Transcriptional Functions of Nuclear Receptors in Cancer

癌症中核受体的转录功能

• 批准号: 7328842
• 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/7328842
• 关键词: Transcriptional; Functions; Nuclear; Receptors; Cancer

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 as part of two specific aims. The 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 P21, PLZF 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 focusing on a member of the human SWI/SNF complex, BRG1 associated factors. 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 regulated genes that are 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, which directly link these research objectives. In pursuit of our second specific aim my group has recently embarked on an exciting new area of research that examines the fundamental nature of human embryonic stem cells. We have begun to characterize the chromatin remodeling and chromatin modifying complexes that are present in these cells. This is complimented by analyses of the master regulatory proteins OCT4 and Nanog to determine the genetic and epigenetic targets that underlie the biological program for stem cells. 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.

作为体内平衡和发育的主要障碍，类固醇受体是环境内分泌干扰物的特别重要的目标，对人类健康造成许多后果。虽然这些药物在结构、活性和生物利用度方面极其多样化，但许多（如果不是全部）活性都是通过这些受体介导的。染色质和基因表达部分的主要科学重点是响应生理和环境信号启动基因表达的机制以及这些信号如何由类固醇受体介导。因此，这些受体作用机制的分子描述将为评估它们对乳腺癌的生理和临床影响提供精确的基础。 为此，我们追求两个高度互动的目标，作为两个具体目标的一部分。第一个是提供核受体、染色质重塑机器和启动子染色质结构在类固醇受体活性调节中之间关系的分子定义。在这个目标中，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实现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来了解糖皮质激素、孕激素和雌激素受体（GR、PR、ER）。这一目标已对人类 P21、PLZF 和核 Kappa B α 基因抑制剂进行了初步表征。最近，我们开始开发小鼠模型，探究染色质重塑蛋白所起的具体作用，重点关注人类 SWI/SNF 复合体的成员 BRG1 相关因子。 我们的努力基于压倒性的证据，即对转录控制的充分理解需要了解靶基因染色质结构和释放类固醇受体调节潜力所需的分子机器所发挥的作用。该方法是双向的，致力于了解交易蛋白和受翻译后修饰影响的染色质的蛋白质结构。为了实现这一目标，我们将注意力集中在哺乳动物 BRG1 染色质重塑复合物上，该复合物是酵母 SWI/SNF 复合物的同源物，及其与糖皮质激素和黄体酮受体的相互作用和调节。该复合物的活性已在人和小鼠细胞内染色质的背景下进行了评估。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。 我们的许多模型（人类和小鼠癌细胞）的性质也表明了我们对女性健康和乳腺癌的积极兴趣。通过合作，我们对人类乳腺癌易感基因 BRCA1 的表观遗传调控保持了浓厚的兴趣，该基因最初是在 NIEHS 发现的。我们继续将与乳腺癌患者不良临床结果相关的雌激素受体调节基因视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，这些研究直接将这些研究目标联系起来。 为了实现我们的第二个具体目标，我的团队最近开始了一个令人兴奋的新研究领域，该领域检查人类胚胎干细胞的基本性质。我们已经开始表征这些细胞中存在的染色质重塑和染色质修饰复合物。通过对主调控蛋白 OCT4 和 Nanog 的分析来确定干细胞生物学程序基础的遗传和表观遗传目标，对此进行了补充。 我们的研究计划是评估染色质重塑蛋白、受体和启动子染色质结构对调节内源性和环境信号的转录反应的贡献。