DIETARY MODULATION OF CELL CYCLE REGULATORS

细胞周期蛋白依赖性激酶抑制剂是一个最近的特点 一类调节细胞数量稳态和进展的蛋白质 细胞周期。其中之一，p21（WAF 1/CIP 1），可以是 由肿瘤抑制因子p53转录激活（特别是在 对DNA损伤的反应），因此将细胞周期的调节与 肿瘤发生p21的转录也可以独立地被诱导 p53的。p21的一个作用是在细胞周期中引起细胞周期停滞， G1期;根据细胞类型，G1期阻滞可以允许时间 修复受损的DNA或导致凋亡性死亡。缺少的细胞 p53功能不能诱导p21的p53依赖性表达， 增加基因组不稳定性和减少细胞周期转运时间。 为了进一步研究p53和p21之间的联系，我们研究了p53和p21之间的关系。 p21在p53基因敲除小鼠中的表达，并表明饮食 修改，大大推迟了不可避免的发展， 该模型中的自发肿瘤也调节p21表达。之间 这些成功的操作是饮食施用 脱氢表雄酮（DHEA），一种肾上腺类固醇，具有全身代谢 除了化学预防作用之外。研究 各种药物对细胞周期调节因子表达的影响更多 直接在体外模型系统中，我们已经开发了胚胎 来自有或没有p53的胎儿的成纤维细胞系。在该系统中 DHEA确实减缓了细胞周期，即使在p53缺陷细胞中， 根据外观评估，对基因组稳定性无直接影响 染色体非整倍性和多倍性。我们目前正在开发 p21结构来研究其他一些 DHEA的作用可能需要p21的诱导。这些结构将 也可以用来解决有关的作用更一般的问题， p21在代谢调节中的作用。

The cyclin-dependent kinase inhibitors are a recently characterized class of proteins that regulate cell number homeostasis and progression of the cell cycle. 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. One 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. Cells that lack p53 function cannot induce p53-dependent expression of p21 and display increased genomic instability and decreased cell cycle transit time. Following up on the link between p53 and p21, we examined the expression of p21 in the p53-"knockout" mouse and showed that dietary modifications that significantly delay the inevitable development of spontaneous tumors in this model also modulate p21 expression. Among these successful manipulations is dietary administration of dehydroepiandrosterone (DHEA), an adrenal steroid with global metabolic effects in addition to its chemopreventive activity. To study the effects of various agents on expression of cell cycle regulators more directly in an in vitro model system, we have developed embryonic fibroblast cell lines from fetuses with or without p53. In this system DHEA indeed slowed the cell cycle, even in p53-deficient cells, but had no direct effect on genomic stability, as assessed by the appearance of chromosomal aneuploidy and polyploidy. We are currently developing p21 constructs to investigate the possibility that some of the other actions of DHEA may require the induction of p21. These constructs will also be used to address more general questions concerning the role of p21 in regulation of metabolism.