Developmental of New Hormone Responsive Models in Mammary Cells

乳腺细胞新激素反应模型的开发

• 批准号: 6227950
• 负责人: TREVOR K ARCHER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 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/6227950
• 关键词: brca gene; breast neoplasms; cAMP response element binding protein; cathepsin D; estrogen receptors; gene expression; genetic promoter element; genetic regulation; genetic susceptibility; genetic transcription; human tissue; methylation; neurofibromatosis; posttranslational modifications; tissue /cell culture; transcription factor

It is becoming increasingly clear that post-translational modifications of DNA and proteins play an important role in human health and many disease states. Within FY1999 we have extended our studies on the impact of DNA methylation on human cancers. Using a combination of human tumor samples and in vitro biochemistry and molecular biology we have ascertained the methylation status on the promoter for the human hereditary breast and ovarian cancer susceptibility gene, BRCA-1. These studies revealed a critical requirement for the cyclic- AMP response element binding (CREB) protein in the transcription of this gene. We have extened our stdies of CREB and methylation by demonstrating that Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors. This is particularly interesting given the intense interest in a protein that binds CREB known as CREB binding protein or CBP and its ability to acetylate histones and the tumor suppressor gene p53. Additional experiments have described the transcriptional mechanisms that underlie the estrogen receptor dependent activation of the cathepsin D gene in human breast cancer cells. The continued evaluation of these and other human genes will provide the underpinning of our efforts to define a molecular map of the hormone dependent changes that occur in human cells. - Methylation, CREB, cathepsin D, BRCA-1, Breast Cancer

越来越清楚的是，DNA和蛋白质的翻译后修饰在人类健康和许多疾病状态中发挥着重要作用。在1999财年，我们扩展了DNA甲基化对人类癌症影响的研究。利用人类肿瘤标本，结合体外生物化学和分子生物学，我们确定了人类遗传性乳腺癌和卵巢癌易感基因BRCA-1启动子上的甲基化状态。这些研究揭示了在该基因的转录中对环-AMP反应元件结合蛋白(CREB)的关键要求。我们通过证明神经纤维瘤病(NF1)启动子中的位点特异性DNA甲基化干扰CREB和SP1转录因子的结合，扩展了我们对CREB和甲基化的研究。这是特别有趣的，因为人们对一种结合CREB的蛋白质，即CREB结合蛋白或CBP，以及它对组蛋白和肿瘤抑制基因P53进行乙酰化的能力非常感兴趣。其他实验还描述了人类乳腺癌细胞中依赖雌激素受体激活组织蛋白酶D基因的转录机制。对这些和其他人类基因的持续评估将为我们确定人类细胞中发生的激素依赖性变化的分子图谱提供基础。-甲基化、CREB、组织蛋白酶D、BRCA-1、乳腺癌