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信号转导途径在发育和组织期间指导基本的细胞过程 稳态。 Wnt信号的放松管制导致许多发育缺陷和触发90％ 结直肠癌，绝大多数是由肿瘤抑制剂灭活腺瘤而引起的 息肉病（APC）。尽管我们知道APC在Wnt中起着核心作用已有二十年来 信号传导，APC函数的机械基础基础仍然难以捉摸。我们的长期目标是 了解APC调节Wnt信号传导的机制，因为此知识对于设计至关重要 针对WNT驱动疾病的新策略。 APC及其结合伴侣Axin建立了多蛋白 通过促进转录共激活因子的周转β-抑制Wnt信号传导的“破坏复合物” Catenin，Wnt途径激活的关键介体。 Axin不仅在破坏络合物中扮演关键角色，而且还发挥 而且还包括“信号体”的组装，该复合物在Wnt刺激后激活信号传导。在 Wnt信号的流行模型，APC的作用仅限于促进β-catenin降解，因此 未刺激状态下的途径抑制。但是，我们在当前资助期间的意外发现 由于我们发现了APC功能的完全新颖方面，因此该模型的力修订。我们的新 调查结果表明，APC的主要作用是控制Axin的两个基本作用：抑制信号传导 未刺激的状态，并激活Wnt刺激后的信号传导。我们发现APC调节两个 在Wnt的抑制和激活中，翻译后的修饰至关重要 信号。在即将到来的资金期间，我们建议阐明APC的新型机制 调节Axin，从而控制破坏复合物和信号体的组装。我们有 开发了用于果蝇中体内Wnt途径解剖和培养的创新实验系统 哺乳动物细胞以及体外途径用爪蟾卵提取物和纯化的蛋白质重构。我们 提案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。这些研究从基本机制中获得的知识 APC功能在开发WNT驱动疾病的未来治疗方法中将是无价的。