SCHWANN CELL GROWTH FACTOR SIGNALING

描述(改编自申请人的摘要)：这是一个长远的目标 项目是了解控制雪旺细胞的分子基础 增殖分化。施万细胞在发育过程中的分裂 确保产生足够的雪旺细胞来包裹和形成髓鞘 轴突。雪旺细胞分裂的刺激是由hereglin家族提供的 外周神经元产生的生长因子。Hereglin对施万氏的刺激 细胞导致erbB2和erbB3受体的磷酸化，并 MAP激酶ERK1和ERK2的激活。雪旺细胞在体内的增殖 然而，对Hereguline的反应需要与一种 提高细胞内cAMP水平，如Forsklin。建议的目标是 研究旨在阐明HERG和cAMP协同作用的机制。 调节雪旺细胞分裂。福司可林对受体无影响 磷酸化或MAP激酶激活对Heregine的反应，但 细胞周期蛋白D的表达是至关重要的 细胞分裂对有丝分裂反应的决定因素 刺激。Hereguline和Forsklin协同激活转录 细胞周期蛋白D3基因进入雪旺细胞。CAMP依赖的调节 转录受cAMP反应元件(Cres)在启动子中的调节 靶基因，并通过Cre结合蛋白的磷酸化而激活 CREB。大鼠细胞周期蛋白D3基因含有一个功能性的Cre。主要的CREB 雪旺细胞中的激酶被Hereguline激活，但持续积聚 磷酸化CREB的合成需要与Forsklin共同刺激。拟议的工作将 探索cAMP的功能是作为共激活剂的假设 依赖于细胞色素的关键基因的转录，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启动子中协同作用所需的DNA元件 由Hereglin和cAMP激活的转录，2)阐明分子 CAMP和hereglin协调调节磷酸化CREB水平的途径， 以及3)确定调节机制的扰动如何 磷酸化CREB水平影响细胞周期蛋白D转录和雪旺细胞 扩散。对调控雪旺细胞的分子机制的认识 增殖将促进调节雪旺蛋白活性的能力 神经受伤和病变。

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.