Metabolic stress responses and eIF2 kinase GCN2

描述（由申请人提供）：环境压力引发旨在修复细胞损伤或诱导细胞凋亡的基因表达程序。胁迫适应的一个重要贡献者是磷酸化真核起始因子-2 （elF2）的蛋白激酶家族。这一建议集中在elF2激酶GCN2 （EIF2AK4）上，该激酶在氨基酸饥饿、紫外线照射和蛋白酶体抑制的反应中被激活。GCN2磷酸化的elF2减少了全局翻译，允许细胞保存资源，并启动基因表达的重新配置，以有效地管理压力。伴随着这种一般的蛋白质合成控制，elF2磷酸化诱导特定mrna的翻译，例如编码bZIP转录调节因子ATF4的mrna。ATF4还诱导额外的转录因子ATF3和CHOP/GADD153的表达，这些转录因子有助于应激反应基因的表达。elF2磷酸化减少翻译也可以通过降低不稳定的IDB调节蛋白的稳态水平来激活NF-nB。虽然由elF2磷酸化诱导的许多基因在不同的环境胁迫之间是共享的，但GCN2与其他应激途径（如由MAP激酶调节的途径）一起起作用，以引发针对特定应激条件量身定制的基因表达程序。我们的假设是GCN2识别不同的应激并促进基因表达，这对于改善细胞损伤和治疗和预防疾病很重要。与这一观点一致的是，GCN2基因缺失的小鼠表现出对营养缺乏和异常饮食行为的敏感性。在本文中，我们将描述GCN2的调节机制及其在细胞修复和解毒中对环境应激的反应。我们提出了四个目标。目的1：表征GCN2在不同细胞应激下的激活机制。目的2：表征elF2磷酸化对ATF4翻译的调节机制。目的3表征ATF3在elF2激酶应激反应中的作用。目的4：表征GCN2在抗癌治疗中的作用。解决这些主要问题将增加我们对细胞适应环境压力的过程及其在治疗和预防人类疾病（如糖尿病、神经功能障碍、饮食失调和癌症）中的作用的理解。

DESCRIPTION (provided by applicant): Environmental stresses elicit programs of gene expression designed to remedy cellular injury, or alternatively induce apoptosis. An important contributor to stress adaptation is a family of protein kinases that phosphorylate eukaryotic initiation factor -2 (elF2). This proposal is centered on the elF2 kinase GCN2 (EIF2AK4) that is activated in response to amino acid starvation, UV irradiation and proteasome inhibition. GCN2 phosphorylation of elF2 reduces global translation, allowing cells to conserve resources and to initiate a reconfiguration of gene expression to effectively manage stress. Accompanying this general protein synthesis control, elF2 phosphorylation induces translation of specific mRNAs, such as that encoding the bZIP transcriptional regulator ATF4. ATF4 also induces the expression of additional transcription factors, ATF3 and CHOP/GADD153, that assist in expression of stress responsive genes. Reduced translation by elF2 phosphorylation can also activate NF-nB by lowering the steady state-levels of the labile IDB regulatory protein. While many of the genes induced by elF2 phosphorylation are shared between different environmental stresses, GCN2 functions in conjunction with other stress pathways, such as those regulated by MAP kinases, to elicit gene expression programs that are tailored for the specific stress condition. Our hypothesis is that GCN2 recognizes different stresses and facilitates gene expression that is important for ameliorating cellular damage and treating and preventing disease. Consistent with this idea, mice deleted for GCN2 show sensitivity to nutritional deficiencies and aberrant eating behaviors. In this proposal, we will characterize the mechanisms regulating GCN2 and its role in cellular repair and detoxification in response to environmental stress. We propose four aims. Aim 1 Characterize mechanisms activating GCN2 in response to diverse cellular stresses. Aim 2 Characterize the mechanisms regulating ATF4 translation in response to elF2 phosphorylation. Aim 3 Characterize the role of ATF3 in the elF2 kinase stress response. Aim 4 Characterize the role of GCN2 in anti-cancer treatment. Addressing these major questions will increase our understanding of the process of cellular adaptation to environmental stress and its role in the treatment and prevention of human diseases such as diabetes, neurological dysfunctions, eating disorders, and cancer.