NGF SIGNAL-TRANSCRIPTION COUPLING IN HUMAN NEUROECTODERMAL TUMORS

神经母细胞瘤和髓母细胞瘤是常见的神经外胚层肿瘤。 童年的记忆。肿瘤细胞通常具有以下分子特征 神经母细胞瘤。大多数神经母细胞瘤和三分之一的髓母细胞瘤表达 质膜神经生长因子受体(NGFR)。只有一个 少数NGFR+网系与NGF处理有差异，尽管NGF 诱导更多的c-fos基因。最近的研究表明，c-fos只是 一个NGF可诱导转录因子家族的成员，并且协调 对NGF的核反应，包括所有这些基因产物，都需要 启动神经元所需基因表达的变化 差异化。使用模型神经元细胞系，我们已经证明 这种直接早期基因级联的任何组件的扰动都可以 阻断NGF诱导的分化。基于这些观察，我们 假设一些人类网络的出现是因为即刻早期基因 肿瘤细胞对NGF的反应不能反式激活基因 是神经元分化所必需的。为了检验这一假设，我们计划了一项 综合分析Fos-Jun和Egr家族的作用 神经生长因子诱导人类网络分化中的转录因子 对NGF的反应。这些研究应该允许一种新的分类 基于致病机制的人类网络方案，并可能建议 改进治疗的途径。

Neuroblastoma and medulloblastoma are common neuroectodermal tumors (NETs) of childhood. The tumor cells usually have molecular features of neuroblasts. Most neuroblastomas and a third of medulloblastomas express plasma membrane nerve growth factor (NGF) receptors (NGFR). Only a minority of NGFR + NET lines differentiate with NGF treatment, though NGF induces c-fos in many more. Recent studies indicate that c-fos is only one of a family of NGF-inducible transcription factors, and that a coordinated nuclear response to NGF, involving all these gene products, is required to initiate the changes in gene expression required for neuronal differentiation. Using model neuronal cell lines, we have shown that perturbation of any component of this immediate-early gene cascade can block NGF-induced differentiation. Based on these observations, we hypothesize that some human NETs arise because the immediate-early gene response to NGF in the tumor cells is incompetent to transactivate genes required for neuronal differentiation. To test this hypothesis, we plan a comprehensive analysis of the role of the Fos-Jun and Egr family of transcriptional factors in NGF-induced differentiation of human NET responses to NGF. These studies should permit a novel classification scheme for human NETs based on pathogenetic mechanisms, and may suggest avenues for improved therapy.