AIMP2 Controls Intestinal Stem Cell Compartments and Tumorigenesis by Modulating Wnt/β-Catenin Signaling
| Autor: | Young Woo Jo, Eun Byul Lee, Al Eum Lee, Ji Hoon Kim, Sunghoon Kim, Young-Yun Kong, Jong Seol Kang, Yoon Young Kim, Jung Min Han, Min Kyu Yum, Hyun Kim, Ji Yun Seo, Jinwoo Seong |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Angiogenesis Biology medicine.disease_cause Mice 03 medical and health sciences medicine Animals Humans Intestinal Mucosa Autocrine signalling Wnt Signaling Pathway beta Catenin Wnt signaling pathway Nuclear Proteins LRP6 LRP5 Cell biology 030104 developmental biology Oncology Apoptosis Stem cell Signal Transduction |
| Zdroj: | Cancer Research. 76:4559-4568 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Wnt/β-catenin (CTNNB1) signaling is crucial for the proliferation and maintenance of intestinal stem cells (ISC), but excessive activation leads to ISC expansion and eventually colorectal cancer. Thus, negative regulators are required to maintain optimal levels of Wnt/β-catenin signaling. Aminoacyl-tRNA synthetase–interacting multifunctional proteins (AIMP) function in protein synthesis, but have also been implicated in signaling cascades affecting angiogenesis, immunity, and apoptosis. In this study, we 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 gene 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 the regulation of ISC abundance and activity. Cancer Res; 76(15); 4559–68. ©2016 AACR. |
| Databáze: | OpenAIRE |
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