APC Tumor Suppressor in Cell Differentiation and Death

APC 肿瘤抑制因子在细胞分化和死亡中的作用

• 批准号: 9383490
• 负责人: Yasmath Ahmed
• 金额: $ 32.4万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383490
• 关键词: ADP ribosylation; Adenomatous Polyposis Coli; Adult; Binding; Biochemical; Biological; Birth; Cell Death; Cell Differentiation process; Cell physiology; Cells; Colorectal Cancer; Complex; Coupled; Defect; Development; Disease; Dissection; Drosophila genus; Embryonic Development; Equilibrium; Funding; Future; Genetic; Goals; Homeostasis; Human; In Vitro; Investigation; Knowledge; Laboratories; Left; Malignant Neoplasms; Mammalian Cell; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Modeling; Multiprotein Complexes; Mutagenesis; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Process; Proteins; Proteolysis; Regulation; Reporting; Role; Scaffolding Protein; Signal Transduction; Signal Transduction Pathway; Site; System; Testing; Textbooks; Therapeutic Intervention; Tissues; Transcription Coactivator; Tumor Suppressor Proteins; WNT Signaling Pathway; Work; Xenopus; beta catenin; combat; egg; human disease; in vivo; innovation; multidisciplinary; novel; novel therapeutics; overexpression; public health relevance; reconstitution; scaffold; targeted treatment; therapeutic development

The Wnt signal transduction pathway directs fundamental cellular processes during development and tissue homeostasis. Deregulation of Wnt signaling results in numerous developmental defects and triggers 90% of colorectal cancers, the vast majority of which result from inactivation of the tumor suppressor, Adenomatous polyposis coli (APC). Although we have known for more than two decades that APC plays a central role in Wnt signaling, the mechanistic basis underlying APC function has remained elusive. Our long-term goal is to understand the mechanisms by which APC regulates Wnt signaling, as this knowledge is critical for devising new strategies that target Wnt-driven diseases. APC and its binding partner, Axin, establish a multiprotein “destruction complex” that inhibits Wnt signaling by promoting turnover of the transcriptional coactivator, beta- catenin, the key mediator of Wnt pathway activation. Axin plays key roles not only in the destruction complex, but also in assembly of the “signalosome”, a complex that activates signaling following Wnt stimulation. In the prevailing model for Wnt signaling, the role of APC is limited to promoting beta-catenin degradation and, thus, pathway inhibition in the unstimulated state. However, our unexpected findings in the current funding period force revision of this model, as we have discovered completely novel aspects of APC function. Our new findings indicate that the primary role of APC is to control both of Axin's essential roles: to inhibit signaling in the unstimulated state, and to activate signaling following Wnt stimulation. We found that APC regulates two post-translational modifications critical for Axin function in both the inhibition and the activation of Wnt signaling. In the forthcoming funding period, we propose to elucidate the novel mechanisms by which APC regulates Axin, and thereby controls assembly of both the destruction complex and the signalosome. We have developed innovative experimental systems for in vivo Wnt pathway dissection in Drosophila and cultured mammalian cells as well as in vitro pathway reconstitution with Xenopus egg extracts and purified proteins. We propose to combine our unique genetic and biochemical approaches to interrogate the functions of APC in Wnt pathway regulation. The knowledge gained from these studies on the fundamental mechanisms that underlie APC function will be invaluable in the development of future treatments for Wnt-driven diseases.

Wnt信号转导通路指导发育和组织发育过程中的基本细胞过程。 体内平衡Wnt信号的失调导致许多发育缺陷，并引发90%的发育障碍。 结直肠癌，其中绝大多数是由肿瘤抑制因子腺瘤性结肠癌（Adenomatous 结肠息肉病（APC）。虽然我们已经知道了二十多年，APC在Wnt中发挥着核心作用， 信号，APC功能的机制基础仍然难以捉摸。我们的长期目标是 了解APC调节Wnt信号传导的机制，因为这一知识对于设计 针对Wnt驱动的疾病的新策略。APC及其结合伴侣Axin建立了一个多蛋白 “破坏复合物”，其通过促进转录共激活因子β- 连环蛋白，Wnt通路激活的关键介质。Axin不仅在破坏复合体中发挥关键作用， 而且还参与“信号体”的组装，所述“信号体”是在Wnt刺激后激活信号传导的复合物。在 Wnt信号传导的流行模型，APC的作用限于促进β-连环蛋白降解，因此， 在非刺激状态下的通路抑制。然而，我们在当前融资期内的意外发现 力修订这一模型，因为我们已经发现了APC功能的全新方面。我们的新 研究结果表明，APC的主要作用是控制Axin的两个基本作用： 未受刺激的状态，并激活Wnt刺激后的信号传导。我们发现APC调节两个 翻译后修饰在Wnt抑制和激活中对Axin功能至关重要 信号在即将到来的资助期内，我们建议阐明APC 调节Axin，从而控制破坏复合物和信号体的组装。我们有 开发了用于果蝇体内Wnt通路解剖的创新实验系统， 哺乳动物细胞以及用非洲爪蟾卵提取物和纯化的蛋白质进行体外途径重建。我们 我建议联合收割机结合我们独特的遗传和生化方法来询问APC在Wnt中的功能 途径调节从这些研究中获得的关于 APC功能在Wnt驱动疾病的未来治疗方法的开发中将是非常宝贵的。