NUTRITIONAL REGULATION OF RAS PROTO-ONCOGENE ACTIVITY

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Ras-mediated escape from normal regulation appears to be a frequent event in the multi-step genesis of cancer. A number of in vitro studies have demonstrated interactions between ras and other proto-oncogene products, especially myc and the tumor suppressor p53. A useful model for the study of these interactions is the commercially available p53 "knockout" mouse, a transgenic mouse in which null p53 germ line mutations prevent the expression of either one or both alleles for p53. Such p53-deficient animals develop normally but are prone to early tumorigenesis; indeed, 75% of homozygotes develop spontaneous neoplasms by 6 months of age. These mice can be used to study the effects of p53 gene dosage and various diets on carcinogenesis, or they can be used as a model of accelerated carcinogenesis that does not require exposure to chemicals that initiate and/or promote tumorigenesis. Moreover, fibroblasts cultured from embryos with the various genetic backgrounds afford a powerful in vitro system for addressing some of the same issues. We will use cDNA probes for ras, myc and p53 to assess the expression of these proto-oncogene mRNAs in various tissues from transgenic mice. Studies in progress with Dr. S. Hursting are investigating the effect of caloric restriction (a potent but poorly understood dietary regimen that dramatically inhibits tumor development in rodents); these studies will determine how this dietary manipulation combines with the gene dosage of p53 to affect proto-oncogene expression. Another area of interest is the dietary effect of the monoterpene, limonene, a major component of orange oil that has been shown to inhibit tumorigenesis in animal models. Part of the action of limonene may be through its inhibition of the farnesylation of ras proteins; this post- translational lipid modification is required for location of ras to the plasma membrane and hence ras activity. Using the sensitive semi- quantitative assay for ras we previously developed, we will be able to examine the effects of limonene on ras in p53-deficient mice in vivo and in vitro.