The p53 tumor suppressor gene is the most frequently observed genetic lesion in human cancers. To further study the role of p53 in tumorigenesis, the investigator has developed mice with inactivated germ line p53 alleles by gene targeting methods in embryonic stem cells. These p53 deficient mice are highly susceptible to early onset spontaneous tumors of various kinds. The major goals of this proposal are to (1) further characterize tumorigenesis and oogenesis in the p53 deficient mice; (2) study the role of p53 missense mutants in tumorigenesis in a mouse model; and (3) explore the interactions of the oncogene mdm-2 with p53 in an in vivo context. The major tumor groups which arise in the p53-deficient mice are lymphomas and sarcomas. The investigator will attempt, using the techniques of comparative genomic hybridization and SSLP PCR, to identify tumor suppressor genes and oncogene mutations which may cooperate frequently with p53 loss to form sarcomas and lymphomas in the p53-deficient mice. In addition, the female mice lacking p53 will be examined for defects in oogenesis and folliculogenesis, which is suggested by preliminary data. Some initial tumorigenesis data in the p53-deficient mice suggest the possibility that wild type p53 may play an important extracellular role in inhibition of tumorigenesis. To follow up on this possibility, the investigator is performing in vivo transplantation experiments to determine whether mice with normal levels of wild type p53 can inhibit the growth of tumors formed in p53-deficient animals. If successful, further in vitro studies will be performed in an attempt to identify the critical factors in p53-mediated tumor inhibition. Since in most human tumors, p53 mutations are missense mutations and not deletions, the investigator would like to explore the role of selected p53 missense mutants in an in vivo context by expressing mutant p53s in a mouse model with or without endogenous p53. He thinks this may provide new insights into the biological activities of mutant p53s in tumorigenesis. Finally, he is in the process of generating mdm-2 transgenic mice and mdm-2 deficient mice in an attempt to understand further the role of mdm-2 in development and tumorigenesis. In addition, crossing the mdm-2 mice to his p53-deficient mice will allow formulating experiments to analyze functional interactions of these two proteins in tumorigenesis and DNA damage response pathways.
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