Inactivation of retinoblastoma protein in uveal melanoma by phosphorylation of sites in the COOH-terminal region

Uveal melanoma is the mast common malignancy of the eye, but little is know n about its underlying genetic defects. Melanomas of uveal origin, unlike t hose of the skin, are rarely familial and have not been linked consistently to mutations in tumor suppressor genes. Here, we investigated the Rb pathw ay in uveal melanoma, Most tumors displayed strong immunostaining for Rb an d p16, suggesting that they were not mutationally inactivated. However, Rb was frequently phosphorylated at serine-807 and serine-811, and cyclin D1 w as expressed in many of the tumors, Mutation of these serine residues preve nted cyclin D-dependent phosphorylation from inactivating Rb in cultured ce lls. We conclude that Rb is frequently inactivated in uveal melanoma by pho sphorylation of residues in the COOH-terminal region that regulate its acti vity, and one mechanism for this phosphorylation is overexpression of cycli n D.