Development of New Hormone Responsive Models from Cancer

开发新的癌症激素反应模型

• 批准号: 6535172
• 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/6535172
• 关键词: acetylation; brca gene; breast neoplasms; cAMP response element binding protein; corticosteroid receptors; endocrine gland /system; environmental toxicology; estrogen receptors; gene expression; genetic promoter element; genetic regulation; genetic susceptibility; genetic transcription; histones; hormone regulation /control mechanism; human tissue; methylation; neoplastic cell; osteosarcoma; ovary neoplasms; p53 gene /protein; posttranslational modifications; protein structure function; tissue /cell culture; transcription factor; transfection

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 FY2001 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. 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. We are currently exploring the mechanisms by which p53 may influence glucocorticoid receptor activation of transcription. As models we are using recently developed human osteosarcoma cells that lack p53 in comparison to cells that retain wild type 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 additional novel human genetic systems will provide the underpinning of our efforts to define a molecular map of the hormone dependent changes that occur in human cells. This will be critical for an enhanced understanding of the impact of environmental endocrine disruptors on human health.

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起着重要作用。在2001财政年度，我们扩大了DNA甲基化对人类癌症影响的研究。使用人类肿瘤样本和体外生物化学和分子生物学的组合，我们已经确定了人类遗传性乳腺癌和卵巢癌易感基因BRCA-1启动子的甲基化状态。这些研究揭示了在该基因的转录中对环AMP反应元件结合（CREB）蛋白的关键要求。考虑到人们对结合CREB的蛋白质（称为CREB结合蛋白或CBP）及其乙酰化组蛋白和肿瘤抑制基因p53的能力的强烈兴趣，这一点特别有趣。我们目前正在探索p53可能影响糖皮质激素受体转录激活的机制。作为模型，我们使用最近开发的人骨肉瘤细胞，与保留野生型p53的细胞相比，缺乏p53。另外的实验已经描述了人乳腺癌细胞中组织蛋白酶D基因的雌激素受体依赖性激活的转录机制。对这些和其他新的人类遗传系统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的努力提供基础。这对于加强了解环境内分泌干扰物对人类健康的影响至关重要。