Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity
| العنوان: | Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity |
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| المؤلفون: | Claudia N. Spaan, Jarom Heijmans, Jan Koster, Ruben J. de Boer, Alyson W. MacInnes, Jacqueline Ludovicus Maria Vermeulen, Wouter L. Smit, Gijs R. van den Brink, Tânia Martins Garcia, Jan Paul Medema, Marco Lezzerini, Vanesa Muncan, Prashanthi Ramesh, Bartolomeus J. Meijer |
| المساهمون: | Graduate School, Tytgat Institute for Liver and Intestinal Research, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, CCA - Cancer biology and immunology, Laboratory for General Clinical Chemistry, Oncogenomics, Center of Experimental and Molecular Medicine, Radiotherapy, General Internal Medicine |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America, 117(41), 25560-25570. National Academy of Sciences Proc Natl Acad Sci U S A |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adenoma, Cell division, Mice, Transgenic, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, medicine.disease_cause, Tissue Culture Techniques, Mice, medicine, Animals, Humans, Gene knockdown, Multidisciplinary, Carcinoma, EIF4E, Driver mutations, Translation (biology), Biological Sciences, Colorectal cancer, Cell biology, Intestines, Organoids, HEK293 Cells, Protein Biosynthesis, Mutation, Cancer cell, KRAS, Global translation, Colorectal Neoplasms, Protein synthesis, Reprogramming, Signal Transduction |
| الوصف: | Deregulated global mRNA translation is an emerging feature of cancer cells. Oncogenic transformation in colorectal cancer (CRC) is driven by mutations in APC, KRAS, SMAD4, and TP53, known as the adenoma-carcinoma sequence (ACS). Here we introduce each of these driver mutations into intestinal organoids to show that they are modulators of global translational capacity in intestinal epithelial cells. Increased global translation resulting from loss of Apc expression was potentiated by the presence of oncogenic Kras(G12D). Knockdown of Smad4 further enhanced global translation efficiency and was associated with a lower 4E-BP1-to-eIF4E ratio. Quadruple mutant cells with additional P53 loss displayed the highest global translational capacity, paralleled by high proliferation and growth rates, indicating that the proteome is heavily geared toward cell division. Transcriptional reprogramming facilitating global translation included elevated ribogenesis and activation of mTORC1 signaling. Accordingly, interfering with the mTORC1/4E-BP/eIF4E axis inhibited the growth potential endowed by accumulation of multiple drivers. In conclusion, the ACS is characterized by a strongly altered global translational landscape in epithelial cells, exposing a therapeutic potential for direct targeting of the translational apparatus. |
| اللغة: | English |
| تدمد: | 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ccc285b42dbd5905f7bee76ae706c536Test https://pure.amc.nl/en/publications/driver-mutations-of-the-adenomacarcinoma-sequence-govern-the-intestinal-epithelial-global-translational-capacityTest(b9887a9c-b0c1-49aa-bfe1-d01c5e5c2282).html |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ccc285b42dbd5905f7bee76ae706c536 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00278424 |
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