PROTOONCOGENIC PROPERTIES OF THE DP FAMILY OF PROTEINS

The cellular transcription factor DRTF1/E2F is implicated in the contr ol of cellular proliferation due to its interaction with key regulator s of cell cycle progression, such as the retinoblastoma tumour suppres sor gene product, cyclins and cyclin-dependent kinases. DRTF1/E2F is a heterodimeric DNA binding activity which arises when a member of two distinct families of proteins, DP and E2F, interact as DP/E2F heterodi mers, for example, DP-1 and E2F-1, Tn DRTF1/E2F the activity of DP-1 i s under cell cycle control, possibly by phosphorylation, and in many t ypes of cells it is a frequent, if not general DNA binding component o f DRTF1/E2F. The expression of other DP proteins, such as DP-2, is tis sue-restricted. Here, we show that DP-1 and DP-2 are integrated with a nother growth regulating pathway which involves signal transduction em anating from activated Ras protein. Thus, activated Ha-ras can co-oper ate with DP-1 or DP-2 in the transformation of rat embryo fibroblasts, establishing for the first time that DP proteins are endowed with pro to-oncogenic activity. Moreover, an analysis of a dominant-negative an d mutant DP-l proteins suggests that the primary target through which DP-1 mediates its oncogenic activity is unlikely to be due to the regu lation of E2F site-transcription, suggesting an E2F-independent effect or function for DP-1, These results therefore establish DP genes as pr oto-oncogenes and thus argue that deregulating the normal control of D P protein activity will be important in promoting aberrant cellular pr oliferation.