Protein phosphatase 5 (PP5) plays an important role in cell proliferation, differentiation, and development. Transgenic PP5 mice (Tg-hPP5 mice) overexpressing human PP5 gene were successfully generated by embryo injection. Tg-hPP5 mice spontaneously developed corneal hyperplasia and ocular surface squamous neoplasia (OSSN). To investigate the mechanism behind PP5-induced corneal hyperplasia, we performed immunohistochemistry, quantitative real-time PCR, and Western Blotting analyses on the corneas of Tg-hPP5 mice at 2 months and 9 months of age. We provide the first demonstration that Tg-hPP5 mice develop corneal hyperplasia at 9-months of age demonstrated via histological analysis and in vitro co-transfection investigation. We also present data that the expression of p53 is significantly reduced while the expression of FGF-7 is significantly increased in Tg-hPP5 mice with corneal hyperplasia. Co-transfection of PP5, p53, and FGF-7-promoter-driven luciferase revealed that PP5 promotes while p53 inhibits FGF-7 expression, which indicates PP5 overexpression inhibits p53 phosphorylation, thereby reducing its tumor suppressor function and increasing FGF-7 expression. In conclusion, PP5 plays a pivotal role in corneal hyperplasia development and its downregulation is a potential target for corneal hyperplasia and OSSN treatment. (C) 2020 Elsevier Inc. All rights reserved.