Mutation of the p53 gene occurs frequently in a wide variety of human tumors. The role of these mutations in the growth regulation of cancer cells remains unanswered. The proposed studies involve the utilization of previously established biochemical and transformation assays and the development of new cell proliferation assays in human cells to characterize the biological properties of the human wild-type and mutant p53 proteins. (1). The initial goal of future experiments is to fully characterize the role of p53 mutations discovered in human tumors. The relative transforming activity of a variety of p53 mutants will be determined, and the biochemical properties of p53 proteins that most highly correlate with cellular transformation will be defined, with the goal of providing diagnostic criteria for analysis of human tumors. (2). The effect of a proline-arginine polymorphism (at amino acid 72) on the growth promoting and suppressive properties of the human mutant and wild-type p53 proteins will be determined. (3). The growth promoting properties of mutant human p53 proteins in a normal human cell background will be assayed by determining the ability of these mutants to immortalize or to complement additional oncogenes in the immortalization or transformation of human cells. (4). The endogenous p53 in individuals predisposed to the development of cancer will be characterized (wild-type or mutant), and the effect of mutant p53 over-expression on the in vitro life span of cells derived from such individuals will be assayed. (5). A new in vitro assay for the selection of growth promoting properties of p53 mutant alleles in human cells will be developed.
| Dittmer, D; Pati, S; Zambetti, G et al. (1993) Gain of function mutations in p53. Nat Genet 4:42-6 |
| Finlay, C A (1993) The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth. Mol Cell Biol 13:301-6 |
