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Disrupted cell cycle arrest and reduced proliferation in corneal fibroblasts from GCD2 patients: a potential role for altered autophagy flux

Authors
 Seung-il Choi  ;  Shorafidinkhuja Dadakhujaev  ;  Yong-Sun Maeng  ;  So-yeon Ahn  ;  Tae-im Kim  ;  Eung Kweon Kim 
Citation
 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol.456(1) : 288-293, 2015 
Journal Title
 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 
ISSN
 0006-291X 
Issue Date
2015
MeSH
Adolescent ; Adult ; Autophagy ; Cell Cycle Checkpoints* ; Cell Proliferation ; Child ; Cornea/cytology* ; Corneal Dystrophies, Hereditary/genetics ; Corneal Dystrophies, Hereditary/metabolism ; Corneal Dystrophies, Hereditary/pathology* ; Female ; Fibroblasts/drug effects* ; Fibroblasts/metabolism ; Flow Cytometry ; Gene Expression Regulation* ; Homozygote ; Humans ; Macrolides/chemistry ; Male ; Middle Aged ; Young Adult
Keywords
Cell cycle arrest ; Corneal fibroblasts ; Cyclin ; Defective autophagy flux ; Granular corneal dystrophy type 2
Abstract
This study investigates the role of impaired proliferation, altered cell cycle arrest, and defective autophagy flux of corneal fibroblasts in granular corneal dystrophy type 2 (GCD2) pathogenesis. The proliferation rates of homozygous (HO) GCD2 corneal fibroblasts at 72 h, 96 h, and 120 h were significantly lower (1.102 ± 0.027, 1.397 ± 0.039, and 1.527 ± 0.056, respectively) than those observed for the wild-type (WT) controls (1.441±0.029, 1.758 ± 0.043, and 2.003 ± 0.046, respectively). Flow cytometry indicated a decreased G1 cell cycle progression and the accumulation of cells in the S and G2/M phases in GCD2 cells. These accumulations were associated with decreased levels of Cyclin A1, B1, and E1, and increased expression of p16 and p27. p21 and p53 expression was also significantly lower in GCD2 cells compared to the WT. Interestingly, treatment with the autophagy flux inhibitor, bafilomycin A1, resulted in similarly decreased Cyclin A1, B1, D1, and p53 expression in WT fibroblasts. Furthermore, similar findings, including a decrease in Cyclin A1, B1, and D1 and an increase in p16 and p27 expression were observed in autophagy-related 7 (Atg7; known to be essential for autophagy) gene knockout cells. These data provide new insight concerning the role of autophagy in cell cycle arrest and cellular proliferation, uncovering a number of novel therapeutic possibilities for GCD2 treatment.
Full Text
http://www.sciencedirect.com/science/article/pii/S0006291X14021044
DOI
10.1016/j.bbrc.2014.11.073
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Corneal Dystrophy Research Institute (각막이상증연구소) > 1. Journal Papers
Yonsei Authors
Kim, Eung Kweon(김응권) ORCID logo https://orcid.org/0000-0002-1453-8042
Kim, Tae Im(김태임) ORCID logo https://orcid.org/0000-0001-6414-3842
Maeng, Yong Sun(맹용선) ORCID logo https://orcid.org/0000-0003-1694-8405
Choi, Seung Il(최승일) ORCID logo https://orcid.org/0000-0001-7168-8795
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/139623
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