The p53 protein integrates multiple upstream signals andfunctions as a tumor suppressor by activating distinctdownstream genes1–3. At the cellular level, p53 inducesapoptosis, cell cycle arrest and senescence. A rare mutant formof p53 with the amino acid substitution R175P, found in humantumors, is completely defective in initiating apoptosis butstill induces cell cycle arrest4,5. To decipher the functionalimportance of these pathways in spontaneous tumorigenesis,we used homologous recombination to generate mice withmutant 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 characterizeTrp53-null mice. At 7 months of age, 90% of Trp53-null micehad died, but 85% of Trp53515C/515C mice were alive andtumor-free, indicating that p53-dependent apoptosis was notrequired for suppression of early onset of spontaneous tumors.The lymphomas and sarcomas that eventually developed inTrp53515C/515C mice retained a diploid chromosome number, insharp contrast to aneuploidy observed in tumors and cells fromTrp53-null mice. The ability of mutant p53-R172P to induce apartial cell cycle arrest and retain chromosome stability arecrucial for suppression of early onset tumorigenesis.