CONFORMATIONAL EFFECTS OF ENVIRONMENTALLY-INDUCED, CANCER-RELATED MUTATIONS IN THE P53 PROTEIN

The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. A considerable number of environmentally induced, cancer-related p53 mutations in human tum ors have been found in a highly conserved proline rich sequence of the p53 protein encompassed by amino acid residues 147-158. Using conform ational energy analysis based on ECEPP (Empirical Conformational Energ y for Peptides Program), we have determined the low-energy three-dimen sional structures for this dodecapeptide sequence for the human wild-t ype p53 protein and three environmentally induced, cancer-related muta nt p53 proteins with His-151, Ser-152, and Val-154, respectively. The results suggest that the wild-type sequence adopts a well-defined low- energy conformation and that the mutant peptides adopt well-defined co nformations that are distinctly different from the conformation of the wild-type peptide. These results are consistent with experimental con formational studies demonstrating altered detectability of antigenic e pitopes in wild-type and mutant p53 proteins. These results suggest th at the oncogenic effects of these environmentally induced, cancer-rela ted, mutant p53 proteins may be mediated by distinct local conformatio nal changes in the protein.