Rb is a
tumor suppressor that represses the expression of E2F regulated genes required for cell cycle progression. It is inactivated in
melanomas and other
cancer cells by phosphorylation catalyzed by persistent
cyclin dependent kinase (CDK) activity. CDK activity is sustained in
melanoma cells mostly by the elimination of the CDK inhibitor p16INK4A and by high levels of
cyclins whose expression is maintained by stimuli emanating from activated
cell surface receptors and/or mutated intracellular intermediates, such as N-Ras and B-Raf. However, Rb also suppresses the expression of apoptosis genes, and its presence protects normal melanocytes from cell death. Its high expression in human
melanoma cells and
tumors suggests a similar role in malignant cells as well. The differential release and suppression of E2F transcriptional activity is likely to depend on promoter-specific E2F/Rb interaction. Phosphorylated Rb is displaced from cell cycle genes but not from others. In addition, Rb gene repression is dependent on the nature of Rb-E2F interaction and the activity of the Rb-bound
proteins recruited to the promoter. Deciphering the differences in Rb/E2F complex formation in normal and malignant melanocytes is likely to shed light on the mechanism by which Rb can exert
tumor suppressing and promoting activities in this cellular system. The Rb/E2F pathway provides opportunities for efficient
therapy at multiple levels. Novel drugs can reactivate Rb potential to suppress growth cycle promoting genes. In addition, the high E2F transcriptional activity in
melanoma cells can be exploited to deliver cytotoxic molecules specifically to
tumors, sparing the normal tissues.