Transcription factor E2F plays a central role in the regulation of mammalian cell-cycle progression, differentiation, an apoptosis. E2F-mediated trans-activation is governed in part via its formation of cell-regulated protein complexes with a number of important arbiters of cell-cycle progression, including the product of the retinoblastoma (Rb)-susceptibility gene, the Rb-related proteins p107 and p130, and cyclin/cdk kinases. De-regulation of E2F activity via the functional inactivation of tumor-suppressor genes, such as Rb, is a common occurrence in a variety of human cancers, including retinoblastoma, osteosarcoma, and small cell lung, breast, and bladder carcinomas. As such, analysis of E2F function and regulation has garnered a great deal of research attention. Transcription factor E2F is a heterodimer composed of two gene products, termed E2F and DP. The E2F component of this heterodimeric transcription factor is encoded by a gene family comprised by at least five distinct genes. Recently, the DP portion of this protein complex has also been shown to be encoded by a family of genes. To identify additional members of these gene families the investigator utilized a functional assay, a yeast two-hybrid screen, to isolate human cDNAs encoding novel E2F/DP dimerization partners. These efforts have led to the cloning of two new members of the DP-family, the identification of novel isoforms of these proteins, and the cloning of a novel dimerization partner that is distinct from E2F/DP-family members. This application proposes to characterize the functional properties of these newly-isolated gene products by determining their significance for E2F DNA-binding activity, E2F-mediated transcription, cell-cycle progression, and differentiation. The investigator predicts that significant inroads will be made through this project in the understanding of E2F transcriptional activity and the role of E2F in normal and tumor cell growth.
