LARGE E1B PROTEINS OF ADENOVIRUS TYPE-5 AND TYPE-12 HAVE DIFFERENT EFFECTS ON P53 AND DISTINCT ROLES IN CELL-TRANSFORMATION

The formation of complexes between oncoproteins of DNA tumor viruses a nd the cellular protein p53 is thought to result in inactivation of th e growth suppressor function of p53. In cells transformed by nononcoge nic human adenovirus type 5 (Ad5), the 55-kDa protein encoded by E1B f orms a stable complex with p53 and sequesters it in the cytoplasm. How ever, the homologous 54-kDa protein of highly oncogenic Ad12 does not detectably associate with p53. Yet in Ad12-transformed cells, p53 is m etabolically stable, is present at high levels in the nucleus, and con tributes to the oncogenicity of the cells. Such properties have previo usly been described for mutant forms of p53. Here, we show that stable p53 in Ad12-transformed cells is wild type rather than mutant and tha t stabilization of p53 is a direct consequence of the expression of th e Ad12 E1B protein. We also compared the effects of the E1B proteins o n transformation of rodent cells by different combinations of oncogene s. A synergistic interaction was observed for the gene encoding the 54 -kDa E1B protein of Ad12 with myc plus ras oncogenes, resembling the e ffect of mutant p53 on myc plus ras. In contrast, the Ad5 55-kDa E1B p rotein strongly inhibited transformation by myc plus ras but stimulate d transformation by E1A plus ras. The data are explained in terms of d ifferent interactions of the two E1B proteins with endogenous p53. The results suggest that in cultured rat cells, endogenous wild-type p53 plays an essential role in cell proliferation, even in the presence of myc plus ras. The dependence on p53 is lost, however, when the adenov irus E1A oncogene is present.