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Mutant p53: from guardian to fallen angel?

Oncogene volume 26, pages 2142–2144 (2007)Cite this article

Since its discovery in 1979, the roles of p53 in tumourigenesis have changed remarkably. The ability of the initially cloned TP53 genes to immortalize certain cell types and to cooperate with other oncogenes in cellular transformation classified the TP53 gene as a cellular oncogene. Consistent with this view was the observation that the levels of p53 protein in tumour cells were significantly higher than p53 levels in normal cells. At that time, however, TP53 was ‘just another’ oncogene, and a relatively inefficient one, too, with completely unknown function. Consequently, p53 attracted only a few researchers outside the SV40 field, where p53 was discovered as a cellular protein in complex with the major transforming protein of this small DNA tumour virus, the SV40 T-antigen. As we all know, the story changed dramatically when in 1988 it was discovered that the TP53 genes hitherto used in different laboratories all coded for mutant p53 proteins, and that the corresponding wild-type TP53 gene suppressed, rather than further cellular transformation. Together with data appearing from the mutational analysis of the TP53 gene in human tumours, the TP53 gene turned from an oncogene into a tumour suppressor gene (see e.g. the Introduction by Weisz et al., this issue, for further details on the story). Meanwhile, p53 has developed into one of the most intensely studied proteins in human tumours, with about 3600 citations in PubMed each year.

Although most studies on p53 address the multitude of functions associated with wild-type p53 as a tumour suppressor, the story of mutant p53 as an oncogenic protein still goes on, although discussed controversially. Since the seminal findings by Finlay et al. (1988) that point mutations in the wild-type TP53 gene activate the gene for cooperation with an activated ras gene in cellular transformation, research on the hypothesis that mutant p53 is not just an inactivated tumour suppressor, but displays oncogenic activities on its own, has developed into an important section of p53 biology. The term ‘gain of function’ coined for summarizing the then unknown oncogenic activities of mutant p53 first appeared in a Science article by Halevy et al. (1990) and gained further acceptance after the publication of a Nature Genetics paper in 1993 by Dittmer et al. (1993), where the term ‘gain of function’ appeared in the title. By now, a steadily increasing number of laboratories worldwide pursue the idea of a mutant p53 gain of function (GOF). Significantly, the European Commission (EC) has funded a small research consortium in its framework programme five, and a considerably larger one in its framework programme six, for research on mutant p53 GOF and its clinical implications, emphasizing the growing impact of mutant p53 as an important determinant in human tumour development and progression.

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  1. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Tumor Virology, Hamburg, Germany

    W Deppert

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Deppert, W. Mutant p53: from guardian to fallen angel?. Oncogene 26, 2142–2144 (2007). https://doi.org/10.1038/sj.onc.1210276

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