SCHWANN CELL GROWTH FACTOR SIGNALING

描述（改编自申请人的摘要）：本研究的长期目标 项目是了解控制雪旺细胞的分子基础 增殖和分化。发育过程中的雪旺细胞分裂 确保产生足够的许旺细胞来包鞘和髓鞘形成 轴突雪旺细胞分裂的刺激由heregulin家族提供 由周围神经元产生的生长因子。Heregulin刺激雪旺氏细胞 细胞导致erbB2和erbB3调蛋白受体的磷酸化， MAP激酶ERK 1和ERK 2的激活。雪旺细胞增殖 然而，对调蛋白的应答需要与 提高细胞内cAMP水平，如毛喉素。建议的目标 目的是阐明heregulin与cAMP协同作用的机制 调节雪旺氏细胞分裂。毛喉素对受体无影响 磷酸化或MAP激酶活化，但 表达细胞周期蛋白D所必需的。细胞周期蛋白D的表达是一个关键的 有丝分裂反应中细胞分裂定型的决定因素 刺激.调蛋白和毛喉素协同激活转录 细胞周期蛋白D3基因在雪旺细胞中的表达。cAMP依赖性调节 转录是由启动子中的cAMP应答元件（克雷斯）介导的， 靶向基因，并通过磷酸化的CRE结合蛋白激活 CREB。大鼠细胞周期蛋白D3基因含有功能性CRE。主要CREB 雪旺细胞中的激酶被调蛋白激活，但持续积累 磷酸化CREB需要与毛喉素共刺激。拟议的工作将 探讨cAMP的功能是作为共激活剂的假说 调蛋白依赖的关键基因转录，如细胞周期蛋白D， 通过调节磷酸化CREB水平。具体目标是：（1）确定 细胞周期蛋白D3启动子中的DNA元件， 转录激活heregulin和cAMP，2）以阐明分子 cAMP和heregulin协同调节磷酸化CREB水平的途径， 和3）确定如何扰动的机制，调节 磷酸化CREB水平影响细胞周期蛋白D转录和雪旺细胞 增殖了解调节雪旺细胞的分子机制 增殖将促进调节雪旺氏活性的能力， 受伤和患病的神经。

DESCRIPTION (adapted from applicant's abstract): The long range goal of this project is to understand the molecular basis for control of Schwann cell proliferation and differentiation. Schwann cell division during development ensures that sufficient Schwann cells are produced to ensheath and myelinate axons. The stimulus for Schwann cell division is provided by heregulin family growth factors produced by peripheral neurons. Heregulin stimulation of Schwann cells leads to phosphorylation of erbB2 and erbB3 heregulin receptors and activation of the MAP kinases ERK1 and ERK2. Schwann cell proliferation in response to heregulin, however, requires co-stimulation with an agent that raises intracellular cAMP levels, such as forskolin. The goal of the proposed studies is to elucidate the mechanism by which heregulin and cAMP coordinately regulate Schwann cell division. Forskolin has no effect on receptor phosphorylation or MAP kinase activation in response to heregulin, but is required for expression of cyclin D. Cyclin D expression is a critical determinant of commitment to cell division in response to mitogenic stimulation. Heregulin and forskolin synergistically activate transcription of the cyclin D3 gene ins Schwann cells. cAMP-dependent regulation of transcription is mediated by cAMP response elements (CREs) in the promoters of target genes, and activated through phosphorylation of CRE-binding protein CREB. The rat cyclin D3 gene contains a functional CRE. The principal CREB kinase in Schwann cells is activated by heregulin, but sustained accumulation of phospho-CREB requires co-stimulation with forskolin. The proposed work will explore the hypothesis that the function of cAMP is to serve as a co-activator of heregulin-dependent transcription of critical genes, such as cyclin D, through regulation of phospho-CREB levels. The specific aims are to 1) identify the DNA elements in the cyclin D3 promoter that are required for synergistic transcription activation by heregulin and cAMP, 2) to elucidate the molecular pathways by which cAMP and heregulin coordinately regulate phospho-CREB levels, and 3) to determine how perturbation of the mechanisms that regulate phospho-CREB levels affect cyclin D transcription and Schwann cell proliferation. Knowledge of the molecular mechanisms that regulate Schwann cell proliferation will facilitate the ability to modulate Schwann activity in injured and diseased nerves.