DIETARY MODULATION OF CELL CYCLE REGULATORS

细胞周期调节剂的饮食调节

• 批准号: 6160848
• 负责人: S N PERKINS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160848
• 关键词: DNA damage; DNA repair; apoptosis; cell growth regulation; cyclins; dehydroepiandrosterone; diet; embryo /fetus tissue /cell culture; fibroblasts; genetically modified animals; guanine nucleotide binding protein; hormone regulation /control mechanism; laboratory mouse; nutrition aspect of cancer; nutrition related tag; protooncogene; tumor suppressor genes

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.

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，可以转录 由肿瘤抑制因子p53激活（特别是对DNA的应答） 损伤），因此将细胞周期的调节与肿瘤发生联系起来。 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在G1期; 根据细胞类型，这种G1期阻滞可以为细胞修复提供时间。 损伤DNA或导致凋亡性细胞死亡。缺乏p53的细胞 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，我们检测了p53和p21的表达。 p21在p53缺陷小鼠中的表达，并表明饮食和 化学预防干预，大大推迟了不可避免的 在该模型中自发性肿瘤的发展也调节p21 表情在这些成功的操纵是饮食 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之外，还具有整体代谢效应。 研究不同药物对细胞周期表达的影响 调节更直接地在体外模型系统中，我们已经开发了 来自有或没有p53的胎儿的胚胎成纤维细胞系。在 该系统DHEA确实减慢了细胞周期，即使在p53缺陷的细胞中也是如此。 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构建体以研究一些 DHEA或相关类固醇的其他作用可能需要诱导 p21的。这些结构也将用于解决更一般的 关于p21在代谢调节中的作用的问题。在 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。