Mutant p53: from guardian to fallen angel?

Abstract

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.