The p53 tumor suppressor gene and gene product

Abstract

Three lines of evidence suggest that the p53 gene and gene product may act as a negative regulator of growth or a tumor suppressor gene: (1) in several tumors of mice and humans, both of the p53 alleles have suffered mutations and in some cases large or complete deletions demonstrating a loss of function mutation. (2) The murine wild-type p53 gene can suppress transformation of rat embryo fibroblasts in cell culture by other oncogenes such as the adenovirus E1A plus ras genes. In rat embryo fibroblast cells transfected with the wild-type p53 gene, E1A and ras, the wild-type p53 gene either fails to express any RNA or only a mutant form of this p53 gene is selected for in culture. This is analogous (in cell culture) to the observations made in tumors (in vivo) discussed above. (3) Both the tumor suppressor gene, the retinoblastoma sensitivity gene or Rb and p53 are found in oligomeric protein complexes with the oncogene products of the DNA tumor viruses. Both the SV40 large T antigen and the adenovirus E1A plus E1B-55Kd proteins bind to, and presumably inactivate, these tumor suppressor activities which in turn contributes to cellular transformation. A set of point mutations, deletions or insertion mutations in the murine p53 gene localized between amino acid residues 120-270 (out of 390 amino acids) activate the p53 gene and gene product for cooperation with ras in transforming rat embryo fibroblast cells. The mutant p53 proteins produced by these transformed cells all have several properties in common; (1) a prolonged half-life, which is 20 min for the wild-type gene product to greater than 2 hr for the mutant proteins, (2) very high levels of p53 protein in these transformed cells, (3) a conformational change in the mutant p53 proteins, and (4) the binding of mutant p53 protein to the rat cellular heat shock protein, hsc70. These transformation activating mutations apparently act in a trans-dominant manner with the murine mutant p53, forming an oligomeric protein complex with the wild-type rat p53 proteins, resulting in the inactivation of the wild-type p53 function (rat p53).