NUTRITIONAL REGULATION OF RAS PROTO-ONCOGENE ACTIVITY

细胞周期蛋白依赖的激酶抑制剂是一类新近被表征的药物 调节细胞周期和细胞数量的蛋白质 动态平衡。其中p21/WAF1/CIP1可以转录 被肿瘤抑制基因P53激活(尤其是对DNA的反应 因此，细胞周期的调节与肿瘤的发生有关。 P21的转录也可以不依赖于p53而被诱导。这个 P21的作用是使细胞周期停滞于G1期； 根据细胞类型的不同，这种G1期停滞可以为修复 破坏DNA或导致细胞凋亡。 由于p53和p21之间的联系，我们检查了该表达 P21基因在p53基因敲除小鼠中的表达。我们已经证明了早期的肿瘤 在这些动物中看到的发展(主要是淋巴瘤和一些 肉瘤)可以通过饮食控制来延迟，例如卡路里 限制(CR)。尽管CR降低了基本细胞周期比率，但它 在大多数组织中不影响p21的表达；然而，令人惊讶的是，CR 降低野生型P53和p21蛋白在肝组织中的表达 P53基因缺失的小鼠。因此，CR对p21的作用是 与P53的存在无关，并可能是效应的反映 例如，氧化DNA损伤水平的降低， 需要p21诱导的G1期停滞才能修复。另一个肿瘤--延缓 方案，给予脱氢表雄酮(DHEA)， P53基因敲除特异性降低淋巴瘤的致瘤性 小鼠肝脏中p21的表达增加。差异化效应 CR和DHEA对p21表达和肿瘤谱的影响可能是 相关的。其他饮食调控方法的研究及其作用 P53基因剂量对p21及多种原癌基因表达的影响 正在进行中。此外，我们目前正在开发培养的 以含或不含p53的胎儿胚胎成纤维细胞为模型 不同药剂体外作用的研究系统 细胞周期调节因子的表达。该系统还将用于 解决P53功能丧失如何导致增加的问题 基因组不稳定。

The cyclin-dependent kinase inhibitors are a recently characterized class of proteins that regulate progression of the cell cycle and cell number homeostasis. One of these, p21/WAF1/CIP1, can be transcriptionally activated by the tumor suppressor p53 (especially in response to DNA damage) and so links regulation of the cell cycle and tumorigenesis. Transcription of p21 can also be induced independently of p53. The effect of p21 is to cause an arrest of the cell cycle at the G1 phase; depending on the cell type, this G1 arrest can allow time for repair of damaged DNA or lead to apoptotic death. Because of the link between p53 and p21, we examined the expression of p21 in the p53-knockout mouse. We have shown that the early tumor development seen in these animals (chiefly lymphomas with some sarcomas) can be delayed by dietary manipulations such as calorie restriction (CR). Although CR decreased the basal cell cycle rate, it had no effect on expression of p21 in most tissues; however, CR surprisingly decreased the expression of p21 in the livers of both wildtype-p53 and p53-nullizygous mice. Therefore, the action of CR on p21 is independent of the presence of p53 and may be a reflection of the effects of CR, such as decreased levels of the oxidative DNA damage that requires a p21-induced G1 arrest for repair. Another tumor-delaying regimen, administration of dehydroepiandrosterone (DHEA), which specifically decreased lymphoma tumorigenesis in the p53-knockout mice, increased expression of p21 in the liver. The differential effects of CR and DHEA on both p21 expression and tumor spectrum may be related. Studies on other dietary manipulations, together with effect of p53 gene dosage, on the expression of p21 and various proto-oncogenes are in progress. In addition, we are currently developing cultured embryonic fibroblasts from fetuses with or without p53 as a model system for the study of the in vitro effects of various agents on expression of cell cycle regulators. This system will also be used to address the question of how loss of p53 function results in increased genomic instability.