THE LARGE E1B PROTEIN TOGETHER WITH THE E4ORF6 PROTEIN TARGET P53 FORACTIVE DEGRADATION IN ADENOVIRUS-INFECTED CELLS

It has recently been shown that an adenovirus mutant lacking expressio n of the large E1B protein (Delta E1B) selectively replicates in p53 d eficient cells. However, apart from the large E1B protein the adenovir us early region encodes the E1A and E4orf6 proteins which also have be en reported to affect p53 expression as well as its functioning. After infection with wild-type adenovirus we observed a dramatic decrease i n wild-type p53 expression while no down-regulation of p53 could be de tected after infection with the Delta E1B virus. The different effects of the wild-type and Delta E1B adenovirus on p53 expression were not only found in cells expressing wild-type p53 but mere also observed wh en tumor cells expressing highly stabilized mutant p53 were infected w ith these two viruses. Infection with different adenovirus mutants ind icated the importance of a direct interaction between p53 and the larg e E1B protein for reduced p53 expression after infection. Moreover, co expression of the E4orf6 protein was found to be required for this phe nomenon, while expression of E1A is dispensable. Tn addition, we provi de evidence that p53 is actively degraded in wild-type adenovirus-infe cted cells but not in Delta E1B-infected cells.