, blocked the clinorotation-mediated activation of ERK1/2. The increased ROS induced transcriptional activity of Egr1 and/or Egr2 to stimulate Cbl-b expression through the ERK1/2 pathway in L6 myoblasts, since treatment with Egr1/2 siRNA and an ERK1/2 inhibitor significantly suppressed clinorotation-induced Cbl-b and Egr expression, respectively. Promoter and gel mobility shift assays revealed that Cbl-b was upregulated via an Egr consensus oxidative responsive element at −110 to −60 bp of the Cbl-b promoter. Together, this indicates that under microgravity conditions, elevated ROS may be a crucial mechanotransducer in skeletal muscle cells, regulating muscle mass through Cbl-b expression activated by the ERK-Egr signaling pathway.
掲載誌名
The American Journal of Physiology. Cell Physiology
ISSN
03636143
15221563
cat書誌ID
AA00521122
出版者
The American Physiological Society
314
6
開始ページ
C721
終了ページ
C731
発行日
2018-06-01
備考
内容要旨・審査要旨・論文本文の公開
本論文は, 著者Takayuki Uchidaの学位論文として提出され, 学位審査・授与の対象となっている。
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3146号
学位記番号
甲栄第255号
学位授与年月日
2018-03-23
学位名
博士(栄養学)
学位授与機関
徳島大学
部局
医学系
歯学系