The ESRP1-GPR137 axis contributes to intestinal pathogenesis
| Autor: | Irene Keller, Pascal Juillerat, Viktor H. Koelzer, Bruce Beutler, Eva Karamitopoulou, Ivonne Koeck, Yu Xia, Siegfried Hapfelmeier, Martin Faderl, Philippe Krebs, Andrew J. Macpherson, Cedric Simillion, Christoph Müller, Vera Genitsch, Irina Tcymbarevich, Ruth Lyck, Lukas F. Mager, Regula Stuber, Lester Thoo, Simona P. Pfister, Maya Langenegger, Kathy D. McCoy, Xiaohong Li, Rémy Bruggmann, Inti Zlobec |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Gene isoform Mouse Colorectal cancer QH301-705.5 Science Regulator 610 Medicine & health Mouse model of colorectal and intestinal cancer Biology Inflammatory bowel disease General Biochemistry Genetics and Molecular Biology Receptors G-Protein-Coupled Pathogenesis 03 medical and health sciences Mice medicine Animals Humans Colitis Biology (General) intestine Cancer Biology mRNA alternative splicing General Immunology and Microbiology General Neuroscience Wnt signaling pathway RNA-Binding Proteins General Medicine Cell Biology medicine.disease Inflammatory Bowel Diseases 3. Good health Alternative Splicing 030104 developmental biology Gene Expression Regulation colon cancer Immunology 570 Life sciences biology Medicine GPR137 Colorectal Neoplasms epithelium ESRP1 Research Article Human |
| Zdroj: | eLife, Vol 6 (2017) eLife Mager, Lukas Franz; Kölzer, Viktor Hendrik; Stuber Roos, Regula; Thoo Sin Lang, Lester; Keller, Irene; Köck, Ivonne; Langenegger, Maya; Simillion, Cedric; Pfister, Simona P; Faderl, Martin Richard; Genitsch Gratwohl, Vera; Tcymbarevich, Irina; Juillerat, Pascal; Li, Xiaohong; Xia, Yu; Karamitopoulou, Evanthia; Lyck, Ruth; Zlobec, Inti; Hapfelmeier, Siegfried Hektor; Bruggmann, Rémy; ... (2017). The ESRP1-GPR137 axis contributes to intestinal pathogenesis. eLife, 6 eLife Sciences Publications 10.7554/eLife.28366 |
| DOI: | 10.7554/eLife.28366 |
| Popis: | Aberrant alternative pre-mRNA splicing (AS) events have been associated with several disorders. However, it is unclear whether deregulated AS directly contributes to disease. Here, we reveal a critical role of the AS regulator epithelial splicing regulator protein 1 (ESRP1) for intestinal homeostasis and pathogenesis. In mice, reduced ESRP1 function leads to impaired intestinal barrier integrity, increased susceptibility to colitis and altered colorectal cancer (CRC) development. Mechanistically, these defects are produced in part by modified expression of ESRP1-specific Gpr137 isoforms differently activating the Wnt pathway. In humans, ESRP1 is downregulated in inflamed biopsies from inflammatory bowel disease patients. ESRP1 loss is an adverse prognostic factor in CRC. Furthermore, generation of ESRP1-dependent GPR137 isoforms is altered in CRC and expression of a specific GPR137 isoform predicts CRC patient survival. These findings indicate a central role of ESRP1-regulated AS for intestinal barrier integrity. Alterations in ESRP1 function or expression contribute to intestinal pathology. eLife digest The lining of the intestine is just one cell thick, and yet it can act as an effective barrier between the inside of the body and the contents of the digestive system. This lining is often disturbed during bowel cancer, inflammatory bowel disease and other intestinal diseases, causing the barrier to fail and the gut to become leaky. These diseases often reduce patient life expectancy and quality of life. Intestinal epithelial cells make up the lining of the intestine and the normal activities of these cells are often disturbed during intestinal disease. In the intestine, a protein called ESRP1 is only found in epithelial cells, but its role in maintaining a healthy intestinal lining was not clear. Here, Mager et al. studied the intestines of mice that had been genetically engineered to produce a form of ESRP1 that is less active than normal. The experiments show that lower levels of ESRP1 activity leads to a broken intestinal barrier. The genetically engineered mice were more likely to develop inflammatory bowel disease and more aggressive forms of cancer. ESRP1 controls a gene that encodes another protein called GPR137, which helps to relay signals to the epithelial cells. Lower levels of ESRP1 resulted in a longer form of the GPR137 protein being produced. This in turn affected the protein’s signaling role and disturbed the activities of intestinal epithelial cells. Further experiments on biopsies taken from patients with inflammatory bowel disease or colorectal cancer revealed that these patients had lower levels of ESRP1 compared to healthy individuals. Furthermore, low levels of ESRP1 and increased levels of the long version of GPR137 were associated with poorer outcomes for cancer patients. Together, these findings may help us to better understand how the intestinal barrier fails in mice and humans and could lead to new ways to monitor and treat intestinal disease. |
| Databáze: | OpenAIRE |
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