The p.53 gene and its protein have acquired major importance in the understanding of the origins of neoplasia in human beings. Of all carcinomas, 60-65% contain mutations at thep.53 locus (Levine, 1993) and these mutations take a characteristic form; one p.53 allele usually sustains a point mutation, producing a mis-sense protein that accumulates to high levels in the cancerous cells. The second allele is lost via gene conversion or deletion. This is the property of a tumor-suppressor gene that selects against the presence of a wild-type function of the p53 protein. Proof thatp.53 acts like a tumor-suppressor gene comes from mice in which bothp.53 alleles have been lost through insertional mutagenesis. These mice all develop cancer at a young age (Donehowcr et al., 1992). The function lost by these mutations appears to be the transcription factor activity which is readily detected with the wild-type p53 protein (Zambetti and Levine, 1993). The levels of the p53 transcription factor increase in response to DNA damage (Maltzman and Czyzyk, 1984), resulting in either cellular GI arrest (Kuerbitz et al., 1992) or apoptosis (Yonish-Rouach et al., 1991;Shaw et al., 1992). Thus, the wild-type pS3 protein appears to mediate a pathway that permits damaged DNA to be repaired prior to DNA replication (GI arrest) or moves cells into a pathway which eliminates abnormal cells that would arise from duplication of damaged DNA (apoptosis). By contrast, mutant p53 proteins fail to "guard the genome" from replication errors (mutations) which result from entering S-phase with a DNA template unsuitablc for reproduction of a pcrfect copy.
Our present-day understanding of these concepts has its origins in the study of the DNA tumor viruses and the discovery of the pS3 protein (Linzer and Levine, 1979; Lane and Crawford, 1979). Those observations in turn rely upon the discovery of one of