Nature Genetics36, 63 - 68 (2004)
Published online: 21 December 2003; | doi:10.1038/ng1282
Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice
Geng Liu1, John M Parant1, Gene Lang1, Patty Chau1, Arturo Chavez-Reyes1, Adel K El-Naggar2, Asha Multani1, Sandy Chang1
& Guillermina Lozano1
1
Department of Molecular Genetics, Section of Cancer Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
2
Department of Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
The p53 protein integrates multiple upstream signals and functions as a tumor suppressor by activating distinct downstream genes1,
2,
3. At the cellular level, p53 induces apoptosis, cell cycle arrest and senescence. A rare mutant form of p53 with the amino acid substitution R175P, found in human tumors, is completely defective in initiating apoptosis but still induces cell cycle arrest4,
5. To decipher the functional importance of these pathways in spontaneous tumorigenesis, we used homologous recombination to generate mice with mutant p53-R172P (the mouse equivalent of R175P in humans). Mice inheriting two copies of this mutation (Trp53515C/515C) escape the early onset of thymic lymphomas that characterize Trp53-null mice. At 7 months of age, 90% of Trp53-null mice had died, but 85% of Trp53515C/515C mice were alive and tumor-free, indicating that p53-dependent apoptosis was not required for suppression of early onset of spontaneous tumors. The lymphomas and sarcomas that eventually developed in Trp53515C/515C mice retained a diploid chromosome number, in sharp contrast to aneuploidy observed in tumors and cells from Trp53-null mice. The ability of mutant p53-R172P to induce a partial cell cycle arrest and retain chromosome stability are crucial for suppression of early onset tumorigenesis.
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