The adenoviral E1A oncoproteins interfere with the growth-inhibiting effect of the cdk-inhibitor p21(CIP1/WAF1).

The cdk-inhibitor p21(CIP1/WAF1) inhibits the activities of cyclin-dependent kinases and proliferating cell nuclear antigen, thereby repressing cell-cycle progression and DNA replication. Transforming oncogenes, such as E1A of human adenovirus 5 (Ad5), may interfere with such growth-inhibitory proteins. In this study, we show that in various Ad5E1-transformed cells, p21(CIP1/WAF1) is expressed and that, in general, expression is not downregulated. In addition, colony-formation assays show that in Ad5E1-transformed cells highly overexpressed p21(CIP1/WAF1) can still cause growth inhibition. FACS experiments indicate, however, that a G1 arrest induced by moderate overexpression of p21(CIP1/WAF1) can be overcome by E1A. The E1A proteins may interfere with the function of p21(CIP1/WAF1) by binding. Indeed, p21(CIP1/WAF1) binds with its cyclin/cdk-binding N terminus to the transforming N-terminal and CR1 region of the E1A proteins. Together, these results lend support to the model that E1A can interfere directly with p21(CIP1/WAF1) function and thereby stimulates cell growth.