The large E1B protein together with the E4orf6 protein target p53 for active degradation in adenovirus infected cells.

It has recently been shown that an adenovirus mutant lacking expression of the large E1B protein (deltaE1B) selectively replicates in p53 deficient cells. However, apart from the large E1B protein the adenovirus early region encodes the E1A and E4orf6 proteins which also have been reported to affect p53 expression as well as its functioning. After infection with wild-type adenovirus we observed a dramatic decrease in wild-type p53 expression while no down-regulation of p53 could be detected after infection with the deltaE1B virus. The different effects of the wild-type and deltaE1B adenovirus on p53 expression were not only found in cells expressing wild-type p53 but were also observed when tumor cells expressing highly stabilized mutant p53 were infected with these two viruses. Infection with different adenovirus mutants indicated the importance of a direct interaction between p53 and the large E1B protein for reduced p53 expression after infection. Moreover, coexpression of the E4orf6 protein was found to be required for this phenomenon, while expression of E1A is dispensable. In addition, we provide evidence that p53 is actively degraded in wild-type adenovirus-infected cells but not in deltaE1B-infected cells.