Mole Spo p 53

acrjourna h levels of the critical p53 inhibitor Mdm4 is common in tumors that retain a wild-type p53 allele, ting that Mdm4 overexpression is an important mechanism for p53 inactivation during tumorigenesis. t this hypothesis in vivo, we generated transgenic mice with widespread expression of Mdm4. Two ndent lines of transgenic mice, Mdm4 and Mdm4, developed spontaneous tumors, the most prevf which were sarcomas. To determine whether overexpression of Mdm4 also cooperated with p53 hetosity to induce tumorigenesis, we generated Mdm4 p53 mice. These mice had significantly rated tumorigenesis and a distinct tumor spectrum with more carcinomas and significantly fewer lymas than p53 or Mdm4 mice. Importantly, the remaining wild-type p53 allele was retained in most Tg1 p53 tumors. Mdm4 is thus a bona fide oncogene in vivo and cooperates with p53 heterozygosity to Mdm4 drive tumorigenesis. These Mdm4 mice will be invaluable for in vivo drug studies of Mdm4 inhibitors. Cancer Res; 70(18); OF1–7. ©2010 AACR.