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Involvement of p27^KIP1 Degradation by Skp2 in the Regulation of Proliferation in Response to Wounding of Corneal Epithelium

¹ From the Department of Ophthalmology, Hokkaido University School of Medicine, Sapporo, Japan; the ⁴ Department of Anatomy, Nippon Medical College, Tokyo, Japan; the ³ Department of Molecular and Cellular Biology and the ² Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; and the ⁵ First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.

PURPOSE. To examine the expression of the p27^KIP1in the normal and epithelial-scraped cornea and whether degradation of p27^KIP1by Skp2 is involved in the regulation of cell proliferation in response to wounding of the corneal epithelium.

METHODS. C57Bl6, p27^KIP1-/-, Skp2^-/-, and Skp2^-/-/p27^KIP1-/- double-knockout mice were examined. Normal and epithelial-scraped corneas were analyzed by immunocytochemistry using anti-p27^KIP1 antibody. Cells in the S phase of DNA synthesis were analyzed by immunocytochemistry using anti-bromodeoxyuridine (BrdU) antibody.

RESULTS. The p27^KIP1 was expressed in basal cells of the central and peripheral region of the cornea and limbus. This expression was not detected 24 hours after the epithelial scraping, when there were many cells in the S phase of DNA synthesis in the corneal epithelium. There were no obvious differences in the thickness and anti-BrdU staining in the corneal epithelium of p27^KIP1-/- mice from that of control animals. Twenty-four hours after epithelial scraping in the Skp2^-/- mice, the corneal epithelium was thinner than in wild-type mice and had many p27^KIP1-positive cells and few BrdU-positive cells. In contrast, 24 hours after epithelial scraping in the Skp2^-/-/p27^KIP1-/- double-knockout mice, the corneal epithelium was as thick as in wild-type mice and had many BrdU-positive cells.

CONCLUSIONS. These results suggest that degradation of p27^KIP1 by Skp2 is involved in the regulation of cell proliferation in response to wounding of the corneal epithelium.

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