S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1
Ribosomal S6 kinase 1 (S6K1) is a major mTOR downstream signaling molecule that regulates cell size and translation efficiency. Here, we report that short isoforms of S6K1 are overproduced in breast cancer cell lines and tumors. Overexpression of S6K1 short isoforms induces transformation of human b...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-01-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124712004172 |
| _version_ | 1818488646390513664 |
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| author | Vered Ben-Hur Polina Denichenko Zahava Siegfried Avi Maimon Adrian Krainer Ben Davidson Rotem Karni |
| author_facet | Vered Ben-Hur Polina Denichenko Zahava Siegfried Avi Maimon Adrian Krainer Ben Davidson Rotem Karni |
| author_sort | Vered Ben-Hur |
| collection | DOAJ |
| description | Ribosomal S6 kinase 1 (S6K1) is a major mTOR downstream signaling molecule that regulates cell size and translation efficiency. Here, we report that short isoforms of S6K1 are overproduced in breast cancer cell lines and tumors. Overexpression of S6K1 short isoforms induces transformation of human breast epithelial cells. The long S6K1 variant (Iso-1) induced opposite effects. It inhibits Ras-induced transformation and tumor formation, while its knockdown or knockout induces transformation, suggesting that Iso-1 has a tumor-suppressor activity. Furthermore, we found that S6K1 short isoforms bind and activate mTORC1, elevating 4E-BP1 phosphorylation, cap-dependent translation, and Mcl-1 protein levels. Both a phosphorylation-defective 4E-BP1 mutant and the mTORC1 inhibitor rapamycin partially blocked the oncogenic effects of S6K1 short isoforms, suggesting that these are mediated by mTORC1 and 4E-BP1. Thus, alternative splicing of S6K1 acts as a molecular switch in breast cancer cells, elevating oncogenic isoforms that activate mTORC1. |
| first_indexed | 2024-12-10T16:53:54Z |
| format | Article |
| id | doaj.art-ef605f8684744ead9409e441b207ff99 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T16:53:54Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-ef605f8684744ead9409e441b207ff992022-12-22T01:40:49ZengElsevierCell Reports2211-12472013-01-013110311510.1016/j.celrep.2012.11.020S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1Vered Ben-Hur0Polina Denichenko1Zahava Siegfried2Avi Maimon3Adrian Krainer4Ben Davidson5Rotem Karni6Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, IsraelDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, IsraelCold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USADepartment of Pathology, Oslo University Hospital, Norwegian Radium Hospital, 0424 Oslo, NorwayDepartment of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, IsraelRibosomal S6 kinase 1 (S6K1) is a major mTOR downstream signaling molecule that regulates cell size and translation efficiency. Here, we report that short isoforms of S6K1 are overproduced in breast cancer cell lines and tumors. Overexpression of S6K1 short isoforms induces transformation of human breast epithelial cells. The long S6K1 variant (Iso-1) induced opposite effects. It inhibits Ras-induced transformation and tumor formation, while its knockdown or knockout induces transformation, suggesting that Iso-1 has a tumor-suppressor activity. Furthermore, we found that S6K1 short isoforms bind and activate mTORC1, elevating 4E-BP1 phosphorylation, cap-dependent translation, and Mcl-1 protein levels. Both a phosphorylation-defective 4E-BP1 mutant and the mTORC1 inhibitor rapamycin partially blocked the oncogenic effects of S6K1 short isoforms, suggesting that these are mediated by mTORC1 and 4E-BP1. Thus, alternative splicing of S6K1 acts as a molecular switch in breast cancer cells, elevating oncogenic isoforms that activate mTORC1.http://www.sciencedirect.com/science/article/pii/S2211124712004172 |
| spellingShingle | Vered Ben-Hur Polina Denichenko Zahava Siegfried Avi Maimon Adrian Krainer Ben Davidson Rotem Karni S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1 Cell Reports |
| title | S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1 |
| title_full | S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1 |
| title_fullStr | S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1 |
| title_full_unstemmed | S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1 |
| title_short | S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1 |
| title_sort | s6k1 alternative splicing modulates its oncogenic activity and regulates mtorc1 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124712004172 |
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