The cellular
transcription factor DRTF1/E2F is implicated in the control of cellular proliferation due to its interaction with key regulators of cell cycle progression, such as the
retinoblastoma tumour suppressor 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 heterodimers, for example, DP-1 and E2F-1. In DRTF1/E2F the activity of DP-1 is under cell cycle control, possibly by phosphorylation, and in many types of cells it is a frequent, if not general
DNA binding component of DRTF1/E2F. The expression of other DP
proteins, such as DP-2, is tissue-restricted. Here, we show that DP-1 and DP-2 are integrated with another growth regulating pathway which involves signal transduction emanating from activated
Ras protein. Thus, activated Ha-ras can co-operate with DP-1 or DP-2 in the transformation of rat embryo fibroblasts, establishing for the first time that DP
proteins are endowed with proto-oncogenic activity. Moreover, an analysis of a dominant-negative and mutant DP-1
proteins suggests that the primary target through which DP-1 mediates its oncogenic activity is unlikely to be due to the regulation of E2F site-transcription, suggesting an E2F-independent effector function for DP-1. These results therefore establish DP genes as proto-oncogenes and thus argue that deregulating the normal control of DP
protein activity will be important in promoting aberrant cellular proliferation.