NUTRITIONAL REGULATION OF RAS PROTO-ONCOGENE ACTIVITY

RAS介导的逃避正常监管似乎是一个频繁的事件 在癌症的多步骤发生过程中。许多体外研究表明， 展示了ras和其他原癌基因产物之间的相互作用， 尤其是myc和肿瘤抑制基因p53。这项研究的有用模型 在这些相互作用中，有一种叫做p53“基因敲除”的小鼠，它是一种转基因小鼠。 哪种无效的p53胚系突变可阻止其中一种或 P53的两个等位基因。这些P53基因缺陷的动物发育正常，但 易于早期发生肿瘤的。我们正在使用这些小鼠来研究 不同饮食和p53基因剂量对肿瘤发生的影响 加速致癌模型，不需要暴露于 引发或促进肿瘤发生的化学物质。此外，成纤维细胞 从具有不同遗传背景的胚胎培养而来的 强大的体外系统，用于解决一些相同的问题。我们是 用ras、myc和p53的探针检测这些原癌基因的表达。 转基因小鼠不同组织中的癌基因。 另一个特别令人感兴趣的是最近描述的一种许多p53的介体 行动，WAF1/Cip1。通过聚合酶链式反应(PCR)，我们有 扩增和克隆了小鼠WAF1序列的一部分，并正在使用它 作为检测这种新蛋白在P53缺失和 经过各种饮食操作的野生型小鼠。 赫斯汀博士正在进行的研究正在调查 两种有效但鲜为人知的饮食方案，大大推迟了 啮齿动物肿瘤的发展：卡路里限制和补充 脱氢表雄酮和相关类固醇。这些研究将确定 这样的饮食控制如何与p53的基因剂量相结合 影响原癌基因的表达和某些关键代谢的活性 酵素。

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.