Rb at the interface between cell cycle and apoptotic decisions

The retinoblastoma (RB) gene was the first tumor suppressor to be identified, and it continues to be the subject of intense scientific interest. Not only is the RB gene mutated in the rare eye tumor and some other cancers, the Rb protein is functionally inactivated in virtually all human cancers, suggesting that it plays a general role in cellular homeostasis. Rb initially was envisaged as a simple 'on-off' regulator of the cell cycle, and this function was thought to account for its role as a tumor suppressor. Subsequently, however, closer scrutiny revealed unexpected and complex properties of Rb that together contribute to the unique role of Rb in cell biology. For example, Rb appears to be dispensable for normal cell cycling, but it has a special role in triggering permanent cell cycle exit associated with differentiation and senescence. Further, although the role of Rb as tumor suppressor is firmly established, it also has the ability to block apoptosis, which is generally thought to be a property of oncogenes. Our lab has been interested in understanding the dual and seemingly incongruous roles of Rb in cell cycle control and apoptosis. For many of these studies, we have chosen the melanocyte lineage as a model cell system because of the established role for Rb in melanocyte differentiation and survival, and the frequent deregulation of the Rb pathway in melanoma.