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An unexpected signaling output for the tumor suppressor APC

肿瘤抑制因子 APC 的意外信号输出

基本信息

批准号：
9504746
负责人：
PETER S KLEIN
金额：
$ 8.29万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-16 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9504746
关键词：
APC gene Adenomatous Polyposis Coli Adult Animal Model Apoptosis Binding Biopsy Cancer Etiology Cells Colon Carcinoma Colorectal Cancer Complex Cyclin D1 Data Development Drosophila genus Embryo Embryonic Development FRAP1 gene Gastrointestinal Polyp Gene Targeting Genetic Genetic Models Glycogen Synthase Kinase 3 Human Impairment Intestines Lead Link Malignant neoplasm of gastrointestinal tract Maps Mediating Modeling Molecular Genetics Mus Mutate Mutation Neoplasms Nuclear Nutrient Output Pathway interactions Patients Pharmacology Phenotype Phosphorylation Play Point Mutation Polyps Proliferation Marker Raptors Recruitment Activity Recurrence Regulation Role Signal Pathway Signal Transduction Study models TSC2 gene Testing Tissues Tuberous sclerosis protein complex Tumor Suppressor Genes Tumor Suppressor Proteins WNT Signaling Pathway Zebrafish adenoma beta catenin c-myc Genes cell type genetic approach in vitro activity in vivo in vivo Model loss of function mutant neoplastic novel novel strategies novel therapeutics polyposis response sensor tumor tumorigenesis

项目摘要

Summary This proposal identifies a new function for Adenomatous polyposis coli (APC), a tumor suppressor and negative regulator of Wnt signaling. Homozygous loss of APC causes polyposis and colon cancer in humans and deletion in early embryos causes multiple developmental phenotypes in model organisms such as Drosophila, zebrafish, and mouse. Apc mutations cause accumulation of ß-catenin, which activates Wnt target genes such as c-myc and cyclin D1. However, nuclear ß-catenin is not detectable in early adenomas of patients with germline APC mutations (familial adenomatous polyposis (FAP)) nor in the developing intestines of apc mutant zebrafish, suggesting that additional effectors are required downstream of APC. We find that APC directly enhances the activity of glycogen synthase kinase-3 (GSK-3), providing an unexpected mechanism for APC-dependent suppression of multiple downstream targets, including the nutrient sensor mTOR (mechanistic Target of Rapamycin) and ß-catenin. APC mutations reduce GSK-3 activity, thereby activating mTORC1 in diverse in vivo settings including adenomas from patients with FAP, intestinal adenomas in mice, and apc mutant zebrafish embryos. Our overall hypothesis is that APC directly activates GSK-3 and that this signaling motif regulates multiple pathways, including ß-catenin and mTOR signaling. This model reveals a critical, new function for APC, provides a mechanism for mTOR activation caused by APC mutations, and suggests a link between APC and other signaling pathways that are independent of Wnt/ß-catenin. In aim 1 of this proposal, we will map the GSK-3 activation domain of APC. In aim 2, we will explore the mechanism of mTOR regulation by APC in vivo, including FAP patients. Aim 3 explores the surprising observation that apc mutation causes a dramatic neoplastic phenotype in zebrafish within 3 days that requires mTOR activation. We will use molecular and genetic approaches in zebrafish to characterize these tumors as a highly accessible, in vivo model to explore APC signaling and tumorigenesis.

总结