Egr transcription factors in neuronal plasticity

描述（由申请人提供）：此修订后的R 01申请侧重于 我们最近发现，Egr家族的显性负性抑制剂 转录调节因子的表达是一种新的高效的 抑制c-Jun激活的手段。这一观察结果来自我们的 研究表明Egr抑制剂结构阻断了NGF诱导的神经突 在PC 12细胞中生长。在旨在了解他们如何运用 这种影响，我们已经获得了令人信服的初步证据，他们这样做 通过阻断NGF诱导磷酸化和激活的能力， 由于c-Jun激活在几种神经元中起关键作用， 细胞凋亡范例，我们检查是否Egr抑制剂结构是有效的 在这方面也是如此。为此，我们发现Egr抑制剂是 对小脑颗粒细胞凋亡有保护作用 缺钾导致的死亡此外，我们还获得了 有令人信服的证据表明它们是通过阻断c-Jun激活来实现这一目的的。 在初步研究中，旨在破译介导这一过程的机制， 效应，我们已经确定了一个新的影响，Egr家族的原型 我们发现Egri与c-Jun共沉淀。这 新的发现表明，Egr蛋白可能通过以下途径控制c-Jun激活： 蛋白质-蛋白质相互作用，而不是通过其传统的作用模式， 即通过结合其同源DNA应答来控制靶基因表达 元素根据这些调查结果，本提案的总体目标是 定义Egr家族成员如何控制c-Jun激活，并评估Egr是否 抑制剂在阻断其他神经元细胞死亡中也是有效的。 依赖于c-Jun激活的细胞凋亡范例。

DESCRIPTION (provided by applicant): This revised R01 application focuses on pursuing our recent finding that dominant negative inhibitors of the Egr family of transcription regulatory factors represent a novel and highly effective means of suppressing activation of c-Jun. This observation emerged from our studies demonstrating that Egr inhibitor constructs block NGF induced neurite outgrowth in PC12 cells. In studies aimed at understanding how they exerted this effect, we have obtained compelling preliminary evidence that they do so by blocking the ability of NGF to induce phosphorylation and activation of c-Jun. Since c-Jun activation plays a critical role in several neuronal apoptosis paradigms, we examined whether Egr inhibitor constructs are effective in this context as well. To this end, we have found that Egr inhibitors are highly effective in protecting cerebellar granule cells from apoptotic cell death induced by potassium deprivation. Furthermore, we have obtained compelling evidence that they do so by blocking c-Jun activation. In preliminary studies aimed at deciphering the mechanism(s) mediating this effect, we have identified a novel effect of Egri, the prototype Egr family member, on c-Jun. We have found that Egri co-precipitates with c-Jun. This novel finding suggests that Egr proteins may control c-Jun activation via protein-protein interactions, rather than via its conventional mode of action, i.e. control of target gene expression by binding to its cognate DNA response element. Based on these findings, the overall goal of this proposal is to define how Egr family members control c-Jun activation and assess whether Egr inhibitors are also effective in blocking cell death in other neuronal apoptosis paradigms that are dependent on c-Jun activation.