Control of IGF-1 Gene Transcription by Growth Hormone

胰岛素样生长因子-1（IGF-1）是一种保守的70个氨基酸残基的分泌蛋白，在胰岛素抵抗中起着重要作用。 哺乳动物和其他脊椎动物物种的体细胞生长。尽管有大量证据表明 许多研究支持IGF-1是一种主要的出生后生长因子，受生长激素（GH）调节， 提出了这种肽的更广泛的功能，包括对局部组织生长的作用， 在整个生命周期中的维护和修复，以及癌症和衰老的有害影响。这些 观察结果反过来暗示，不仅IGF-1合成的控制可能是多因素的，而且每个因素 调节途径可能对生长、发育和疾病的不同方面发挥关键的关键作用。 作为了解IGF-1合成和作用机制的长期努力的一部分， 控制在不同的生理条件下，应用的重点将是调节IGF-1 GH基因转录。关键目标将是确定GH控制IGF-1的分子机制 通过转录因子StatSb表达。为此目的，以下四个具体目标是： 提议： 1.目的：明确GH通过StatSb激活IGF-1基因转录的起始步骤。 2.研究GH刺激IGF-1转录终止的机制。 3.为了确定IGF-1基因座的HS 7区域是否是介导GH-1的必要和足够的区域， 调节IGF-1基因的激活。 4.为了表征人StatSb中天然氨基酸取代功能障碍的机制， 与严重的生长障碍有关

Insulin-like growth factor-1 (IGF-1), a conserved 70-residue secreted protein, plays a fundamental role in somatic growth in mammals and other vertebrate species. Although much evidence has accumulated supporting IGF-1 as a major postnatal growth factor, regulated by growth hormone (GH), many studies have suggested a broader range of functions for this peptide, including actions on local tissue growth, maintenance, and repair throughout the life span, as well as deleterious effects in cancer and aging. These observations in turn imply not only that control of IGF-1 synthesis may be multi-factorial, but also that each regulatory pathway may exert key critical actions on different aspects of growth, development, and disease. As part of a long-term effort to understand the mechanisms by which IGF-1 synthesis and action are controlled under different physiological conditions, the focus of the application will be on regulation of IGF-1 gene transcription by GH. Key goals will be to define the molecular mechanisms by which GH controls IGF-1 expression via the transcription factor, StatSb. Toward this end the following four Specific Aims are proposed: 1. To define the initial steps in activation of IGF-1 gene transcription by GH through StatSb. 2. To characterize mechanisms of termination of GH-stimulated IGF-1 transcription. 3. To determine if the HS7 region of the IGF-1 locus is both necessary and sufficient to mediate GH- regulated IGF-1 gene activation. 4. To characterize mechanisms of dysfunction of a natural amino acid substitution in human StatSb that is associated with profound growth failure.