THE 1993 WALTER-HUBERT-LECTURE - THE ROLE OF THE P53 TUMOR-SUPPRESSORGENE IN TUMORIGENESIS

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 throug h the transcriptional transactivation activity of the protein. Overexp ression of the p53 protein results either in arrest in the G(1) 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 th ought that p53 acts to protect cells against the accumulation of mutat ions 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 (thymocyte s). Cells lacking p53 have lost this cell cycle control and presumably accumulate damage-induced mutations that result in tumorigenesis. Thu s, the role of p53 in suppressing tumorigenesis may be to rescue the c ell or organism from the mutagenic effects of DNA damage. Loss of p53 function accelerates the process of tumorigenesis and alters the respo nse of cells to agents that damage DNA, indicating that successful str ategies for radiation therapy may well need to take into account the t issue of origin and the status of p53 in the tumour.