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

Journal Article · Fri Jan 02 04:00:00 EST 2015 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2014.11.073· OSTI ID:22416881

Choi, Seung-il; Dadakhujaev, Shorafidinkhuja; Maeng, Yong-Sun; Ahn, So-yeon; Kim, Tae-im ^[1]

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1. Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)

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.

• OSTI ID: 22416881
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1 Vol. 456; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BUILDUP
CELL CYCLE
CELL PROLIFERATION
COMPARATIVE EVALUATIONS
FIBROBLASTS
GENES
PATHOGENESIS
PATIENTS
THERAPY