GSK3beta: Signaling and apoptosis

GSK3beta：信号传导和细胞凋亡

• 批准号: 6942590
• 负责人: RICHARD S. JOPE
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6942590
• 关键词: Alzheimer' s disease; apoptosis; binding proteins; biological signal transduction; cAMP response element binding protein; cadherins; calcium flux; cell line; cell nucleus; clinical research; cysteine endopeptidases; endoplasmic reticulum; enzyme activity; enzyme mechanism; genetic transcription; neural plasticity; nuclear factor kappa beta; phosphorylation; presenilin; protein localization; protein protein interaction; protein structure function; serine threonine protein kinase; thapsigargin; transcription factor

DESCRIPTION (provided by applicant): Glycogen synthase kinase-3beta (GSK3b) is linked to most key aspects of Alzheimer's disease. These include: GSK3b phosphorylates tau and amyloid precursor protein, Abeta peptide activates GSK3b and inhibition of GSK3b protects from Ab-toxicity, and presenilin-1 binds and regulates the activity of GSK3b, actions altered by mutant presenilin-l. Also, GSK3b impairs neural plasticity, facilitates apoptotic signaling cascades, and inhibits the activities of multiple transcription factors (CREB, AP-1, NFkB, myc, b-catenin, and others), all actions likely important in Alzheimer's disease. These actions and associations indicate that GSK3b may be an important modulator of neuropathological processes associated with Alzheimer's disease as well as other neurodegenerative conditions, but much remains to be learned about the actions of GSK3b. The overall goal of this project is to investigate mechanisms regulating GSK3b and to delineate its effects on cell function, especially neural plasticity and apoptosis. The aims are based on our findings that (i) thapsigargin, which increases intracellular calcium levels and causes endoplasmic reticulum (ER)-stress, conditions associated with Alzheimer's disease, activates GSK3b, and GSK3b is obligatory for thapsigargin-induced apoptosis, (ii) apoptotic stimuli cause intranuclear accumulation of GSK3b, and (iii) GSK3b inhibits the function of the key transcription factor CREB. Specific Aim 1 will test the hypothesis that GSK3b is activated by, and is a critical mediator of, toxicity induced by thapsigargin and other agents perturbing calcium or the ER, and will identify the mechanisms involved in GSK3b activation and assess the regulatory roles of GSK3b-binding proteins. Specific Aim 2 will test the hypothesis that apoptotic stimuli induce nuclear accumulation of GSK3b, identify the mechanisms controlling the intranuclear distribution of GSK3b, and test if nuclear GSK3b contributes to apoptotic signaling. Specific Aim 3 will test the hypothesis that GSK3b has dual functions in apoptosis, both attenuating antiapoptotic signals, with a focus on survival-promoting transcription factors, and facilitating proapoptotic signals connecting ER stress to caspase activation. Overall, these experiments will clarify mechanisms regulating GSK3b and its effects on neural plasticity and survival.

描述（由申请人提供）：糖原合成酶激酶-3β (GSK3b) 与阿尔茨海默氏病的大多数关键方面有关。这些包括：GSK3b 磷酸化 tau 和淀粉样前体蛋白，Abeta 肽激活 GSK3b，抑制 GSK3b 可防止 Ab 毒性，早老素-1 结合并调节 GSK3b 的活性，而突变体早老素-1 会改变其作用。此外，GSK3b 还会损害神经可塑性，促进细胞凋亡信号级联反应，并抑制多种转录因子（CREB、AP-1、NFkB、myc、b-连环蛋白等）的活性，所有这些作用可能对阿尔茨海默病很重要。这些作用和关联表明 GSK3b 可能是与阿尔茨海默氏病以及其他神经退行性疾病相关的神经病理过程的重要调节剂，但关于 GSK3b 的作用还有很多需要了解的地方。该项目的总体目标是研究 GSK3b 的调节机制并描述其对细胞功能的影响，特别是神经可塑性和细胞凋亡。这些目标基于我们的发现：(i) 毒胡萝卜素可增加细胞内钙水平并导致内质网 (ER) 应激（与阿尔茨海默氏病相关的病症），激活 GSK3b，而 GSK3b 对于毒胡萝卜素诱导的细胞凋亡是必需的，(ii)细胞凋亡刺激导致 GSK3b 在核内积累，并且 (iii) GSK3b 抑制关键转录因子 CREB ​​的功能。具体目标 1 将检验以下假设：GSK3b 被毒胡萝卜素和其他干扰钙或 ER 的药物诱导的毒性激活，并且是其关键介导物，并将确定 GSK3b 激活所涉及的机制并评估 GSK3b 的调节作用结合蛋白。具体目标 2 将测试细胞凋亡刺激诱导 GSK3b 核积累的假设，确定控制 GSK3b 核内分布的机制，并测试核 GSK3b 是否有助于细胞凋亡信号传导。具体目标 3 将检验 GSK3b 在细胞凋亡中具有双重功能的假设，既减弱抗细胞凋亡信号，重点关注促进存活的转录因子，又促进将 ER 应激与 caspase 激活联系起来的促细胞凋亡信号。总的来说，这些实验将阐明 GSK3b 的调节机制及其对神经可塑性和存活的影响。