The cellular phosphoprotein p53 inhibits progression through the mammalian cell cycle. Both p53 alleles are frequently mutated in human tumours, indicating that p53 is a tumour suppressor. Recent studies have suggested that p53 functions as a transcriptional activator, but the significance of this activity in cell-cycle control has not been established. The adenovirus 2 (Ad2) early 1B (E1B) 55K protein binds to p53 in transformed cells and contributes to oncogenic transformation by Ad2 (refs 10-12). Here we report that mutants of E1B 55K and wild-type Ad12 E1B 54K proteins show a strong correlation between their ability to inhibit p53-mediated transcriptional activation and their ability to cooperate with adenovirus E1A protein in the transformation of primary cells. These results indicate that p53 probably inhibits cell cycling by functioning as a transcription factor.

Many DNA tumor viruses express a protein that inhibits transcriptional activation by the tumor-suppressing transcription factor p53. We report that adenovirus ElB 55K represses p53-mediated activation by a mechanism not described previously. ElB 55K binds p53 without displacing it from its DNA-binding site. A fusion of ElB 55K to the GAL4 DNA-binding domain represses transcription from a variety of promoters with engineered upstream GAL4-binding sites. Mutations within ElB 55K that interfere with its transforming activity and its ability to inhibit p53-mediated trans-activation also interfere with transcriptional repression by the GAL4-55K fusion. These results demonstrate that ElB 55K functions as a direct transcriptional repressor that is targeted to p53-responsive genes by binding to p53.

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