PMID- 23363291
OWN - NLM
STAT- MEDLINE
DCOM- 20140725
LR  - 20211203
IS  - 1600-079X (Electronic)
IS  - 0742-3098 (Linking)
VI  - 54
IP  - 4
DP  - 2013 May
TI  - Melatonin induces autophagy via an mTOR-dependent pathway and enhances clearance 
      of mutant-TGFBIp.
PG  - 361-72
LID - 10.1111/jpi.12039 [doi]
AB  - The hallmark of granular corneal dystrophy type 2 (GCD2) is the deposit of mutant 
      transforming growth factor-beta (TGF-beta)-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.
CI  - (c) 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.
FAU - Choi, Seung-Il
AU  - Choi SI
AD  - Corneal Dystrophy Research Institute; Department of Ophthalmology, Yonsei 
      University College of Medicine, Seoul, South Korea.
FAU - Kim, Kyu Seo
AU  - Kim KS
FAU - Oh, Jun-Young
AU  - Oh JY
FAU - Jin, Jun-Yup
AU  - Jin JY
FAU - Lee, Ga-Hyun
AU  - Lee GH
FAU - Kim, Eung Kweon
AU  - Kim EK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130131
PL  - England
TA  - J Pineal Res
JT  - Journal of pineal research
JID - 8504412
RN  - 0 (DNA Primers)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - JL5DK93RCL (Melatonin)
SB  - IM
MH  - Animals
MH  - Autophagy/*drug effects
MH  - Base Sequence
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - DNA Primers
MH  - Humans
MH  - Melatonin/*pharmacology
MH  - Microscopy, Electron, Transmission
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transforming Growth Factor beta1/*metabolism
OTO - NOTNLM
OT  - (mTOR)
OT  - LC3
OT  - TGFBIp
OT  - autophagy
OT  - granular corneal dystrophy type 2
OT  - melatonin
EDAT- 2013/02/01 06:00
MHDA- 2014/07/26 06:00
CRDT- 2013/02/01 06:00
PHST- 2012/09/11 00:00 [received]
PHST- 2012/12/21 00:00 [accepted]
PHST- 2013/02/01 06:00 [entrez]
PHST- 2013/02/01 06:00 [pubmed]
PHST- 2014/07/26 06:00 [medline]
AID - 10.1111/jpi.12039 [doi]
PST - ppublish
SO  - J Pineal Res. 2013 May;54(4):361-72. doi: 10.1111/jpi.12039. Epub 2013 Jan 31.