GENE REGULATION BY STEROID RECEPTOR PROTEINS

类固醇受体蛋白的基因调控

• 批准号: 6150000
• 负责人: KEITH Robert YAMAMOTO
• 金额: $ 59.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-12-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150000
• 关键词: Caenorhabditis elegans; DNA binding protein; X ray crystallography; acyltransferase; allosteric site; androgen receptor; chromatin; corticosteroid receptors; crystallization; gene expression; genetic regulation; genetic regulatory element; genetically modified animals; glucocorticoids; histones; hormone receptor; hormone regulation /control mechanism; laboratory mouse; ligands; protein protein interaction; protein structure function; receptor binding; thyroid hormones; transcription factor; yeast two hybrid system

The long term objectives of this project are to understand metazoan transcriptional regulation, and mechanisms by which a regulatory factor can specify different programs of gene expression as a function of developmental or physiological cues. The general strategy of the proposed research is to analyze regulation by members of the intracellular receptor (IR) superfamily, which includes receptors for steroids, thyroid hormone, retinoids, and other small lipophilic ligands. Combinatorial regulation likely reflects the controlled assembly of multifactor regulatory complexes, whose components and functions are context-dependent. Thus, the assembly and functions of IR regulatory complexes in different contexts will be dissected mechanistically, in settings ranging from pure proteins to whole organisms. The specific aims of the present study are to characterize the structure and activities of IR regulatory complexes under conditions in which the ligand (which defines a cell-specific context) or the response element (which defines a gene-specific context) are varied within the complexes. Four goals are envisioned: (1) determine how functionally distinct regulatory complexes are specified by ligands; (2) determine how gene-specific regulatory complexes and IR functions are specified by response elements; (3) determine the structure and significance of receptor interactions with Swi/Snf chromatin remodeling complexes; (4) investigate IR regulatory complex formation and function in the simple metazoan C. elegans. In these experiments, molecular genetic, biochemical and structural approaches will be used to identify functional surfaces and interacting factors that specify transcriptional activation, repression, composite regulation and synergy in vitro, in cells and in whole animals. IRs have been implicated in a wide range of diseases, including cancer, hypertension and inflammation, and IR ligands are widely used as therapeutics, diagnostics and chemopreventatives. Thus, understanding the principles and mechanisms of IR action has important implications for health, and for detecting, treating and curing disease.

该项目的长期目标是了解后生动物的转录调控，以及调节因素可以指定基因表达的不同程序作为发育或生理提示的函数的机制。拟议研究的一般策略是分析细胞内受体（IR）超家族成员的调节，其中包括类固醇，甲状腺激素，视网膜类动物和其他小亲脂性配体的受体。组合调节可能反映了多因子调节复合物的受控组装，其组成部分和功能依赖于上下文。因此，在从纯蛋白到整个生物的设置中，将在机械上解剖IR调节复合物的组装和功能。本研究的具体目的是表征在配体（定义细胞特异性上下文）或响应元件（定义基因特异性上下文的响应元件）的条件下，IR调节复合物的结构和活性在复合物中有所不同。 设想了四个目标：（1）确定配体在功能上不同的调节络合物中如何指定； （2）确定基因特异性调节复合物和IR功能如何通过响应元素指定； （3）确定受体相互作用与SWI/SNF染色质重塑复合物的结构和重要性； （4）研究IR调节复合物的形成和功能，在简单的后田曲曲霉中。在这些实验中，将使用分子遗传，生化和结构方法来识别在细胞和整个动物中指定转录激活，抑制，复合调节和体外协同作用的功能表面和相互作用因子。 IRS与各种疾病有关，包括癌症，高血压和炎症，IR配体被广泛用作治疗，诊断和化学预防剂。因此，了解IR作用的原理和机制对健康以及检测，治疗和治愈疾病具有重要意义。