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ID 109380
Title Alternative
N末端へミリストイル化を施したCbl-bユビキチン化活性阻害剤は、グルココルチコイド誘導性の筋萎縮を抑制する。
Author
Ochi, Arisa The University of Tokushima
Abe, Tomoki The University of Tokushima KAKEN Search Researchers
Nakao, Reiko The University of Tokushima|National Institute of Advanced Industrial Science and Technology Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Yamamoto, Yoriko The University of Tokushima
Kitahata, Kanako The University of Tokushima
Takagi, Marina The University of Tokushima
Hirasaka, Katsuya The University of Tokushima KAKEN Search Researchers
Ohno, Ayako The University of Tokushima
Taesik, Gwag Yonsei University
Choi, Inho Yonsei University
Kawamura, Tomoyuki The University of Tokushima
Keywords
Cbl-b
IRS-1
Mice
Skeletal muscle atrophy
Ubiquitin ligase inhibitor
Content Type
Thesis or Dissertation
Description
A DGpYMP peptide mimetic of tyrosine608-phosphorylated insulin receptor substrate-1 (IRS-1), named Cblin, was previously shown to significantly inhibit Cbl-b-mediated IRS-1 ubiquitination. In the present study, we developed N-myristoylated Cblin and investigated whether it was effective in preventing glucocorticoid-induced muscle atrophy. Using HEK293 cells overexpressing Cbl-b, IRS-1 and ubiquitin, we showed that the 50% inhibitory concentrations of Cbl-b-mediated IRS-1 ubiquitination by N-myristoylated Cblin and Cblin were 30 and 120 μM, respectively. Regarding the DEX-induced atrophy of C2C12 myotubes, N-myristoylated Cblin was more effective than Cblin for inhibiting the DEX-induced decreases in C2C12 myotube diameter and IRS-1 degradation. The inhibitory efficacy of N-myristoylated Cblin on IRS-1 ubiquitination in C2C12 myotubes was approximately fourfold larger than that of Cblin. Furthermore, N-myristoylation increased the incorporation of Cblin into HEK293 cells approximately 10-folds. Finally, we demonstrated that N-myristoylated Cblin prevented the wet weight loss, IRS-1 degradation, and MAFbx/atrogin-1 and MuRF-1 expression in gastrocnemius muscle of DEX-treated mice approximately fourfold more effectively than Cblin. Taken together, these results suggest that N-myristoylated Cblin prevents DEX-induced skeletal muscle atrophy in vitro and in vivo, and that N-myristoylated Cblin more effectively prevents muscle atrophy than unmodified Cblin.
Journal Title
Archives of Biochemistry and Biophysics
ISSN
00039861
10960384
NCID
AA00547159
AA11539811
Publisher
Elsevier
Volume
570
Start Page
23
End Page
31
Published Date
2015-02-14
Remark
内容要旨・審査要旨・論文本文の公開:
内容要旨・審査要旨 : LID201505251025.pdf
論文本文 : k2850_fulltext.pdf
本論文は,著者Arisa Ochi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。
著者の申請により要約(2015-05-26公開)に替えて論文全文を公開(2020-04-20)
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第2850号
Diploma Number
甲栄第228号
Granted Date
2015-03-23
Degree Name
Doctor of Nutritional Science
Grantor
Tokushima University
departments
Medical Sciences
Pharmaceutical Sciences
Bioscience and Bioindustry