NUTRITIONAL REGULATION OF RAS PROTO-ONCOGENE ACTIVITY

点击翻译按钮获取中文摘要

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.