The p53 protein and its interactions with the oncogene products of the small DNA tumor viruses.

The p53 protein was first described 10 years ago in studies from three independent laboratories (Linzer and Levine, 1979; Lane and Crawford, 1979; DeLeo et a/., 1979). p53 was shown to form oligomeric protein complexes with the SV40 large tumor antigen (T antigen) in SV40-infected or -transformed cells (Linzer and Levine, 1979; Lane and Crawford, 1979). That the p53 protein was not encoded by SV40 and was not a proteolytic breakdown product of T antigen was demonstrated by immunoprecipitation of p53 protein from transformed cells not containing the SV40 genome (chemically transformed cells and embryonal carcinoma cells) (DeLeo et a/., 1979; Linzer and Levine, 1979) using antisera from animals bearing SV40-induced tumors. By virtue of these observations, p53 was therefore termed a tumor antigen which interacted with a viral oncogene product, the SV40 large T antigen. In many different transformed cells, the levels of p53 protein were elevated some 5to 1 OO-fold above the nontransformed cell counterpart. In a cell transformed with a temperature-sensitive SV40 T antigen mutant, both the transformed phenotype and p53 levels were regulated in a temperature conditional fashion (Linzer et al., 1979). The level of this regulation was shown to be at the post-translational stage, where p53 protein from transformed cells had a much longer halflife than p53 detected in nontransformed cells (Oren et al., 1981; Reich et a/., 1983). Because genomic and cDNA clones of p53 were first shown to immortalize cells in culture (Jenkins et a/., 1984) or cooperate with the ras oncogene to transform primary rat embryo fibroblasts (Parada eta/., 1984; Eliyahu eta/., 1984), p53 was termed an oncogene. When it was demonstrated that these p53 genomic and cDNA clones were all mutant forms of this gene and that the wild-type p53 gene failed to have these biological activities (Eliyahu eT a/., 1988; Hinds et a/., 1989a), alternative hypotheses were considered. In particular, evidence began to emerge that the function of wild-type ~53 might be to negatively regulate the growth of some cells and that p53 appears to act as a tumor suppressor gene under some circumstances (Mowat et al., 1985; Finlay et al., 1989; Baker et a/., 1989). Thus, the identity of the p53 gene and gene product has evolved from tumor antigen to oncogene to tumor suppressor gene over a 1 Oyear period.