Control of IGF-1 Gene Transcription by Growth Hormone

生长激素对 IGF-1 基因转录的控制

• 批准号: 8193456
• 负责人: Peter S Rotwein
• 金额: $ 33.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193456
• 关键词: Acute; Address; Adult; Aging; Amino Acids; Beryllium; Binding; Biological; Chromatin; Complex; Development; Enhancers; Environment; Epigenetic Process; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Growth Factor; Homeostasis; Human; Indium; Individual; Insulin-Like Growth Factor I; Lead; Liver; Maintenance; Malignant Neoplasms; Mammals; Mediating; Metabolism; Pathway interactions; Physiological; Physiological Processes; Physiology; Play; Production; Property; Proteins; Published Comment; Regulation; Research; Role; Signal Transduction; Site; Somatotropin; Testing; Wound Healing; base; chromatin modification; design; in vivo; insight; programs; promoter; repaired; response; tissue regeneration; transcription factor

DESCRIPTION (provided by applicant): GH plays a pivotal role in physiology, and is essential for normal somatic growth, tissue regeneration and repair, and intermediary metabolism. Many of the biological effects of GH are mediated by insulin- like growth factor I (IGF-I), a conserved secreted protein whose expression is potently induced by GH by activation of IGF-I gene transcription. As evidenced by linkage of GH and IGF-I with development of several cancers, and by their collective negative impact on aging, aberrant expression of IGF-I by GH may have deleterious pathogenic consequences, implying that its production must be tightly regulated to maintain homeostasis. The focus of this application will be on mechanisms by which GH controls IGF-I gene expression via the transcription factor Stat5b. Our studies will test the provocative hypothesis that IGF-I is fundamentally different from other GH-Stat5b target genes, and that multiple dispersed Stat5b-binding transcriptional enhancers, and other potentially inhibitory elements, are key agents in a complex regulatory program necessary to control expression of a potent growth factor with both positive and negative biological effects. The following two Specific Aims will test this idea: 1. To identify and characterize the chromosomal enhancers and repressors responsible for GH- and Stat5b-regulated Igf1 gene transcription. The major hypothesis to be tested is that discrete GH- activated enhancers with distinct functional properties interact with individual Igf1 gene promoters and are responsible collectively for mediating the acute transcriptional response to GH. A corollary hypothesis is that some GH-regulated elements in Igf1 chromatin are not transcriptional enhancers, but rather are putative negative regulators, and interfere with Igf1 promoter function in the absence of GH or sequester GH-stimulated Stat5b from positive sites. 2. To define the roles of GH and Stat5b in regulating chromatin plasticity of the Igf1 gene. The major hypothesis to be tested is that sustained GH-mediated signaling is required to establish an open chromatin environment at the Igf1 promoters, but that Stat5b is dispensable. A corollary hypothesis is that Stat5b is responsible for the acute chromatin modifications necessary for rapid induction of Igf1 gene transcription by GH. Proposed research has the potential impact to establish a new paradigm about mechanisms of GH action to regulate IGF-I gene expression, and to lead to new physiologically significant insights about how GH-mediated signaling controls epigenetic pathways, chromatin plasticity, and gene regulation. PUBLIC HEALTH RELEVANCE: GH actions are essential for normal somatic growth, for tissue maintenance and repair, and for normal intermediary metabolism in humans and other species, and are primarily mediated by IGF-I, a conserved secreted protein whose expression is induced by GH. The GH - IGF-I pathway also has been implicated in cancer development and in the negative aspects of aging, implying that its aberrant regulation has deleterious pathogenic consequences, and that its activity must be constrained at least in the adult to maintain homeostasis. The focus of this application is on the mechanisms by which GH regulates IGF-I gene expression through the conserved transcription factor, Stat5b, and is part of a longer-term goal to define how GH actions control epigenetic pathways and how chromatin modifications can potently regulate Stat5b functions in physiologically meaningful ways.

描述（由申请人提供）：GH在生理学中起关键作用，对于正常的体细胞生长，组织再生和修复以及中间代谢至关重要。 GH的许多生物学作用都是由胰岛素类似生长因子I（IGF-I）介导的，这是一种保守的分泌蛋白，其表达是通过激活IGF-I基因转录而受到GH的有效诱导的。正如GH和IGF-I与几种癌症的发展之间的联系所证明的那样，通过GH对IGF-I的异常表达的集体负面影响可能会带来有害的致病后果，这意味着必须严格调节其生产以维持稳态。该应用的重点将放在GH通过转录因子STAT5B控制IGF-I基因表达的机制上。我们的研究将检验挑衅性的假设，即IGF-1与其他GH-STAT5B靶基因根本不同，并且多个分散的STAT5B结合转录增强剂以及其他潜在的抑制性元素是控制有效生长因子具有阳性和负生物学作用的有效生长因子所必需的复杂调控程序中的关键药物。以下两个具体目标将测试这一想法：1。识别和表征负责GH-和STAT5B调节的IGF1基因转录的染色体增强剂和阻遏物。要测试的主要假设是，具有不同功能特性的离散GH-激活的增强子与单个IGF1基因启动子相互作用，并且负责共同负责 用于介导对GH的急性转录反应。推论假设是，IGF1染色质中的某些GH调节元件不是转录增强子，而是假定的负调节剂，并且在没有GH或持续GH刺激的STAT5b的STAT5B的情况下干扰IGF1启动子的功能。 2。定义GH和STAT5B在调节IGF1基因的染色质可塑性中的作用。要测试的主要假设是，需要持续的GH介导的信号传导才能在IGF1启动子上建立开放的染色质环境，但是该STAT5B是可置处的。推论假设是STAT5B负责 GH快速诱导IGF1基因转录所需的急性染色质修饰。拟议的研究具有潜在的影响，以建立有关GH作用机制调节IGF-I基因表达的机制的新范式，并就GH介导的信号控制如何控制表观遗传途径，染色质可塑性和基因调节的新生理上具有重要意义的见解。 公共卫生相关性：GH的作用对于正常的体细胞生长，组织维持和修复以及人类和其他物种的正常中介代谢至关重要，并且主要由IGF-I介导，IGF-I是一种保守的分泌蛋白，其表达是由GH诱导的。 GH -IGF -1途径也与癌症的发展和衰老的负面方面有关，这意味着其异常调节具有有害的致病后果，并且至少在成年人中必须限制其活性以维持体内平衡。该应用的重点是GH通过保守的转录因子STAT5B调节IGF-I基因表达的机制，并且是定义GH动作如何控制表观遗传途径以及染色质修饰如何在物理学上有意义的有意义的方式中迅速调节STAT5B功能的长期目标的一部分。