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Hetian Lei, Andrius Kazlauskas; A Role of Phosphatidylinoitol 5-Phosphate 4-Kinases in Proliferative Vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):398.
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© ARVO (1962-2015); The Authors (2016-present)
Proliferative vitreoretinopathy (PVR) is the major cause of failure in retinal detachment (RD) surgery. The p53 codon polymorphism (rs1042522) is associated with PVR, and the T309G in the MDM2 gene, a key negative regulator of p53, is also associated with a higher risk of developing PVR in patients undergoing a RD surgery. In addition, we recently found that vitreous suppress expression of p53 by engaging platelet-derived growth receptor (PDGFR)a/PI3K/Akt pathway. Intriguingly, reducing the level of p53 is required for experimental PVR. However, molecularly suppressing p53 does not fully phenocopy stimulation with vitreous. Thus it appears that vitreous does more than suppress p53 to promote cellular responses that are associated with PVR. The viability of tumor cells in which p53 is suppressed depends on elevation of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks). Thus we hypothesized that vitreous-mediated elevation of PI5P4K(s) was an essential event in PVR pathogenesis.
Vitreous-induced expression of PI5P4Ks in ARPE19, ARPE19 with PDGFRa overexpression (ARPE19a), and ARPE19 with PDGFRa silence (ARPE19KD) was examined using Western blot. Knockdown of p53 or PDGFRa in ARPE19 cells was achieved by shRNA. Overexpression of PI5P4Ks or PDGFRa in ARPE19 cells was accomplished by using a retrovirus-based approach. The resulting cells were subjected to proliferation, survival and collagen gel contraction assays.
Normal rabbit vitreous, which contains a variety of growth factors but not PDGFs, induced PI5P4Ks expression in a PDGFRa-dependent manner. In addition, we found that knockdown of p53 caused collagen gel contraction, but the extent of contraction was less than what occurred in response to vitreous. The extent of contraction in p53 knockdown cells increased to the level attained in response to vitreous by overexpressing PI5P4Ks. Finally, overexpression of PI5P4Ks in the p53 knockdown cells promoted additional PVR-associated cellular response including proliferation and survival. These data indicate that experimental PVR may require not only a knockdown in p53, but also an increase in PI5P4Ks.
These findings suggest that inhibition of PI5P4Ks and activation of p53 are novel approaches to prevent PVR.
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