장 내 항상성 및 암 형성에서의 AIMP2 의 기능 연구

학위논문 (박사)-- 서울대학교 대학원 : 생명과학부 생명과학전공, 2017. 2. 공영윤.Wnt/β-catenin (CTNNB1) signaling is crucial for the proliferation and maintenance of intestinal stem cells (ISCs). In the absence of Wnt/β-catenin signaling, the ISCs undergo immediate apoptosis and subsequently the whole intestinal crypt degenerates. The ISCs niche, Paneth and Cryptal mesencymal cells secrete abundant Wnt ligands at the crypt base. However, excessive activation of Wnt/β-catenin signaling leads to ISC expansion and eventually colorectal cancer. Thus, negative regulators are required to maintain optimal levels of Wnt/β-catenin signaling. Colorectal cancer is the third most common cancer and second leading cause of cancer-related death worldwide. Early diagnosis enables a person with cancer to receive treatment. In order to help in treating the disease, it is important to understand the early events of colorectal cancer. Because it is known that the ISCs are origin of colorectal cancer and their expansion is one of the earliest events in tumorigenesis, understanding molecular mechanisms that controls the size of ISC compartment and eventually the tumor incidence is essential. Aminoacyl-tRNA synthetase interacting multifunctional proteins (AIMPs) function in protein synthesis as housekeepers. They stabilize the assembly of Aminoacyl-tRNA synthetases into the multi-tRNA synthetase which is macromolecular enzyme that attach specific amino acids to their corresponding tRNAs. Besides their housekeeping function in amino-acylation, the AIMPs have been implicated in signaling cascades affecting angiogenesis, immunity and apoptosis. Recently, it has also been reported that these AIMPs are associated with signaling pathways relevant to cancers. In this study, I investigated the relationship between AIMP2 and Wnt/β-catenin signaling in a murine model of intestinal homeostasis and tumorigenesis. Hemizygous deletion of Aimp2 resulted in enhanced Wnt/β-catenin signaling, increased proliferation of cryptic epithelial cells and expansion of ISC compartments. In an ApcMin/+ background, Aimp2 hemizygosity increased adenoma formation. Mechanistically, AIMP2 disrupted the interaction between AXIN and Dishevelled-1 (DVL1) to inhibit Wnt/β-catenin signaling by competing with AXIN. Furthermore, AIMP2 inhibited intestinal organoid formation and growth by suppressing Wnt/β-catenin signaling in an AIMP2 dosage-dependent manner. Collectively, our results showed that AIMP2 acts as a haploinsufficient tumor suppressor that fine-tunes Wnt/β-catenin signaling in the intestine, illuminating a novel role for the regulation of ISC abundance and activity.BACKGROUND 1 INTRODUCTION 27 RESULTS 31 DISCUSSION 90 MATERIALS & METODS 96 REFERENCES 104 국문초록 113Docto