How TP53 (almost) became an oncogene

Like the histories of many other genes, the discovery and characterization of p53 are associated with some false leads, dead ends, and major detours. The chronicle of p53’s early years is no exception. As is now well known, the protein was actually discovered independently by three groups—those of Arnie Levine, David Lane, and Lloyd Old. The year 1979 was truly the annus mirabilis of p53 research. In March of that year, the laboratory of Lionel Crawford and his then-post-doctoral fellow, David Lane, described the association of p53 with the SV40 large T antigen, against which they had developed an effective immunoprecipitation (Lane and Crawford, 1979). Two months later, two others research groups—those of Arnie Levine whose career we celebrate here and of Lloyd Old—reported the existence of this protein and tumor antigen independently (DeLeo et al., 1979; Linzer and Levine, 1979). This, on its own, was an unusual convergence of three fully independent research efforts occurring essentially simultaneously. The research in the Lloyd Old Laboratory at Memorial Sloan-Kettering was led by Albert DeLeo. He found that the tumors created by methyl-cholanthrene-induced mouse sarcoma cells elicited an antibody response reactive with a protein of ∼ 53 kDa; the same anti-serum detected this protein in a variety of other transformed murine cell lines. He noted that the protein was generally not very immunogenic, that the source of its immunogenicity when expressed by the methyl-cholanthrene-induced sarcoma cells was unclear, and that it was likely a protein of cellular origin, since it was expressed in a variety of murine cancer cell lines tested, some of which had no indication of viral infection (DeLeo et al., 1979). The subsequent development by the Old Laboratory of an anti-p53 monoclonal antibody led this group to demonstrate its widespread expression in a variety of tumor cell lines, its nuclear localization, and the fact that its elevated expression was associated with the active proliferation of cells. This association of p53 expression with cell proliferation was not observed in certain neoplastic cells, which instead expressed it constitutively. Among other hypotheses, this group speculated that p53 might be involved in initiating DNA synthesis. In another work, they reported in May of 1981 the fact that this protein formed complexes with SV40 large T antigen and the fact that cross-reactive proteins could be found in the tumor cells of other species. Over the next four decades, DeLeo’s group, then in Pittsburgh, pursued p53 as an antigen that might serve as an attractive target for anti-tumor immunotherapy (DeLeo, 1998; Dippold et al., 1981). By 1980, the protein had been found in a variety of transformed cells including those transformed by Abelson murine leukemia virus. Research on this protein, termed variously p53, p50, even p48, soon exploded, and by 1983 a workshop was held in the UK focusing specifically on p53 and attended by almost two dozen researchers whose laboratories had already made the study of this protein a significant focus of their research agenda. The allure of this protein was irresistible. Its expression in a wide range of cancer cell types held the promise of finally yielding a universally expressed tumor antigen that could serve as a target of anti-tumor immunotherapy. Already by 1979, the major fork in the road of p53 research was apparent. DeLeo’s group, as said, focused on the role of this protein as a tumor antigen; the other groups—those of Levine and Crawford—turned their attention to the functional role of the p53 protein, specifically its cell-physiologic role in cell transformation. Arnie Levine’s group, soon including Moshe Oren, and that of Lionel Crawford and importantly his trainee David Lane, soon led the charge in the functional characterization of p53 (Lane and Crawford, 1979; Linzer and Levine, 1979). At this point, it is instructive to recall the mindset of cancer biologists at the time. In 1976, the research in the group of Harold Varmus and Mike Bishop had revealed the existence of the Rous sarcoma virus src oncogene and its derivation from the corresponding normal proto-oncogene, c-src (Stehelin et al., 1976). It is difficult to overestimate the conceptual impact of this finding, specifically the existence of genes in the normal cellular genome that, when reshaped in various ways, could function as dominant alleles in driving cell transformation. Amidst the subsequent