Reproductive Hormones - Biological and Molecular Actions

描述(申请人提供)：类固醇激素刺激生长、成熟和内分泌目标器官中新的生化能力的发展，是了解多种疾病的关键。它们通过与其同源核受体结合并招募一系列共调节(共激活/共抑制)蛋白来发挥作用，这些蛋白执行转录的所有子步骤，并影响激素的非核功能。尽管性激素发挥生化作用的基本途径是已知的，但它们在正常和病理组织中调节功能的详细机制仍然不清楚。例如，在过去的12年里，我们发现了NR共激活因子的存在，确定了它们在染色质重塑和转录的各个步骤中的功能，并认识到它们在影响疾病发生和发展方面的巨大潜力。现在，我们需要确切地了解共激活剂发挥作用的机制。例如，一个辅活化子如何在哺乳动物组织中执行如此多不同的重要功能？共激活剂是如何被“激活”以形成细胞功能的不同多聚体共激活剂复合体的？共激活子如何与转录因子(或其他转录因子)不同地结合，以在选定的启动子上进行转录激活？共激活子如何引导不同的转录亚反应(如染色质重塑、转录起始、RNA链延长、RNA剪接、终止等)？一个辅活化子如何一方面参与调控转录的分子亚步骤，另一方面又在完全不同的细胞室中发挥作用，以控制mRNA翻译、线粒体生物学或膜启动的细胞运动？最后，同一共同调节者如何在某些情况下充当“协同激活者”，在其他情况下充当“协同抑制者”？更令人困惑的是，一个特定的辅活化子如何在某些细胞环境中作为刺激物(例如，癌基因)而在其他细胞环境中作为抑制物(例如，肿瘤抑制物)？我们很高兴最近发现这些功能的秘密在于共激活子的“翻译后修饰(PTM)编码”。我们相信，了解这个PTM编码，将揭示所有正常功能的机制秘密，以及无数内分泌和生殖疾病的诊断、治疗和预防所需的信息。与公共健康相关：类固醇激素刺激其内分泌靶器官的生长、成熟和新的生化能力的发展，是了解多种疾病的关键。它们通过与其同源核受体结合并招募一系列共调节(共激活/共抑制)蛋白来发挥作用，这些蛋白执行转录的所有子步骤，并影响激素的非核功能。

DESCRIPTION (provided by applicant): Steroid hormones stimulate growth, maturation and the development of new biochemical capacities in their endocrine target organs and are keys to understanding multiple diseases. They act by binding to their cognate nuclear receptors and recruiting a series of coregulator (coactivator/corepressor) proteins that carry out all substeps of transcription and also influence non-nuclear functions of the hormones. Although the basic overall pathways by which sex steroids exert their biochemical actions are known, the detailed mechanisms by which they act to regulate functions in normal and pathological tissues remain elusive. For example, in the past 12 years, we have discovered the existence of NR coactivators, determined how they function at various steps of chromatin remodeling and transcription, and realized their enormous potential in influencing the initiation and progression of disease. Now, we need to understand the mechanisms by which coactivators function in precise detail. For example, how does one coactivator perform so many different important functions in mammalian tissues? How does a coactivator become `activated' to form distinct multimeric coactivator complexes for cellular functions? How does a coactivator differentially bind to NRs (or other transcription factors) for transcriptional activation at select promoters? How does a coactivator direct distinct subreactions of transcription (eg., chromatin remodeling, transcriptional initiation, RNA chain elongation, RNA splicing, termination, etc.)? How can one coactivator participate in regulating molecular substeps of transcription on one hand, and then on the other hand, function in totally different cellular compartments to control mRNA translation, mitochondrial biology, or membrane initiated cell motility? Finally, how does the same coregulator function as a `coactivator' in certain instances, and as a `corepressor' in other instances? Even more perplexing, how can a specific coactivator function as a stimulator (eg., oncogene) in certain cell contexts and a repressor (eg., tumor suppressor) in others? We are excited to have recently discovered that the secret to these functions lies in the `posttranslational modification (PTM) coding' of coactivators. It is our belief that understanding this PTM coding, will disclose the mechanistic secrets of all normal function and the information required for the diagnosis and treatment and prevention of myriad endocrine and reproductive diseases. PUBLIC HEALTH RELEVANCE: Steroid hormones stimulate growth, maturation and the development of new biochemical capacities in their endocrine target organs and are keys to understanding multiple diseases. They act by binding to their cognate nuclear receptors and recruiting a series of coregulator (coactivator/corepressor) proteins that carry out all substeps of transcription and also influence non-nuclear functions of the hormones.