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Expression of the F-Box Protein SKP2 Induces Hyperplasia, Dysplasia, and Low-Grade Carcinoma in the Mouse Prostate¹

Departments of Genetics [E-H. S., H. S., H. Z.], Internal Medicine [H-L. N., Y-J. K.], and Comparative Medicine [L. J., C. Z.], Yale University School of Medicine, New Haven, Connecticut 06520

Low or absent expression of the cyclin-dependent kinase inhibitor p27^Kip1 serves as an excellent malignant marker for prostate and other human cancers. The level of p27^Kip1 is regulated primarily by the ubiquitin E3 ligase SCF^SKP2 through ubiquitin-dependent proteolysis. Expression of the F-box protein SKP2 is inversely correlated with p27 in many cancers. To determine the role of SCF^SKP2 in proliferation and tumorigenesis, we established transgenic mouse lines that specifically expressed SKP2 in the prostate gland. Unscheduled expression of SKP2 promoted marked overproliferation, resulting in hyperplasia, dysplasia, and low-grade carcinoma in the prostate gland. Consistent with its critical role in p27 proteolysis, SKP2 expression caused significant down-regulation of p27 in prostate glands from transgenic animals. Immunohistological staining indicated that SKP2 expression is restricted to the hyperplastic/dysplastic regions and that there is an inverse relationship between SKP2 and p27 expression in the ductal epithelium in transgenic animals. The prostate glands from transgenic mice also exhibited high levels of proliferative and mitotic markers such as Ki67 and cyclin B1. Our data suggest that SKP2 acts as an oncoprotein in the mouse prostate gland, probably through its function as a limiting factor for ubiquitin-dependent degradation of p27.

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