The germline- and tissue-specific effects of endogenous point-mutant p53

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2005.Vita.Includes bibliographical references.p53 is frequently altered in human tumors through missense mutations that result in accumulation of mutant p53 protein. These mutations may confer dominant-negative or gain-of- function properties to p53. To ascertain the physiological effects of tumor-associated point- mutations in p53, the structural mutant p53R172H and the contact mutant p53R270H (codons 175 and 273 in humans) were engineered into the endogenous p53 locus in mice. p53R270H/+ and p53R172H/+ mice are mouse models of Li-Fraumeni Syndrome (LFS). They developed allele- specific tumor spectra that were distinct from p53+/- mice and that better reflect the broad spectrum of tumors found in LFS patients. Dominant effects that varied by allele and function were observed in primary cells derived from these mice. In addition, p53R270H/- and p53R172H/- mice developed novel tumors compared to p53-/- mice, including hemangiosarcomas and variety of carcinomas. These data support a gain-of-function effect by mutant p53 toward the development of epithelial and endothelial tumors. Furthermore, conditional mutant p53 alleles were used in combination with a conditional activated K-ras allele to generate mouse models of advanced lung adenocarcinoma. In this system, the effects of endogenous mutant p53 were found to be both allele-specific and tissue- specific. This work provides insight into the spectrum of p53 mutations in human cancers and demonstrates that point-mutant p53 alleles expressed under physiological control have enhanced oncogenic potential beyond the simple loss ofp53 function.bu Kenneth Paul Olive.Ph.D