Large E1B proteins of adenovirus types 5 and 12 have different effects on p53 and distinct roles in cell transformation.
The formation of complexes between oncoproteins of DNA tumor viruses and the cellular protein p53 is thought to result in inactivation of the growth suppressor function of p53. In cells transformed by nononcogenic human adenovirus type 5 (Ad5), the 55-kDa protein encoded by E1B forms a stable complex with p53 and sequesters it in the cytoplasm. However, the homologous 54-kDa protein of highly oncogenic Ad12 does not detectably associate with p53. Yet in Ad12-transformed cells, p53 is metabolically stable, is present at high levels in the nucleus, and contributes to the oncogenicity of the cells. Such properties have previously been described for mutant forms of p53. Here, we show that stable p53 in Ad12-transformed cells is wild type rather than mutant and that stabilization of p53 is a direct consequence of the expression of the Ad12 E1B protein. We also compared the effects of the E1B proteins on transformation of rodent cells by different combinations of oncogenes. A synergistic interaction was observed for the gene encoding the 54-kDa E1B protein of Ad12 with myc plus ras oncogenes, resembling the effect of mutant p53 on myc plus ras. In contrast, the Ad5 55-kDa E1B protein strongly inhibited transformation by myc plus ras but stimulated transformation by E1A plus ras. The data are explained in terms of different 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 adenovirus E1A oncogene is present.
van den Heuvel
S J
SJ
Laboratory of Molecular Carcinogenesis, Sylvius Laboratory, University of Leiden, The Netherlands.
van Laar
T
T
The
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van der Eb
A J
AJ
D017501:Adenovirus E1B Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005347:Fibroblasts; D016158:Genes, p53; D011905:Genes, ras; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344; D015183:Restriction Mapping; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
D017501:Adenovirus E1B Proteins; D009838:Oligodeoxyribonucleotides; D016159:Tumor Suppressor Protein p53