TUMOR SUPPRESSOR HETEROZYGOTES AS GENOTOXICANT REPORTERS

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The overall goal of this Project is to determine the early mutational events that can occur in a cell during tumor progression. To this end we will incorporate gene-based mutation detection systems into mice already harboring mutations in genes known to play a role in growth control and tumor suppression. We have chosen to study mice with deficiencies in p53, TGFbeta1, and p27KIP1. p53 is a known tumor suppressor and is one of the most commonly mutated gene found in tumor cells. However, early mutations events resulting from a p53 mutation need to be measured because it is unclear how cells progress from a tumor suppressor deficiency to the neoplastic state. With respect to TGFbeta1, we have determined that although it is a potent regulator of growth for many cell types, it probably has only an indirect role to play in tumor suppression. Altered tumor profiles of mice with combined deficiencies in p53 and TGFbeta1 indicate that TGFbeta1 can "modify" p53 tumor suppression; cultured TGFbeta1 deficient cells have decreased genomic stability, though only when placed under some form of mutagenic pressure; and TGFbeta1+/-animals live as long as their wildtype littermates without developing tumors at a higher rate, though they do have an increased incidence of gastric mucosal hyperplasia. Consequently, we believe TGFbeta1 to be a modifier of tumor suppressor activity because under mutagenic pressure from other sources, it can increase the threshold level of protection. p27KIP1 is a cyclin dependent kinase inhibitor whose levels are regulated by TGFbeta1. Although it functions to block the phosphorylation inactivation of Rb that leads to G/S transition, there is no evidence that it is commonly mutated in human tumors. The p27KIP1 knockout mouse will provide answers to the question whether it is a tumor suppressor gene or whether it functions more as a modifier of tumor suppression, much like seems to be the case for TGFbeta1.