Growth Hormone Signaling to the Nucleus

生长激素（GH）对生长和代谢具有重要的生理作用， 与胰岛素抵抗和癌症有关对GH的许多反应取决于它的能力， 调节基因转录。我们假设生长激素调节的转录是由 多组分核蛋白复合物在靶基因上的有序组装， 关键蛋白质的诱导修饰可以引导它们进出复合物。我们 一种方法是使用 染色质免疫沉淀（ChIP）和re-ChIP，以确定GH调节的成分， 复合物，并确定模型基因c-fos上组装的动力学。同时，我们将 还检查了GH对转录因子C/EBPp诱导的翻译后修饰， 其对于GH刺激的c-fos转录是必需的。复杂装配的顺序将 与C/EBPp翻译后修饰的时机和组合相关，包括 磷酸化、乙酰化和类小泛素化。当确定GH对复合物的调节时， 我们将在体内验证它们对GH调节基因表达的功能重要性。 相关性：GH用于治疗GH缺乏症中的身材矮小。的合成代谢特性 生长激素被用于治疗，以改善伤口愈合和扭转艾滋病毒的浪费 患者然而，GH也是致糖尿病的，并降低对胰岛素的敏感性。最近，GH- IGF轴与癌症有关，扩大了我们了解GH作用基础的需要。 拟议的研究将提供有关生长激素如何改变细胞功能的基本信息， 调节基因有了这些信息，我们可以确定新的分子靶点， 有效治疗对GH有反应的疾病，并避免GH相关并发症， 如糖尿病和癌症。

Growth hormone (GH) exerts profound physiological effects on growth and metabolism, and is implicated in insulin resistance and possibly cancer. Many responses to GH depend on its ability to regulate gene transcription. We hypothesize that GH-regulated transcription is mediated by the ordered assembly of multicomponent nucleoprotein complexes on target genes and that GH- induced modifications of critical proteins can direct them into and out of the complexes. Our approach is to dissect the assembly of the multicomponent complexes in response to GH using chromatin immunoprecipitation (ChIP) and re-ChIP to define GH-regulated components of complexes and determine the dynamics of assembly on the model gene c-fos. In parallel, we will also examine post-translational modifications induced by GH on the transcription factor C/EBPp, which is essential for GH-stimulated transcription of c-fos. The sequence of complex assembly will be related to the timing and combinations of post-translational modifications of C/EBPp including phosphorylation, acetylation and sumoylation. When regulation of complexes by GH is determined, we will validate their functional importance for GH-regulated gene expression in vivo. Relevance: GH is used for treatment of short stature in GH deficiency. The anabolic properties of GH are being used therapeutically to improve wound healing and to reverse wasting in HIV patients. However, GH is also diabetogenic and reduces sensitivity to insulin. Recently, the GH- IGF axis has been implicated in cancer, broadening our need to understand the basis of GH action. The proposed studies will provide fundamental information about how GH alters cell function by regulating genes. With this information, we can identify new molecular targets to develop more effective therapies for conditions responsive to GH and to avoid GH-related complications in conditions such as diabetes and cancer.