GENES IN THE RB PATHWAY AND THEIR KNOCKOUT IN MICE

The retinoblastoma susceptibility gene (RB) the first identified human tumor suppressor gene, has been shown to be directly involved in the genesis of a variety of human cancers. RB is actually one of a family of three closely related genes including p107 and p130. Many elegant b iochemical studies have demonstrated that RB is a critical component o f the cell cycle regulatory machinery and have characterized the downs tream effecters which the RB gene product regulates. More recent advan ces have demonstrated that the function of RB and RB-related genes is positively and negatively regulated by an intricate network of cell cy cle regulatory proteins, some of which have also been implicated as tu mor suppressor genes. Despite the detailed understanding of these bioc hemical and genetic pathways, the full function of genes in the RB pat hway in the context of a whole organism is only now being addressed. U sing gene knockout technology, it is now known that RB, and RB-related proteins p107 and p130, have important functions during early mouse d evelopment. Furthermore, despite its ubiquitous expression, RB has tis sue- and cell-type specific effects which account for its function as a tumor suppressor but may also be independent of its role as a cell c ycle regulator Analysis of mice lacking regulatory genes upstream of R B and effector genes downstream of RB have confirmed that other genes in this pathway have tissue-specific effects on development and tumor susceptibility in mice.