APC Tumor Suppressor in Cell Differentiation and Death

描述（由申请人提供）：腺瘤性大肠息肉病（APC）抑癌基因失活可引发结肠、十二指肠、胃息肉和癌的发生。APC是进化保守的Wnt/ss-catenin信号转导通路的关键效应因子，该信号转导通路在后生动物发育过程中指导细胞增殖、分化和死亡，并在几种类型的癌症中异常激活。我们研究的目的是了解APC调节Wnt通路活性的机制。我们在果蝇中开发了一个强大的遗传系统来研究APC功能，并确定决定APC丢失的细胞后果的效应物。我们的研究结果出乎意料地揭示了苍蝇APC同源物在Wnt转导中具有双重正调控和负调控作用，这些作用是由不同结构域介导的。我们发现，除了在破坏ss-catenin稳定方面有充分证据的负调控作用外，APC还通过介导轴蛋白（Wnt信号传导的负效应因子）的降解来促进Wnt转导。我们建议使用遗传、细胞生物学和生化方法的组合来确定APC介导轴蛋白降解的机制。此外，我们建议描述在我们的遗传筛选中发现的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. PUBLIC HEALTH RELEVANCE: The proposed studies aim to understand how inactivation of the Adenomatous polyposis coli (APC) tumor suppressor triggers the development of the majority of colorectal cancers. We will investigate the function of APC during normal development, and identify proteins that determine the cellular consequences of APC loss.