APC Tumor Suppressor in Cell Differentiation and Death

描述(申请人提供)：结肠腺瘤性息肉病(APC)抑癌基因失活会引发结直肠、十二指肠、胃息肉和癌症的发展。在进化上保守的Wnt/ss-catenin信号转导通路中，APC是一个关键的效应因子，它在后生动物发育过程中指导细胞的增殖、分化和死亡，并且在几种类型的癌症中被异常激活。我们研究的目的是了解APC调节Wnt通路活性的机制。我们已经在果蝇中开发了一个强大的遗传系统来研究APC的功能，并识别决定APC丢失的细胞后果的效应器。我们的发现意外地揭示了Fly APC同源物在Wnt转导中具有双重的正向和负向调节作用，这是由结构不同的结构域介导的。我们发现，APC除了在破坏ss-catenin的稳定中发挥负调控作用外，还通过介导Wnt信号的负效应降解Axin来促进Wnt的转导。我们建议结合遗传学、细胞生物学和生物化学的方法来确定APC介导轴蛋白降解的机制。此外，我们建议描述在我们的基因筛查中揭示的对APC丢失的细胞反应的一个调节因子。我们期望这项工作将有助于我们对APC功能和Wnt信号转导的理解。

DESCRIPTION (provided by applicant): Inactivation of the adenomatous polyposis coli (APC) tumor suppressor triggers the development of colorectal, duodenal, and gastric polyps and carcinoma. APC is a critical effector in the evolutionarily conserved Wnt/ss-catenin signal transduction pathway, which directs cell proliferation, differentiation, and death during metazoan development, and is aberrantly activated in several types of cancer. The objective of our research is to understand the mechanisms by which APC regulates the activity of the Wnt pathway. We have developed a powerful genetic system in Drosophila to study APC function, and to identify effectors that determine the cellular consequences of APC loss. Our findings have revealed, unexpectedly, that fly APC homologs have dual positive and negative regulatory roles in Wnt transduction that are mediated by structurally distinct domains. We found that in addition to a well-documented negative regulatory role in destabilizing ss-catenin, APC also promotes Wnt transduction by mediating the degradation Axin, a negative effector of Wnt signaling. We propose to determine the mechanisms by which APC mediates Axin degradation using a combination of genetic, cell biological, and biochemical approaches. In addition, we propose to characterize one regulator of the cellular response to Apc loss that was revealed in our genetic screens. We anticipate that this work will inform our understanding of APC function and Wnt signal transduction.