title: Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice.
abstract: The p53 protein integrates multiple upstream signals and functions as a tumor suppressor by activating distinct downstream genes. 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 arrest. 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 (Trp53(515C/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 Trp53(515C/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 Trp53(515C/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.
authors.affiliation: Department of Molecular Genetics, Section of Cancer Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
authors.forename: Geng
authors.initials: G
authors.lastname: Liu
authors.forename: John M
authors.initials: JM
authors.lastname: Parant
authors.forename: Gene
authors.initials: G
authors.lastname: Lang
authors.forename: Patty
authors.initials: P
authors.lastname: Chau
authors.forename: Arturo
authors.initials: A
authors.lastname: Chavez-Reyes
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.forename: Asha
authors.initials: A
authors.lastname: Multani
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D043171:Chromosomal Instability; D016158:Genes, p53; D008223:Lymphoma / Q000235:genetics* / Q000517:prevention & control; D051379:Mice; D008817:Mice, Mutant Strains; D011003:Ploidies