APC Tumor Suppressor in Cell Differentiation and Death

描述（由申请人提供）：大肠腺瘤性息肉病（APC）抑癌基因失活可引发绝大多数结直肠癌的发生。我们的目标是在体内解剖APC的功能，以及APC失活的分子和细胞后果。由于APC从果蝇到人类的进化保守，我们开发了果蝇的敏感遗传系统来研究APC的功能。该模型的数据提供了确凿的证据，证明APC是保守的Wnt/Wingless （Wg）信号转导通路中中心转录激活因子β -catenin负调控所必需的。此外，这些数据表明，在Apc丢失后，β -catenin过度激活不仅可以诱导细胞增殖和细胞分化，还可以诱导凋亡细胞死亡。我们的方法是通过分离和表征Apc失活时发生的减弱Wg信号过度激活的突变，来确定诱导Apc失活反应的基本成分。这些研究已经确定了5个候选基因座，它们可以编码在Wg通路中起作用的蛋白质。我们发现其中一个突变体是无腿的等位基因，这是Wg转导所必需的基因。我们对无腿突变体的分离验证了该方法检测Wg信号所需基因的能力。我们已经从分子上确定了另外两个基因座，我们提出的研究目标是进一步表征这两个基因。我们预计这项工作的完成将大大扩展Wg信号模型，同时为Apc失活后如何诱导不同的细胞程序提供基本见解。从果蝇到人类，APC和大多数已知的Wnt通路成员的高度保守性表明，对APC本身及其在果蝇中的下游效应物的表征，可能有助于更好地理解人类APC失活诱导的疾病过程。

DESCRIPTION (provided by applicant): Inactivation of the adenomatous polyposis coli (APC) tumor suppressor triggers the development of the vast majority of colorectal carcinomas. Our goal is to dissect the function(s) of APC, and the molecular and cellular consequences of APC inactivation, in vivo. As APC has been evolutionary conserved from flies to humans, we have developed a sensitive genetic system in Drosophila to study APC function. Data from this model provided conclusive evidence that APC is required for the negative regulation of beta-catenin, the central transcriptional activator in the conserved Wnt/Wingless (Wg) signal transduction pathway. In addition, these data revealed that upon Apc loss, beta-catenin hyperactivation can induce not only cell proliferation and cell differentiation, but also apoptotic cell death. Our approach is to identify essential components that induce the response to Apc inactivation by isolating and characterizing mutations that attenuate the hyperactivation of Wg signaling that occurs upon Apc loss. These studies have led to the identification of five loci that are candidates to encode proteins that act in the Wg pathway. We have found that one of these mutants is an allele of legless, a required gene in Wg transduction. Our isolation of a legless mutant verifies the ability of the approach to detect genes required in Wg signaling. We have molecularly identified two of the other loci, and the goal of the proposed research is to further characterize these two genes. We anticipate that the accomplishment of this work will significantly extend models for Wg signaling and at the same time provide basic insight into how dramatically different cellular programs can be induced upon Apc inactivation. The great conservation of APC and most known members of the Wnt pathway from flies to humans indicates that the characterization of Apc itself, as well as its downstream effectors in Drosophila, may provide a better understanding of the disease processes that are induced by the inactivation of APC in humans.