P53 E1B58KDA COMPLEX REGULATES ADENOVIRUS REPLICATION/

We have explored a role for the adenovirus (Ad5) E1b58kDa/p53 protein complex in adenovirus replication. This was done by using virus mutant s containing different defects in the E1b58kDa gene and cell lines tha t express either a wildtype p53 protein or a mutant p53 protein. We fi nd that infection of wild-type p53-containing cells with wild-type Ad5 causes a shutoff of p53 and Lu-actin protein synthesis by distinct me chanisms, but neither occurs in mutant p53 cells. Our data also indica te that the shutoff is dependent on formation of the p53/E1b complex a nd may also involve another virus protein, E40RF6. Following from thes e observations we asked whether failure to form the complex resulted i n impaired adenovirus replication. Our experiments showed that neither wild-type Ad5 nor the E1b mutant d1338 could replicate in cells expre ssing a mutant p53 protein, but that wild-type adenovirus replicated w ell in wild-type p53-expressing cells. Collectively, our data suggest that the interaction between p53 and the E1b58kDa protein is necessary for efficient adenovirus replication. This is the first rime such a d irect link between the complex and virus replication has been demonstr ated. These data raise serious questions about the usefulness of E11b- defective viruses in tumor therapy. (C) 1997 Academic Press.