Adenovirus E1A protein perturbs the cell cycle and promotes cell transformation. Although E1A is relatively unstable, regulation of E1A stability has not been fully elucidated. Here, we showed that E1A was ubiquitinated and degraded using a proteasome in vivo system. Interestingly, we found that BS69, one of the E1A-binding proteins, inhibited ubiquitination of E1A. Moreover, we demonstrated that overepression of BS69 stabilized E1A in vivo. These results suggest that BS69 controls E1A stability via inhibition of ubiquitination. (c) 2005 Elsevier Inc. All rights reserved.