The E6 protein encoded by the oncogenic human papillomavirus types 16 and 16 is one of two viral products expressed in HPV-associated cancers. E6 is an oncoprotein which cooperates with E7 to immortalize primary human keratinocytes. Insight into the mechanism by which E6 functions in oncogenesis is provided by the observation that the E6 protein encoded by HPV-16 and HPV-16 can complex the wild-type~ 53 protein in vitro. Wild-type p53 gene has tumor suppressor properties, and is a target for several of the oncoproteins encoded by DNA tumor viruses. In this study we demonstrate that the E6 proteins of the oncogenic HPVs that bind p53 stimulate the degradation of~ 53. The EG-promoted degradation of~ 53 is ATP dependent and involves the ubiquitin-dependent protease system. Selective degradation of cellular proteins such as~ 53 with negative regulatory functions provides a novel mechanism of action for dominantacting oncoproteins.