The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4
Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2014
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| Online Access: | http://hdl.handle.net/1721.1/91506 https://orcid.org/0000-0001-6909-4568 |
| _version_ | 1826199539642531840 |
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| author | Csibi, Alfred Fendt, Sarah-Maria Li, Chenggang Poulogiannis, George Choo, Andrew Y. Chapski, Douglas J. Jeong, Seung Min Dempsey, Jamie M. Parkhitko, Andrey Morrison, Tasha Henske, Elizabeth P. Haigis, Marcia C. Cantley, Lewis C. Stephanopoulos, Gregory Yu, Jane Blenis, John |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Csibi, Alfred Fendt, Sarah-Maria Li, Chenggang Poulogiannis, George Choo, Andrew Y. Chapski, Douglas J. Jeong, Seung Min Dempsey, Jamie M. Parkhitko, Andrey Morrison, Tasha Henske, Elizabeth P. Haigis, Marcia C. Cantley, Lewis C. Stephanopoulos, Gregory Yu, Jane Blenis, John |
| author_sort | Csibi, Alfred |
| collection | MIT |
| description | Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach. |
| first_indexed | 2024-09-23T11:21:36Z |
| format | Article |
| id | mit-1721.1/91506 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:21:36Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/915062022-09-27T19:00:44Z The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 Csibi, Alfred Fendt, Sarah-Maria Li, Chenggang Poulogiannis, George Choo, Andrew Y. Chapski, Douglas J. Jeong, Seung Min Dempsey, Jamie M. Parkhitko, Andrey Morrison, Tasha Henske, Elizabeth P. Haigis, Marcia C. Cantley, Lewis C. Stephanopoulos, Gregory Yu, Jane Blenis, John Massachusetts Institute of Technology. Department of Chemical Engineering Fendt, Sarah-Maria Stephanopoulos, Gregory Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach. German Science Foundation (Fellow FE-1185) 2014-11-07T19:16:59Z 2014-11-07T19:16:59Z 2013-05 2013-03 Article http://purl.org/eprint/type/JournalArticle 00928674 1097-4172 http://hdl.handle.net/1721.1/91506 Csibi, Alfred, Sarah-Maria Fendt, Chenggang Li, George Poulogiannis, Andrew Y. Choo, Douglas J. Chapski, Seung Min Jeong, et al. “The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4.” Cell 153, no. 4 (May 2013): 840–854. © 2013 Elsevier Inc. https://orcid.org/0000-0001-6909-4568 en_US http://dx.doi.org/10.1016/j.cell.2013.04.023 Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier Open Archive |
| spellingShingle | Csibi, Alfred Fendt, Sarah-Maria Li, Chenggang Poulogiannis, George Choo, Andrew Y. Chapski, Douglas J. Jeong, Seung Min Dempsey, Jamie M. Parkhitko, Andrey Morrison, Tasha Henske, Elizabeth P. Haigis, Marcia C. Cantley, Lewis C. Stephanopoulos, Gregory Yu, Jane Blenis, John The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 |
| title | The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 |
| title_full | The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 |
| title_fullStr | The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 |
| title_full_unstemmed | The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 |
| title_short | The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 |
| title_sort | mtorc1 pathway stimulates glutamine metabolism and cell proliferation by repressing sirt4 |
| url | http://hdl.handle.net/1721.1/91506 https://orcid.org/0000-0001-6909-4568 |
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