REGULATION OF P53 LEVELS BY THE E1B 55-KILODALTON PROTEIN AND E40RF6 IN ADENOVIRUS-INFECTED CELLS

The adenovirus type 5 243R EIA protein induces p53-dependent apoptosis in the absence of the 19- and 55-kDa E1B polypeptides. This effect ap pears to result from an accumulation of p53 protein and is unrelated t o expression of E1B products. We now report that in the presence of th e E1B 55-kDa polypeptide, the 289R E1A protein does not induce such p5 3 accumulation and, in fact, is able to block that induced by E1A 243R . This inhibition also requires the 289R-dependent transactivation of E4orf6 expression. E4orf6 is known to form complexes with the E1B 55-k Da protein and to function both in the transport and stabilization of viral mRNA and in shutoff of host cell protein synthesis, We demonstra ted that the block in p53 accumulation is not due to the generalized s hutoff of host cell metabolism. Rather, it appears to result from a me chanism targeted specifically to p53, most likely involving a decrease in the stability of p53 protein. The E1B 55-kDa protein is known to i nteract with both E4orf6 and p53, and as demonstrated recently by othe rs, we showed that E4orf6 also binds directly to p53. Thus, multiple i nteractions between all three proteins may regulate p53 stability, res ulting in the maintenance of low levels of p53 following virus infecti on.