The goal of this proposal is to determine the tumor suppressor role of the wild type K-ras gene in chemical carcinogenesis. Although the ras genes have long been established as proto-oncogenes, their dominant role in cell transformation has been questioned in previous studies. Recently, a lung tumor bioassay in heterozygous K-ras deficient mice was conducted by us to evaluate the effect of presence of the wild type K-ras allele on mouse lung tumorigenesis. Mice with a heterozygous K-ras deficiency had a significantly increased susceptibility to the chemical induction of lung tumors when compared to wild type mice, suggesting that a single copy of a wild-type K-ras allele could suppress chemically induced lung carcinogenesis. In addition, wild type K-ras allele inhibited colony formation and tumor development of a transformed cell line that contained a mutant K-ras. Moreover, published data suggest that the wild type K-ras allele is deleted in mouse lung adenocarcinomas carrying a mutant K-ras. In this proposal, we hypothesize that the wild type K-ras allele has tumor suppressor activity and is lost during tumor progression. Accordingly, four specific aims are proposed to test our hypothesis: 1) to examine the effect of the wild type K-ras allele on tumorigenesis and growth characteristics of lung tumor cell lines; 2) to evaluate the correlation between the presence of a mutant K-ras allele and the loss of wild type K-ras allele in human lung tumors; 3) to determine the role of the wild type K-ras allele at various stages of mouse lung carcinogenesis; and 4) to determine the effect of K-ras heterozygous deficiency on mouse lymphomagenesis and colon carcinogenesis. We believe that we have uncovered a novel tumor suppressor function of a gene identified and characterized as a classical oncogene. The K-ras gene seems to have dual function. On one hand it promotes cancer development as a gain-of-function oncogene and on other hand, it inhibits cancer as a loss of function tumor suppressor gene. Understanding the newly discovered role of the wild type K-ras has immediate and important implications for the development of various ras-directed gene therapy and drug development. Thus, this proposal offers a unique opportunity to characterize the tumor suppressor role of the wild type K-ras gene in carcinogenesis.
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