NUTRITIONAL REGULATION OF RAS PROTO-ONCOGENE ACTIVITY

ras介导的逃避正常调节似乎是一个经常发生的事件

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 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. We are using these mice both to study the effects of various diets and p53 gene dosage on carcinogenesis, and as a model of accelerated carcinogenesis that does not require exposure to chemicals that initiate 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 are using probes for ras, myc, and p53 to assess the expression of these proto- oncogenes in various tissues from transgenic mice. Also of special interest is a recently described mediator of many p53 actions, WAF1/Cip1. With the polymerase chain reaction (PCR), we have amplified and cloned a portion of the mouse WAF1 sequence and are using it as a probe to examine the role of this novel protein in p53-deficient and wildtype mice that have undergone various dietary manipulations. Studies in progress with Dr. S. Hursting are investigating the effects of two potent but poorly understood dietary regimens that dramatically delay tumor development in rodents: calorie restriction and supplementation with dehydroepiandrosterone and related steroids. These studies will determine how such dietary manipulations combine with the gene dosage of p53 to affect proto-oncogene expression and the activity of certain key metabolic enzymes.