A RETINOBLASTOMA-BINDING PROTEIN THAT AFFECTS CELL-CYCLE CONTROL AND CONFERS TRANSFORMING ABILITY

The retinoblastoma (RB) gene is one of the most extensively studied tu mour-suppressor genes(1). Deletion or inactivation of both RE alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma that arise in families that carry mutant RE (ref. 2) . RE inactivation is also found in other human tumours(3-8). Whereas l oss of RE function is associated with the loss of cellular proliferati ve control, introduction of a wild-type RE can suppress cell growth an d tumorigenicity(5,9-12). Thus, identification of factors that interfe re with and/or control the function of the RE protein is critical for understanding both cell-cycle control and oncogenesis. Here we describ e a new gene, Bog (for B5T over-expressed gene), which was identified and shown to be overexpressed in several transformed rat liver epithel ial (RLE) cell lines resistant to the growth-inhibitory effect of TGF- beta 1, as well as in primary human liver tumours. The Bog protein sha res homology with other retinoblastoma-binding proteins and contains t he Rb-binding motif LXCXE. Using the yeast two-hybrid system and co-im munoprecipitation. we demonstrated that Bog binds to Rb. In vivo, Bog/ Rb complexes do not contain E2F-1, and Bog can displace E2F-1 from E2F -1/Rb complexes in vitro. Overexpression of Bog in normal RFE cells co nferred resistance to the growth-inhibitory effect of TGF-beta 1. Furt hermore, normal RLE cells are rapidly transformed when Bog is continuo usly overexpressed and form hepatoblastoma-like tumours when transplan ted into nude mice. These data suggest that Bog may be important in th e transformation process, in part due to its capacity to confer resist ance to the growth-inhibitory effects of TGF-beta 1 through interactio n with Rb and the subsequent displacement of E2F-1.