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The many faces of p53: something for everyone

A. Levine

Published 2019 in Journal of Molecular Cell Biology

ABSTRACT

The p53 gene, from discovery to classification: the first 10 years Forty years ago four research laboratories in London, Paris, New York/Bethesda, and Princeton uncovered the existence of the p53 protein (Deleo et al., 1979; Lane and Crawford, 1979; Linzer and Levine, 1979; Kress et al., 1979). Each laboratory came upon this protein for a different reason and with a different experimental approach that uncovered this unanticipated result. Together, the four papers permitted one to conclude the following: (i) in SV40-infected and transformed cells the SV40-encoded oncogene protein, the large T-antigen, formed a protein complex with a cellular-encoded protein of ∼53000 daltons in size. (ii) This p53 protein was detected at high levels in a variety of transformed cells derived from viral, chemical, or inherited (teratocarcinomas) transformation events. (iii) Nontransformed cells expressed lower levels of the p53 protein. (iv) Animals bearing tumors produced antibodies directed against the p53 protein. A temperature-sensitive mutation in the SV40 large T-antigen gene (the oncogene of this virus) was employed to demonstrate that the p53–T-antigen complex was formed at the permissive temperature, where the cells are transformed, but not at the nonpermissive temperature, where the cells behave normally (Linzer and Levine, 1979; Linzer et al., 1979). At a later date p53 protein complexes with viral oncogene products were observed, including the adenovirus E1b-58kd protein (Sarnow et al., 1982) and the human papilloma virus E6 oncoprotein (Scheffner, et al. 1990; Werness et al., 1990; which is the cause of human cervical cancers and some head and neck cancers). In order to explore the functions of the p53 protein, several p53 cDNAs were isolated and cloned (Oren and Levine, 1983; Oren et al., 1983; Pennica et al., 1984). These clones were tested for oncogene activities and found to cooperate with the RAS oncogene in transforming embryonic cells (Eliyahu et al., 1984; Parada et al., 1984). Thus, it appeared that the p53 gene was an oncogene whose protein forms a complex with viral oncogene proteins, possibly mediating transformation. However, the cDNA clone isolated by Pennica failed to transform cells in culture and had a single amino acid change when compared with the Oren cDNA clone, which did transform cells. Was the amino acid difference between these clones significant? Was this difference a sequencing mistake? A polymorphism? Or a mutation? If it was a mutation, which clone was the wild-type and which was the mutant? To address these questions, Oren and Levine exchanged clones (and reproduced each other’s observations). By 1989 it became clear that mutations in the p53 cDNA clones resulted in cellular transformation, and wild-type p53 protein prevented transformation and functioned as a tumor suppressor (Eliyahu et al., 1989; Finlay et al., 1989). p53 mutations in both p53 alleles in colon cancers of humans resulted in the same conclusion; p53 functioned as a tumor suppressor gene that helped to prevent cancer (Baker et al., 1990a, b, Nigro et al., 1995). From 1979 to 1989 the p53 protein was alternatively referred to as a fetal antigen expressed in the teratocarcinoma stem cells, a tumor antigen that induced antibodies in animals and humans with tumors, an oncogene whose mutant forms could transform cells, and, finally, a tumor suppressor gene that prevented cancers. During this time the p53 protein was demonstrated to increase its concentration in response to DNA damage (Maltzman and Czyzyk, 1984). Over these first 10 years of research the p53 protein was shown to have many diverse faces and activities, functioning as an oncogene and a tumor suppressor gene while responding to DNA damage in a cell.

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