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Tytuł:
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Oncogene-dependent sloppiness in mRNA translation.
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Autorzy:
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Champagne J; Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Pataskar A; Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Blommaert N; Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Nagel R; Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Wernaart D; Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Ramalho S; Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Kenski J; Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Bleijerveld OB; Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Zaal EA; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, Utrecht University and Netherlands Proteomics Centre, Utrecht, the Netherlands.
Berkers CR; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, Utrecht University and Netherlands Proteomics Centre, Utrecht, the Netherlands.
Altelaar M; Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, Utrecht University and Netherlands Proteomics Centre, Utrecht, the Netherlands.
Peeper DS; Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Faller WJ; Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Agami R; Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Erasmus MC, Rotterdam University, Rotterdam, the Netherlands. Electronic address: .
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Źródło:
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Molecular cell [Mol Cell] 2021 Nov 18; Vol. 81 (22), pp. 4709-4721.e9. Date of Electronic Publication: 2021 Sep 24.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Cambridge Ma : Cell Press
Original Publication: Cambridge, Mass. : Cell Press, c1997-
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MeSH Terms:
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Oncogenes*
Protein Biosynthesis*
Neoplasms/*genetics
RNA, Messenger/*metabolism
T-Lymphocytes/*cytology
Animals ; Carcinogenesis ; Cell Membrane/metabolism ; Disease Progression ; Drug Resistance, Neoplasm ; Frameshift Mutation ; Frameshifting, Ribosomal ; Humans ; Immunotherapy/methods ; MAP Kinase Signaling System ; Melanoma/metabolism ; Mice ; Neoplasms/metabolism ; Peptides/chemistry ; Protein Kinase Inhibitors ; Ribosomes/metabolism ; T-Lymphocytes/metabolism ; Tryptophan/chemistry ; Tryptophan/metabolism
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Contributed Indexing:
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Keywords: MAPK pathway; T cell killing; T cell recognition; aberrant peptides; acquired drug resistance; antigen presentation; cancer; protein synthesis; ribosomal frameshifting
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Substance Nomenclature:
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0 (Peptides)
0 (Protein Kinase Inhibitors)
0 (RNA, Messenger)
8DUH1N11BX (Tryptophan)
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Entry Date(s):
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Date Created: 20210925 Date Completed: 20220107 Latest Revision: 20220107
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Update Code:
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20240105
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DOI:
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10.1016/j.molcel.2021.09.002
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PMID:
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34562372
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mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis. Despite protein quality control mechanisms, amino acid shortage in melanoma induces aberrant proteins by ribosomal frameshifting. The extent and the underlying mechanisms related to this phenomenon are yet unknown. Here, we show that tryptophan depletion-induced ribosomal frameshifting is a widespread phenomenon in cancer. We termed this event sloppiness and strikingly observed its association with MAPK pathway hyperactivation. Sloppiness is stimulated by RAS activation in primary cells, suppressed by pharmacological inhibition of the oncogenic MAPK pathway in sloppy cells, and restored in cells with acquired resistance to MAPK pathway inhibition. Interestingly, sloppiness causes aberrant peptide presentation at the cell surface, allowing recognition and specific killing of drug-resistant cancer cells by T lymphocytes. Thus, while oncogenes empower cancer progression and aggressiveness, they also expose a vulnerability by provoking the production of aberrant peptides through sloppiness.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
