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Melatonin induces autophagy via an mTOR-dependent pathway and enhances clearance of mutant-TGFBIp

Authors
 Seung-Il Choi  ;  Kyu Seo Kim  ;  Jun-Young Oh  ;  Jun-Yup Jin  ;  Ga-Hyun Lee  ;  Eung Kweon Kim 
Citation
 JOURNAL OF PINEAL RESEARCH, Vol.54(4) : 361-372, 2013 
Journal Title
 JOURNAL OF PINEAL RESEARCH 
ISSN
 0742-3098 
Issue Date
2013
MeSH
Animals ; Autophagy/drug effects* ; Base Sequence ; Blotting, Western ; Cells, Cultured ; DNA Primers ; Humans ; Melatonin/pharmacology* ; Microscopy, Electron, Transmission ; TOR Serine-Threonine Kinases/metabolism* ; Transforming Growth Factor beta1/metabolism*
Keywords
(mTOR) ; LC3 ; TGFBIp ; autophagy ; granular corneal dystrophy type 2 ; melatonin
Abstract
The hallmark of granular corneal dystrophy type 2 (GCD2) is the deposit of mutant transforming growth factor-β (TGF-β)-induced protein (TGFBIp) in the cornea. We have recently shown that there is a delay in autophagic degradation of mutant-TGFBIp via impaired autophagic flux in GCD2 corneal fibroblasts. We hypothesized that melatonin can specifically induce autophagy and consequently eliminate mutant-TGFBIp in GCD corneal fibroblasts. Our results show that melatonin activates autophagy in both wild-type (WT) and GCD2-homozygous (HO) corneal fibroblast cell lines via the mammalian target of rapamycin (mTOR)-dependent pathway. Melatonin treatment also led to increased levels of beclin 1, which is involved in autophagosome formation and maturation. Furthermore, melatonin significantly reduced the amounts of mutant- and WT-TGFBIp. Treatment with melatonin counteracted the autophagy-inhibitory effects of bafilomycin A1, a potent inhibitor of autophagic flux, demonstrating that melatonin enhances activation of autophagy and increases degradation of TGFBIp. Cotreatment with melatonin and rapamycin, an autophagy inducer, had an additive effect on mutant-TGFBIp clearance compared to treatment with either drug alone. Treatment with the selective melatonin receptor antagonist luzindole did not block melatonin-induced autophagy. Given its ability to activate autophagy, melatonin is a potential therapeutic agent for GCD2.
Full Text
http://onlinelibrary.wiley.com/doi/10.1111/jpi.12039/abstract
DOI
10.1111/jpi.12039
Appears in Collections:
5. Research Institutes (연구소) > Corneal Dystrophy Research Institute (각막이상증연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Eung Kweon(김응권) ORCID logo https://orcid.org/0000-0002-1453-8042
Oh, Jun Young(오준영)
Lee, Ga Hyun(이가현)
Jin, Jun Yup(진준엽)
Choi, Seung Il(최승일) ORCID logo https://orcid.org/0000-0001-7168-8795
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/87090
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