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      Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome.

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          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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          Author and article information

          Journal
          Cell
          Cell
          Elsevier BV
          0092-8674
          0092-8674
          Dec 17 2004
          : 119
          : 6
          Affiliations
          [1 ] Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
          Article
          S0092867404010463
          10.1016/j.cell.2004.11.004
          15607980
          6a82ee3d-d20b-4c36-8576-0d6e4b170b3b
          History

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