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TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential
Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, y...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Nature Singapore
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406918/ https://www.ncbi.nlm.nih.gov/pubmed/37550284 http://dx.doi.org/10.1038/s41421-023-00567-7 |
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author | He, Jing Lin, Mingen Zhang, Xinchao Zhang, Ruonan Tian, Tongguan Zhou, Yuefan Dong, Wenjing Yang, Yajing Sun, Xue Dai, Yue Xu, Yue Zhang, Zhenru Xu, Ming Lei, Qun-Ying Xu, Yanping Lv, Lei |
author_facet | He, Jing Lin, Mingen Zhang, Xinchao Zhang, Ruonan Tian, Tongguan Zhou, Yuefan Dong, Wenjing Yang, Yajing Sun, Xue Dai, Yue Xu, Yue Zhang, Zhenru Xu, Ming Lei, Qun-Ying Xu, Yanping Lv, Lei |
author_sort | He, Jing |
collection | PubMed |
description | Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC “eraser” by mRNA oxidation, abolishes YBX1–HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors. |
format | Online Article Text |
id | pubmed-10406918 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Nature Singapore |
record_format | MEDLINE/PubMed |
spelling | pubmed-104069182023-08-09 TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential He, Jing Lin, Mingen Zhang, Xinchao Zhang, Ruonan Tian, Tongguan Zhou, Yuefan Dong, Wenjing Yang, Yajing Sun, Xue Dai, Yue Xu, Yue Zhang, Zhenru Xu, Ming Lei, Qun-Ying Xu, Yanping Lv, Lei Cell Discov Article Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC “eraser” by mRNA oxidation, abolishes YBX1–HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors. Springer Nature Singapore 2023-08-08 /pmc/articles/PMC10406918/ /pubmed/37550284 http://dx.doi.org/10.1038/s41421-023-00567-7 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article He, Jing Lin, Mingen Zhang, Xinchao Zhang, Ruonan Tian, Tongguan Zhou, Yuefan Dong, Wenjing Yang, Yajing Sun, Xue Dai, Yue Xu, Yue Zhang, Zhenru Xu, Ming Lei, Qun-Ying Xu, Yanping Lv, Lei TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
title | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
title_full | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
title_fullStr | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
title_full_unstemmed | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
title_short | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
title_sort | tet2 is required to suppress mtorc1 signaling through urea cycle with therapeutic potential |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406918/ https://www.ncbi.nlm.nih.gov/pubmed/37550284 http://dx.doi.org/10.1038/s41421-023-00567-7 |
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