APC Tumor Suppressor in Cell Differentiation and Death

描述（由申请方提供）：腺瘤性结肠息肉病（APC）肿瘤抑制因子的失活触发结直肠、十二指肠和胃息肉和癌的发生。APC在进化保守的细胞中是一个关键的效应子。 Wnt/β-连环蛋白信号转导途径，其在后生动物发育期间指导细胞增殖、分化和死亡，并且在几种类型的癌症中异常激活。我们的研究目的是了解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功能，并确定决定APC丢失的细胞后果的效应器。我们的研究结果出乎意料地揭示了，苍蝇APC同源物在Wnt转导中具有双重正和负调节作用，其由结构上不同的结构域介导。我们发现，除了在使β-连环蛋白不稳定中充分记录的负调节作用之外，APC还通过介导Wnt信号传导的负效应物Axin的降解来促进Wnt转导。我们建议确定APC介导Axin降解的机制，使用遗传学，细胞生物学和生物化学方法的组合。此外，我们建议表征一个调节器的细胞响应的APC损失，揭示了在我们的遗传筛选。我们预计，这项工作将告知我们的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.