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Inactivation of Retinoblastoma Protein in Uveal Melanoma by Phosphorylation of Sites in the COOH-Terminal Region¹

Center for Ocular Oncology, Department of Ophthalmology and Visual Sciences [M. A. B., J. W. H.], and Division of Molecular Oncology [J. W. H.], Washington University, St. Louis, Missouri 63110

Uveal melanoma is the most common malignancy of the eye, but little is known about its underlying genetic defects. Melanomas of uveal origin, unlike those of the skin, are rarely familial and have not been linked consistently to mutations in tumor suppressor genes. Here, we investigated the Rb pathway in uveal melanoma. Most tumors displayed strong immunostaining for Rb and p16, suggesting that they were not mutationally inactivated. However, Rb was frequently phosphorylated at serine-807 and serine-811, and cyclin D1 was expressed in many of the tumors. Mutation of these serine residues prevented cyclin D-dependent phosphorylation from inactivating Rb in cultured cells. We conclude that Rb is frequently inactivated in uveal melanoma by phosphorylation of residues in the COOH-terminal region that regulate its activity, and one mechanism for this phosphorylation is overexpression of cyclin D.

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