A CELLULAR REPRESSOR OF E1A-STIMULATED GENES THAT INHIBITS ACTIVATIONBY E2F

The adenovirus ELA protein both activates and represses gene expressio n to promote cellular proliferation and inhibit differentiation. Here we report the identification and characterization of a cellular protei n that antagonizes transcriptional activation and cellular transformat ion by E1A. This protein, termed CREG for cellular repressor of E1A-st imulated genes, shares limited sequence similarity with E1A and binds both the general transcription factor TBP and the tumor suppressor pRb in vitro. In transfection assays, CREG represses transcription and an tagonizes 12SE1A-mediated activation of both the adenovirus E2 and cel lular hsp70 promoters. CREG also antagonizes E1A-mediated transformati on, as expression of CREG reduces the efficiency with which E1A and th e oncogene ras cooperate to transform primary cells. Binding sites for E2F, a hey transcriptional regulator of cell cycle progression, were found to be required for repression of the adenovirus E2 promoter by C REG, and CREG was shown to inhibit activation by E2F. Since both the a denovirus E1A protein and transcriptional activation by E2F function t o promote cellular proliferation, the results presented here suggest t hat CREG activity may contribute to the transcriptional control of cel l growth and differentiation.