The 1993 Walter Hubert Lecture: the role of the p53 tumour-suppressor gene in tumorigenesis

Abstract

The p53 tumour-suppressor gene is mutated in 60% of human tumours, and the product of the gene acts as a suppressor of cell division. It is thought that the growth-suppressive effects of p53 are mediated through the transcriptional transactivation activity of the protein. Overexpression of the p53 protein results either in arrest in the G1 phase of the cell cycle or in the induction of apoptosis. Both the level of the protein and its transcriptional transactivation activity increase following treatment of cells with agents that damage DNA, and it is thought that p53 acts to protect cells against the accumulation of mutations and subsequent conversion to a cancerous state. The induction of p53 levels in cells exposed to gamma-irradiation results in cell cycle arrest in some cells (fibroblasts) and apoptosis in others (thymocytes). Cells lacking p53 have lost this cell cycle control and presumably accumulate damage-induced mutations that result in tumorigenesis. Thus, the role of p53 in suppressing tumorigenesis may be to rescue the cell or organism from the mutagenic effects of DNA damage. Loss of p53 function accelerates the process of tumorigenesis and alters the response of cells to agents that damage DNA, indicating that successful strategies for radiation therapy may well need to take into account the tissue of origin and the status of p53 in the tumour.

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

“…The recent demonstration that mouse ®broblasts with truncated BRCA2 are more sensitive to UV irradiation than controls (perhaps due to defective nucleotide or base excision repair) is clearly of interest in the context of this observation (Patel et al, 1998). Previous studies of sporadic breast cancer have revealed three codons at which mutation most commonly occurs: 175, 248 and 273 (Levine et al, 1994;Hollstein et al, 1994). Two BRCA1-associated and one BRCA2-associated tumour contained mutation at these`hot spot' codons, these being the tandem 247, 248 CC4TT mutation alluded to above in two cases and a single CGG4TGG transition at codon 248 in one BRCA1 tumour.…”

Conformational phenotype of p53 is linked to nuclear translocation

“…The p53 tumor suppressor plays a crucial role in the maintenance of genomic stability by transcriptionally activating genes involved in DNA repair, growth arrest and apoptosis (Levine, 1997;Levine et al, 1994). P53 is activated by genotoxic agents and although the events involved in the activation of p53 are not well understood, the process is thought to be a complicated one, involving the stabilization of the protein (Kubbutat and Vousden, 1998), its translocation into the nucleus (Shaulsky et al, 1991b,c), and tetramerization (McLure and Lee, 1998), all of which are important steps in the process that lead to its activation for DNA binding and induction of target gene expression.…”

Absence of p53 permits propagation of mutant cells following genotoxic damage

“…p53 mutations are frequently found in human cancer (Hollstein et al, 1991) especially in association with progression or high grade malignancy (Carder et al, 1993). This is generally regarded as re¯ecting the importance, in the genesis of malignant clones, of by-passing the cell cycle constraints that facilitate repair or promote apoptosis (Levine et al, 1994) and so restrict the potential mutational impact of DNA damage. In line with this interpretation, mice de®cient in p53 by homologous recombination knockout are spontaneously highly susceptible both to leukaemia/lymphoma and solid tumours (Donehower et al, 1992;Purdie et al, 1994;Kemp et al, 1994) and progression of experimentally induced tumours is more rapid in the absence of p53 function (Kemp et al, 1993).…”