Transcriptional Functions of Nuclear Receptors in Cancer

癌症中核受体的转录功能

• 批准号: 7007468
• 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/7007468
• 关键词: DNA binding protein; breast neoplasms; cathepsin D; chromatin; chromatin immunoprecipitation; corticosteroid receptors; estrogen receptors; gene induction /repression; genetic promoter element; genetic transcription; histones; hormone inhibitor; hormone regulation /control mechanism; hormone related neoplasm /cancer; human embryonic stem cell line; laboratory mouse; mouse mammary tumor virus; nuclear receptors; phosphorylation; progesterone receptors; proteasome; receptor expression; steroid hormone receptor; transcription factor; transfection; women' s health

As major determents of homeostasis and development, the steroid receptors are particularly important targets for environmental endocrine disruptors that have many human health consequences. While these agents are extremely diverse in structure, activity and bioavailability, many if not all activities are mediated via these receptors. The chromatin and gene expression section?s primary scientific focus is the mechanisms by which gene expression is initiated in response to physiological and environmental signals and how those signals are mediated by steroid receptors. Consequently a molecular description of the mechanism of action of these receptors will provide a precise underpinning to evaluate their physiological and clinical impact with a specific interest in breast cancer. To this end we have pursued two highly interactive objectives. This first is to provide a molecular definition of the relationship between nuclear receptors, chromatin remodeling machines and promoter chromatin structure in the regulation of steroid receptor activity. Within this objective we will continue to make use of the Mouse Mammary Tumor Virus (MMTV) system, see below, as the preeminent model for a steroid hormone activated promoter in the context of chromatin. The wealth of prior information, extensive reagents and resources allow us pursue a series of goals that are not possible in other systems. The second objective is the development of additional model systems to understand glucocorticoid, progesterone and estrogen receptors (GR, PR, ER). This objective has resulted in initial characterization of the human cathepsin D and Inhibitor of Nuclear Kappa B alpha genes. More recently we have begun to develop mouse models that interrogate the specific role played by chromatin remodeling proteins Our efforts are informed by the overwhelming evidence that a full understanding of transcriptional control requires an appreciation for roles played by the chromatin structure of target genes and the molecular machines that are required to unleash the regulatory potential of steroid receptors. The approach has been bidirectional with efforts geared to understanding transacting proteins and the protein architecture of chromatin that is subject to post-translational modifications. To achieve this we have focused our attention on the mammalian BRG1 chromatin remodeling complex that is the homologue of the yeast SWI/SNF complex and its interactions and regulation by the glucocorticoid and progesterone receptors. The activity of this complex has been evaluated in the context of the chromatin within human and mouse cells. Using the MMTV promoter as our primary model system, we have paid particular attention to the phosphorylation of histone H1 and the acetylation/methylation of the core histones. The nature of many of our models, human and mouse beast cancer cells, is also indicative of our active interest in women?s health and breast cancer specifically. We have, via collaborations, maintained a strong interest in the epigenetic regulation of the human breast cancer susceptibility gene BRCA1 that was initially identified at the NIEHS. We continue to view the estrogen receptor regulation of the cathepsin D, a protease, whose overexpression, is closely associated with a poor clinical outcome for patients with breast cancer as a major focus of our group. Finally, we are very excited about studies that begin to use mouse models for chromatin regulatory proteins, that directly link our research objectives. Our research plan is to assess the contributions that chromatin remodeling proteins, receptors and promoter chromatin architecture make to regulate the transcriptional response to endogenous and environmental signals.

类固醇激素受体是环境内分泌干扰物作用的重要靶点，对人体的健康有着重要的影响。虽然这些药物在结构、活性和生物利用度方面极其多样，但许多（如果不是全部）活性是通过这些受体介导的。染色质和基因表达部分？主要的科学焦点是基因表达在生理和环境信号下启动的机制，以及这些信号如何通过类固醇受体介导。因此，这些受体的作用机制的分子描述将提供一个精确的基础，以评估其生理和临床的影响与乳腺癌的具体利益。 为此，我们追求两个高度互动的目标。这首先是提供一个分子定义的核受体之间的关系，染色质重塑机器和启动子染色质结构的调节类固醇受体的活性。在这个目标内，我们将继续利用小鼠乳腺肿瘤病毒（MMTV）系统，见下文，作为染色质背景下类固醇激素激活启动子的卓越模型。丰富的先验信息、广泛的试剂和资源使我们能够追求一系列在其他系统中不可能实现的目标。第二个目标是开发额外的模型系统，以了解糖皮质激素，孕激素和雌激素受体（GR，PR，ER）。这一目标导致了人组织蛋白酶D和核κ B α基因抑制剂的初步表征。最近，我们已经开始开发小鼠模型，询问染色质重塑蛋白所起的特定作用 我们的努力是由压倒性的证据，充分了解转录控制需要发挥作用的靶基因的染色质结构和释放类固醇受体的调节潜力所需的分子机器的升值通知。该方法是双向的，致力于理解transacting蛋白和染色质的蛋白质结构，这是受翻译后修饰。为了实现这一目标，我们把我们的注意力集中在哺乳动物BRG 1染色质重塑复合物，这是同源的酵母SWI/SNF复合物及其相互作用和调节糖皮质激素和孕酮受体。该复合物的活性已在人和小鼠细胞内的染色质的背景下进行了评价。使用MMTV启动子作为我们的主要模型系统，我们特别关注组蛋白H1的磷酸化和核心组蛋白的乙酰化/甲基化。 我们许多模型的性质，人类和老鼠的癌细胞，也表明我们对女性的积极兴趣？特别是乳腺癌。通过合作，我们对最初在NIEHS发现的人类乳腺癌易感基因BRCA 1的表观遗传调控保持了浓厚的兴趣。我们继续将组织蛋白酶D（一种蛋白酶）的雌激素受体调节与乳腺癌患者的不良临床结局密切相关作为我们小组的主要关注点。最后，我们对开始使用小鼠模型研究染色质调节蛋白的研究感到非常兴奋，这直接联系了我们的研究目标。我们的研究计划是评估的贡献，染色质重塑蛋白，受体和启动子染色质结构，使调节转录响应内源性和环境信号。