GSK3beta: Signaling and apoptosis

GSK3beta：信号传导和细胞凋亡

• 批准号: 6800487
• 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/6800487
• 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）：糖原合酶激酶-3BETA（GSK3B）与阿尔茨海默氏病的大多数关键方面有关。其中包括：GSK3B磷酸化tau和淀粉样蛋白前体蛋白，Abeta肽激活GSK3B并抑制GSK3B可保护AB毒性，而Presenilin-1结合并调节GSK3B的活性，由突变的Presenilin-presenilin-l改变。此外，GSK3B会损害神经可塑性，促进凋亡信号传导级联，并抑制多种转录因子的活性（CREB，AP-1，NFKB，MYC，MYC，B-Catenin等），所有行动都可能在阿尔茨海默氏病中很重要。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，但有关GSK3B的作用还有很多尚待了解。该项目的总体目标是研究调节GSK3B的机制，并描述其对细胞功能的影响，尤其是神经可塑性和凋亡。目的是基于我们的发现，即（i）提高细胞内钙的水平并引起内质网（ER）压力，与阿尔茨海默氏病相关的疾病，激活GSK3B，GSK3B，GSK3B对Thapsigargin诱导的刺激性（II）的APOPTIS（II）的APOPTOSIN（II）是必不可少（iii）GSK3B抑制了关键转录因子CREB的功能。具体目标1将检验以下假设：GSK3B被Thapsigargin诱导的毒性和其他扰动钙或ER造成的毒性的关键介体，并将确定GSK3B激活中涉及的机制并评估GSK3B结合蛋白的调节作用。具体目标2将检验以下假设：凋亡刺激诱导GSK3B的核积累，确定控制GSK3B核内分布的机制，并测试核GSK3B是否有助于凋亡信号传导。具体目标3将检验以下假设：GSK3B在凋亡中具有双重功能，既损害了抗凋亡信号，又关注促进生存的转录因子，并促进将ER应力连接到caspase激活的促凋亡信号。总体而言，这些实验将阐明调节GSK3B的机制及其对神经可塑性和生存的影响。