[HTML][HTML] Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome

KP Olive, DA Tuveson, ZC Ruhe, B Yin, NA Willis… - Cell, 2004 - cell.com
KP Olive, DA Tuveson, ZC Ruhe, B Yin, NA Willis, RT Bronson, D Crowley, T Jacks
Cell, 2004cell.com
The p53 tumor suppressor gene is commonly altered in human tumors, predominantly
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 p53 point mutation, the structural mutant p53 R172H and the
contact mutant p53 R270H (codons 175 and 273 in humans) were engineered into the
endogenous p53 locus in mice. p53 R270H/+ and p53 R172H/+ mice are models of Li …
Abstract
The p53 tumor suppressor gene is commonly altered in human tumors, predominantly 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 p53 point mutation, 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 models of Li-Fraumeni Syndrome; they developed allele-specific tumor spectra distinct from p53+/− mice. In addition, p53R270H/ and p53R172H/ mice developed novel tumors compared to p53−/− mice, including a variety of carcinomas and more frequent endothelial tumors. Dominant effects that varied by allele and function were observed in primary cells derived from p53R270H/+ and p53R172H/+ mice. These results demonstrate that point mutant p53 alleles expressed under physiological control have enhanced oncogenic potential beyond the simple loss of p53 function.
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