The properties of p53 proteins selected for the loss of suppression of transformation.

The wild-type p53 protein can act as a suppressor of transformation in that it will block or reduce the formation of adenovirus E1A plus ras mediated transformants of primary rat embryo fibroblasts (C. A. Finlay et al., Cell, 57: 1083-1093, 1989). In those experiments, all of the transformed cell lines that arose selected for mutations in the transfected p53 gene, and many of these cell lines now express mutant p53 proteins. These mutant p53 genes are unusual because they were selected only for their inability to act as a transformation suppressor of other oncogenes as opposed to mutant p53 genes that arise spontaneously in tumors or transformed cell lines. p53 mutants that arise in tumors may be selected for several properties, and these mutants do have a number of phenotypes in common; for example, (a) they no longer block the cell division of transformed cells in culture (growth suppressor); (b) they cooperate with ras to transform rat embryo cells; (c) they enhance the plating efficiency of rat embryo cells; (d) some mutants have an altered protein conformation; (e) most mutants have a much longer half-life and greater concentration in the cells; and (f) mutants have lost or have a reduced ability to act as a transcription factor. Experiments were carried out to test whether the selection for p53 mutants that fail to block oncogene mediated transformation would also have some or all of the other properties of p53 mutants that arise in spontaneous tumors. Two mutants selected for their lost ability to block transformation were cloned, sequenced, and tested for all of the phenotypes listed above. The properties that these mutants had in common were (a) cooperation with ras to transform cells, (b) enhanced plating efficiency of cells, (c) elevated steady-state expression levels, and (d) a lost or reduced ability to act as a transcription factor.