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Lance Patrick Doucette, Timothy Footz, Michael A Walter; FOXC1 directly regulates prostaglandin receptors EP2, EP3, and EP4: A potential molecular explanation for prostaglandin resistant glaucoma in Axenfeld-Rieger Syndrome. . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5807.
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© ARVO (1962-2015); The Authors (2016-present)
Individuals with mutations in FOXC1 have Axenfeld-Rieger syndrome (ARS), an ocular syndrome in which 50% of patients develop glaucoma. Individuals with FOXC1 mutations do not respond to prostaglandin glaucoma drugs, a common treatment for this condition. We hypothesize that a dysregulation of prostaglandin receptors (FP and EP1-4) by FOXC1 is the basis for this lack of response.<br /> <!--[if !supportLineBreakNewLine]--><br /> <!--[endif]-->
We used ChIP and luciferase assays to show that FOXC1 can bind to and regulate a fragment in the EP3 gene. To examine changes in RNA and protein levels of EP1,2,3,4 and FP in response to FOXC1, we used quantitative PCR (qPCR), and Western analysis respectively. We are currently performing cAMP ELISA analysis to elucidate the biological effect of prostaglandin receptor responses by lowering levels of FOXC1.<br /> <!--[if !supportLineBreakNewLine]--><br /> <!--[endif]-->
We have previously shown that FOXC1 binds within the gene for EP3 using ChIP and Luciferase assays. To examine if this translates to altered expression of the prostaglandin receptors, we conducted FOXC1 overexpression and siRNA knockdown studies. Our data shows that EP2 (p=0.0354), EP3 (p=0.0004), and EP4 (p=0.00005) RNA expression is directly correlated to levels of FOXC1 while EP1 and FP seem to be unaffected. We are currently examining if this lowering of receptor is sufficient to change cAMP signaling.
Our previous data has shown that FOXC1 can directly bind to and regulate the expression of the EP3 gene. Our qPCR data for the remaining EP receptors as well as FP suggest a positive correlation between levels of FOXC1 and EP2, EP3, and EP4 in HeLa cells. Data for the EP3 receptor from Western analysis in both HeLa cells and a TM cell line are also consistent with our qPCR data. Our data suggests a potential role for FOXC1 in the regulation of prostaglandin receptor expression, especially EP 2,3 and 4. This data has downstream potential to change the course of treatment for ARS patients, and to elucidate the effects of FOXC1 on PTGER3 and identify potential drug targets for glaucoma therapies.
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