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

Abstract

Highlights: • Reduced cell proliferation in granular corneal dystrophy type 2. • Abnormal cell cycle arrest by defective autophagy. • Decreased Cyclin A1, B1, and D1 in Atg7 gene knockout cells. • Increase in p16 and p27 expressions were observed in Atg7 gene knockout cells. - 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 G{sub 1} cell cycle progression and the accumulation of cells in the S and G{sub 2}/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 A{sub 1}, resulted in similarly decreased Cyclin A1,more » 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.« less

Authors:
; ; ; ;  [1];  [2];  [1];  [2];  [2]
  1. Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)
  2. (Korea, Republic of)
Publication Date:
OSTI Identifier:
22416881
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 456; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BUILDUP; CELL CYCLE; CELL PROLIFERATION; COMPARATIVE EVALUATIONS; FIBROBLASTS; GENES; PATHOGENESIS; PATIENTS; THERAPY

Citation Formats

Choi, Seung-il, Dadakhujaev, Shorafidinkhuja, Maeng, Yong-Sun, Ahn, So-yeon, Kim, Tae-im, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Kim, Eung Kweon, E-mail: eungkkim@yuhs.ac, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, and BK21 Plus Project for Medical Science and Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul. Disrupted cell cycle arrest and reduced proliferation in corneal fibroblasts from GCD2 patients: A potential role for altered autophagy flux. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2014.11.073.
Choi, Seung-il, Dadakhujaev, Shorafidinkhuja, Maeng, Yong-Sun, Ahn, So-yeon, Kim, Tae-im, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Kim, Eung Kweon, E-mail: eungkkim@yuhs.ac, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, & BK21 Plus Project for Medical Science and Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul. Disrupted cell cycle arrest and reduced proliferation in corneal fibroblasts from GCD2 patients: A potential role for altered autophagy flux. United States. doi:10.1016/J.BBRC.2014.11.073.
Choi, Seung-il, Dadakhujaev, Shorafidinkhuja, Maeng, Yong-Sun, Ahn, So-yeon, Kim, Tae-im, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Kim, Eung Kweon, E-mail: eungkkim@yuhs.ac, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, and BK21 Plus Project for Medical Science and Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul. Fri . "Disrupted cell cycle arrest and reduced proliferation in corneal fibroblasts from GCD2 patients: A potential role for altered autophagy flux". United States. doi:10.1016/J.BBRC.2014.11.073.
@article{osti_22416881,
title = {Disrupted cell cycle arrest and reduced proliferation in corneal fibroblasts from GCD2 patients: A potential role for altered autophagy flux},
author = {Choi, Seung-il and Dadakhujaev, Shorafidinkhuja and Maeng, Yong-Sun and Ahn, So-yeon and Kim, Tae-im and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul and Kim, Eung Kweon, E-mail: eungkkim@yuhs.ac and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul and BK21 Plus Project for Medical Science and Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul},
abstractNote = {Highlights: • Reduced cell proliferation in granular corneal dystrophy type 2. • Abnormal cell cycle arrest by defective autophagy. • Decreased Cyclin A1, B1, and D1 in Atg7 gene knockout cells. • Increase in p16 and p27 expressions were observed in Atg7 gene knockout cells. - 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 G{sub 1} cell cycle progression and the accumulation of cells in the S and G{sub 2}/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 A{sub 1}, 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.},
doi = {10.1016/J.BBRC.2014.11.073},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 456,
place = {United States},
year = {Fri Jan 02 00:00:00 EST 2015},
month = {Fri Jan 02 00:00:00 EST 2015}
}