DIETARY MODULATION OF CELL CYCLE REGULATORS

细胞周期蛋白依赖的激酶抑制剂是最近表征的一种 一类调节细胞数量、动态平衡和进程的蛋白质 对细胞周期的影响。其中一个基因p21WAF1/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。一 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。缺少P53的细胞 功能不能诱导P53依赖的p21的表达和显示 增加了基因组的不稳定性，减少了细胞周期传递时间。 追踪p53和p21之间的联系，我们检测了其表达 P21在P53基因缺陷小鼠中的表达，并表明饮食和 化学预防干预，显著推迟不可避免的 在这个模型中自发肿瘤的发展也调节了p21 表情。在这些成功的操作中，有一种就是饮食 给予脱氢表雄酮(DHEA)，一种肾上腺类固醇 除了其化学预防活性外，还具有全球代谢作用。 研究不同药物对细胞周期表达的影响 在更直接的体外模型系统中，我们开发了 含或不含p53的胎儿胚胎成纤维细胞系。在……里面 这种系统DHEA确实减缓了细胞周期，即使是在p53缺失的情况下也是如此 细胞，但对基因组稳定性没有直接影响。我们目前正在 开发p21结构以调查一些 脱氢表雄酮或相关类固醇的其他作用可能需要诱导 P21。这些构造还将用于处理更一般的 关于p21在新陈代谢调节中的作用的问题。在……里面 此外，我们正在研究其他细胞周期的表达 监管机构对饮食干预的反应。

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, p21WAF1/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 cell 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- deficient mouse and showed that dietary and chemopreventive interventions 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. We are currently developing p21 constructs to investigate the possibility that some of the other actions of DHEA or related steroids 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. In addition we are investigating the expression of other cell cycle regulators in response to dietary interventions.