Abstract
Epigenetic factor CTCF (CCCTC binding factor) plays important roles in genetic controls of the cell fate. Previous studies found in corneal epithelial cells that CTCF is regulated by epidermal growth factor (EGF) through activation of NF-κB p65/p50. It also found that CTCF is suppressed in ultraviolet (UV) stress-induced corneal epithelial cells. However, it is still unknown how UV stress down-regulates CTCF affecting the cell fate. In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription. Unlike the effect of EGF, UV stress-induced Bcl-3 activation suppressed CTCF activity without involving the IκBα and p65 pathway. Thus, results of the study reveal a novel mechanism for regulatory control of CTCF in UV stress-induced human corneal epithelial cells, which requires activation and formation of Bcl-3/p50 complex through a noncanonical NF-κB pathway.
Highlights
Corneal epithelial layer plays an important role in the vision function to form the front barrier that defends eye structures behind from damages of physical, chemical and biological insults
The results indicate that epidermal growth factor (EGF) stimulation increased both p65 and p50 levels, while UV stress activated p50 and Bcl-3 in stimulated cells
We demonstrate that regulation of CTCF is stimulus-dependent to affect Human corneal epithelial (HCE) cell fate [15]
Summary
Corneal epithelial layer plays an important role in the vision function to form the front barrier that defends eye structures behind from damages of physical, chemical and biological insults. Normal wound healing process is important for maintaining the corneal epithelial function [1,2,3,4,5,6]. Corneal epithelial wound healing is facilitated by growth factors and delayed by stimulation of environmental stressors [7,8,9,10,11]. Growth factors and environmental stressors regulate activities of early response genes and other important transcription factors, including CCCTC binding factor, CTCF. In epidermal growth factor (EGF)-stimulated cells, CTCF is up-regulated to mediate growth factor-induced proliferation by suppression of Pax, an eye and corneal epithelial specific gene [15]. The recent study demonstrates that EGF stimulation activates NF-kB p65 and p50 subtypes to form heterodimer complex to directly up-regulate
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