Egr transcription factors in neuronal plasticity

描述(由申请人提供)：本次修订后的R01申请重点关注 根据我们最近的发现，Egr家族的主要负面抑制因子 转录调控因子代表了一种新颖而高效的 抑制c-jun活化的途径。这一观察结果来自我们的 研究表明Egr抑制剂构建阻断NGF诱导的轴突 在PC12细胞中生长。在旨在了解它们如何发挥作用的研究中 这种效果，我们已经获得了令人信服的初步证据，证明他们是这样做的 通过阻断NGF诱导磷酸化和活化的能力 C-Jun.由于c-jun激活在几个神经元中起着关键作用 细胞凋亡范式，我们检查了Egr抑制剂结构是否有效 在这种情况下也是如此。为此，我们发现Egr抑制剂是 高效保护小脑颗粒细胞免受细胞凋亡的影响 缺钾致死。此外，我们还获得了 令人信服的证据表明，他们通过阻止c-jun激活来做到这一点。 在旨在破译这一机制的初步研究中(S) 效应，我们已经确定了eGRI的一种新的效应，原型Egr家族 成员，在c-6月。我们发现Egri与c-June共析出。这 新发现提示Egr蛋白可能通过以下途径控制c-jun的激活 蛋白质之间的相互作用，而不是通过其传统的作用模式， 即通过与其同源DNA反应结合来控制靶基因的表达 元素。基于这些发现，这项提案的总体目标是 定义Egr家族成员如何控制c-jun激活并评估Egr是否 抑制剂也能有效地阻断其他神经元的细胞死亡。 依赖于c-jun激活的细胞凋亡模式。

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.