DEGRADATION OF E2F BY THE UBIQUITIN-PROTEASOME PATHWAY - REGULATION BY RETINOBLASTOMA FAMILY PROTEINS AND ADENOVIRUS TRANSFORMING PROTEINS

E2F transcription factors are key regulators of transcription during t he cell cycle. E2F activity is regulated at the level of transcription and DNA binding and by complex formation with the retinoblastoma pock et protein family. We show here that free E2F-1 and E2F-4 transcriptio n factors are unstable and that their degradation is mediated by the u biquitin-proteasome pathway. Both E2F-1 and E2F-4 are rendered unstabl e by an epitope in the carboxyl terminus of the proteins, in close pro ximity to their pocket protein interaction surface. We show that bindi ng of E2F-1 to pRb or E2F-4 to p107 or p130 protects E2Fs from degrada tion, causing the complexes to be stable. The increased stability of E 2F-4 pocket protein complexes may contribute to the maintenance of act ive transcriptional repression in quiescent cells. Surprisingly, adeno virus transforming proteins, which release pocket protein-E2F complexe s, also inhibit breakdown of free E2F. These data reveal an additional level of regulation of E2F transcription factors by targeted proteoly sis, which is inhibited by pocket protein binding and adenovirus early region 1 transforming proteins.