The long-term goal of the present study is to investigate the effects of growth factor-regulated and stress-induced cell proliferation, differentiation and apoptosis on the corneal epithelial renewal process and wound healing. We recently found that CTCF, an epigenetic regulator that binds to the CCCTC sequence of important genes, plays a central role in the regulation of homeobox Pax6 in corneal epithelia. Undoubtedly, epidermal growth factor (EGF)-elicited activation of CTCF inhibits Pax6 expression to promote proliferation/differentiation during corneal epithelial renewal and wound healing. In contrast, hyper-osmotic and UV stress-induced suppression of CTCF results in retardation of wound healing due to increased corneal epithelial apoptosis. We also found that EGF and other stresses regulate CTCF expression through activation of the inflammation- related NF-kB signaling pathway. Subunit-specific activation of NF-kB dimers dichotomously controls CTCF expression by interacting with a specific element 5'-upstream of the transcription initiation site of the CTCF gene. Our results strongly support the notion that the dichotomous effects of EGF- and stress-induced NF-kB activation on corneal epithelial cell fates are due to the formations of NF-kB heterodimers and homodimers that exert positive and negative effects on CTCF gene transcription, respectively. We hypothesize that CTCF is regulated by NF-kB dimers formed by different NF-kB subunits in EGF- and stress-induced corneal epithelial cells, resulting in controls of important gene expressions that regulate corneal epithelial proliferation and apoptosis and affect wound healing. To test the hypothesis, we will undertake three specific aims including: 1) to characterize the effects of EGF- and stress-induced NF-kB activation on the regulation of CTCF, 2) to elucidate the molecular mechanisms of how NF-kB regulates CTCF activity, and 3) to investigate the role(s) of NF-kB in regulating CTCF function to affect corneal wound healing. Such studies will provide the first step towards testing the physiological significance of CTCF in mediating growth factor- and stress-induced corneal epithelial cell proliferation, differentiation and apoptosis. In addition, the results will also reveal novel regulatory mechanisms that describe why activation of NF-kB by different stimuli results in different cellular responses. Furthermore, the study will provide new insight into the mechanisms of how regulation of CTCF by NF-kB activation mediates EGF- and stress-induced cell fates.

Public Health Relevance

. Corneal epithelial renewal, which is promoted by growth factors and delayed by environmental stresses, is essential in the wound healing process because it enables the tissue to act as a barrier that protects the corneal interior from becoming injured by diseases and noxious environmental agents. This innovative project is the first study to provide evidence showing that both growth factors and environmental stresses activate an inflammatory signaling pathway involving important gene regulators of NF-K:B (nuclear factor-kappa B) and CTCF (CCCTC binding factor). Subsequently, these gene regulators control the expression levels of further downstream genes that determine corneal epithelial proliferation, differentiation and apoptosis (programmed cell death).

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Shen, Grace L
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La Biomed Research Institute/ Harbor UCLA Medical Center
United States
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Tsui, Shanli; Wang, Jie; Wang, Ling et al. (2016) CTCF-Mediated and Pax6-Associated Gene Expression in Corneal Epithelial Cell-Specific Differentiation. PLoS One 11:e0162071
Restuccia, Agnese; Yang, Feikun; Chen, Changyan et al. (2016) Mps1 is SUMO-modified during the cell cycle. Oncotarget 7:3158-70
Tsui, S; Dai, W; Lu, L (2014) CCCTC-binding factor mediates effects of glucose on beta cell survival. Cell Prolif 47:28-37
Wang, Ling; Wu, Xiaolin; Shi, Ting et al. (2013) Epidermal growth factor (EGF)-induced corneal epithelial wound healing through nuclear factor ?B subtype-regulated CCCTC binding factor (CTCF) activation. J Biol Chem 288:24363-71
Wang, Jie; Wang, Yumei; Lu, Luo (2012) De-SUMOylation of CCCTC binding factor (CTCF) in hypoxic stress-induced human corneal epithelial cells. J Biol Chem 287:12469-79
Tsui, Shanli; Gao, Jie; Wang, Charles et al. (2012) CTCF mediates effect of insulin on glucagon expression. Exp Cell Res 318:887-95
Wang, Ling; Deng, Sophie X; Lu, Luo (2012) Role of CTCF in EGF-induced migration of immortalized human corneal epithelial cells. Invest Ophthalmol Vis Sci 53:946-51
Gao, Jie; Wang, Jie; Wang, Yumei et al. (2011) Regulation of Pax6 by CTCF during induction of mouse ES cell differentiation. PLoS One 6:e20954
Wang, Yumei; Lu, Luo (2011) Activation of oxidative stress-regulated Bcl-3 suppresses CTCF in corneal epithelial cells. PLoS One 6:e23984
Wang, Ling; Payton, Reid; Dai, Wei et al. (2011) Hyperosmotic stress-induced ATF-2 activation through Polo-like kinase 3 in human corneal epithelial cells. J Biol Chem 286:1951-8

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