GENES FROM THE FAP LOCUS

描述：(改编自调查人员的摘要)大部分 结直肠癌与APC肿瘤的体细胞突变有关 抑制子基因。同样，家族性腺瘤性息肉病(FAP)患者， 谁继承了生殖系APC突变，就会患上数百例结直肠肿瘤。 因此，很明显，APC突变在 大肠肿瘤的发展，APC是如何正常发挥抑制作用的 肿瘤的发生仍然不清楚。这项计划建议进行的研究包括 重点关注三个主要领域，旨在阐明其机制 APC在正常和疾病状态下的潜在功能。1)APC诱导 细胞凋亡。以往的研究表明，APC在大肠组织中的表达 癌细胞可以导致细胞凋亡。APC诱导细胞凋亡的作用 将通过确定这一观察的一般性来进一步检验，通过 定义对此功能至关重要的APC区域，并通过确定 APC诱导细胞凋亡相关基因表达的变化。2)APC 和β-连环蛋白。β-连环蛋白与APC结合的发现 为APC的功能提供了重要线索。这一互动将是 通过绘制β-连锁素所需的区域来进一步探索 转化，确定APC对β-连环蛋白介导的影响 转化和鉴定存在于细胞中的连接素样蛋白 正常结肠黏膜并与APC结合。3)APC和Wg/WNT信令 路径。结合APC的两种蛋白质(β-连环蛋白和GSK3)在 WG/WNT信号转导通路及其最终的信号转导 导致β-连环蛋白/TCF复合体诱导转录。他们 将通过确定APC和这条途径之间的关系来评估 在结肠上皮细胞中表达的TCF家族成员， 确定APC对β-连环蛋白/TCF诱导转录的影响， 并阐明了β-连环蛋白/TCF激活诱导的基因谱 抄写。 上述研究的结合应能为 APC的功能。

DESCRIPTION: (adapted from the investigator's abstract) The majority of colorectal cancers are associated with somatic mutations of the APC tumor suppressor gene. Similarly, familial adenomatous polyposis (FAP) patients, who inherit germline APC mutations, develop hundreds of colorectal tumors. While it is thus clear that APC mutations play a critical role in the development of colorectal neoplasia, how APC normally functions to suppress tumorigenesis remains obscure. The studies proposed in this project are focused on three major areas and are designed to elucidate the mechanisms underlying APC function in normal and diseased states. 1) APC-Induced Apoptosis. Previous studies have shown that expression of APC in colorectal cancer cells can result in apoptosis. The role of APC-induced apoptosis will be further tested by determining the generality of this observation, by defining the regions of APC critical to this function and by identifying changes in gene expression associated with APC induced apoptosis. 2) APC and beta-Catenin. The discovery that beta-catenin binds to APC jjhas provided an important clue to APC's function. This interaction will be further explored by mapping the regions required for beta-catenin transformation, determining the effects of APC on beta-catenin mediated transformation and identifying catenin-like proteins that are present in normal colonic mucosa and bind to APC. 3) APC and the Wg/WNT Signaling Pathway. Two proteins that bind APC (beta-catenin and GSK3) function in the Wg/WNT signal transduction pathway and signaling in this pathway ultimately results in induction of transcription by beta-catenin/TCF complexes. They will evaluate the relationship between APC and this pathway by identifying the TCF family members that are expressed in colonic epithelial cells, determining the effects of APC on beta-catenin/TCF induced transcription, and elucidating the spectrum of genes induced by beta-catenin/TCF activated transcription. The combination of the above studies should provide important insights into APC's function.