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L. Lu, J. Wang; Hypoxia-Induced De-SUMOylaiton of CTCF Controls Pax6 Activity in Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1958.
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Previous studies revealed that activity of CTCF significantly decreased in response to stress stimulation. Purpose of the present study is to demonstrate that there is a markedly diminished SUMO modification of CTCF in response to hypoxic and oxidative stress stimulation affecting Pax6 activity in corneal epithelial fate.
HCE and HEK293 cells were maintained in 37 °C incubator supplied with 5% CO2. Cells were exposed to 1% oxygen (hypoxic stress) or 1 mM hydrogen peroxide (oxidative stress). The SUMO modification of CTCF was examined by immunoprecipitation and Western analysis. Downstream CTCF-targeting gene alterations were determined by real-time PCR and luciferase reporter assay.
We found that CTCF was modified by SUMO modification in the post-translational level. The Lys-74 and Lys-689 were found to be the major sites for CTCF SUMOylation. The SUMOylated-CTCF is sensitive to both hypoxic and oxidative stimuli. Our data demonstrated: 1) hypoxic and oxidative treatments induced a rapid de-SUMOylation of CTCF; 2) MG132, a proteasome inhibitor, mimicked the oxidative stress-induced effect on SUMOylated-CTCF; 3) the stability and sub-cellular localization of sentrin/SUMO-specific proteases (SENPs) were sensitive to hypoxic and oxidative treatments; 4) SUMO modification of CTCF was required for its ability to control Pax6 actvity; and 5) altered Pax6 gene expression induced by hypoxia was attributed to the de-SUMOylation of CTCF.
Hypoxic and oxidative stresses induce de-SUMOylation of CTCF to regulate Pax6 gene expression. We conclude that the de-SUMOylation is a novel mechanism that involves physiological function of CTCF in response to environmental stresses.
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