APC Tumor Suppressor in Cell Differentiation and Death

Wnt信号转导通路在发育和组织过程中指导基本的细胞过程 动态平衡。取消对Wnt信号的调控会导致许多发育缺陷，并触发90%的 结直肠癌，其中绝大多数是由于肿瘤抑制基因失活引起的，腺瘤 大肠息肉病(APC)。尽管我们早在二十多年前就知道APC在WNT中扮演着核心角色 在信号传递方面，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信号的机制，因为这一知识对于设计 针对WNT驱动的疾病的新战略。APC和它的结合伙伴Axin建立了一个多蛋白 “破坏复合体”，通过促进转录辅助激活因子β-1的周转来抑制Wnt信号传导。 连环蛋白，Wnt途径激活的关键介质。Axin不仅在破坏复合体中扮演着关键角色， 而且在“信号小体”的组装中也是如此，信号小体是一种在Wnt刺激后激活信号的复合体。在 对于Wnt信号的流行模型，APC的作用仅限于促进β-连环蛋白的降解，因此， 非刺激状态下的通路抑制。然而，我们在当前资助期的意外发现 强制修改这个模型，因为我们已经发现了APC功能的全新方面。我们的新产品 结果表明，APC的主要作用是控制Axin的两个基本角色：抑制信号转导 未受刺激的状态，并在Wnt刺激后激活信号。我们发现APC调节两个 翻译后修饰在Wnt的抑制和激活中对Axin功能至关重要 发信号。在即将到来的资助期，我们建议阐明APC通过哪些新机制 调节轴蛋白，从而控制破坏复合体和信号体的组装。我们有 建立了果蝇体内Wnt途径分离和培养的创新实验系统 哺乳动物细胞以及非洲爪哇卵提取液和纯化蛋白的体外途径重建。我们 建议结合我们独特的遗传和生化方法来研究APC在WNT中的功能 途径调控。从这些研究中获得的关于基本机制的知识 APC功能将在未来WNT驱动疾病的治疗发展中发挥不可估量的作用。

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.