دورية أكاديمية
Dissecting the biology of mTORC1 beyond rapamycin.
| العنوان: | Dissecting the biology of mTORC1 beyond rapamycin. |
|---|---|
| المؤلفون: | Yang G; University of Sydney, School of life and Environmental Sciences, Charles Perkins Centre, Sydney, New South Wales 2006, Australia., Francis D; University of Sydney, School of life and Environmental Sciences, Charles Perkins Centre, Sydney, New South Wales 2006, Australia., Krycer JR; University of Sydney, School of life and Environmental Sciences, Charles Perkins Centre, Sydney, New South Wales 2006, Australia., Larance M; University of Sydney, School of life and Environmental Sciences, Charles Perkins Centre, Sydney, New South Wales 2006, Australia., Zhang Z; Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, 600 16th Street, San Francisco, CA 94143, USA., Novotny CJ; Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, 600 16th Street, San Francisco, CA 94143, USA., Diaz-Vegas A; University of Sydney, School of life and Environmental Sciences, Charles Perkins Centre, Sydney, New South Wales 2006, Australia., Shokat KM; Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, 600 16th Street, San Francisco, CA 94143, USA., James DE; University of Sydney, School of life and Environmental Sciences, Charles Perkins Centre, Sydney, New South Wales 2006, Australia.; University of Sydney, Sydney Medical School, Sydney, New South Wales 2006, Australia. |
| المصدر: | Science signaling [Sci Signal] 2021 Sep 21; Vol. 14 (701), pp. eabe0161. Date of Electronic Publication: 2021 Sep 21. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101465400 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1937-9145 (Electronic) Linking ISSN: 19450877 NLM ISO Abbreviation: Sci Signal Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Association for the Advancement of Science |
| مواضيع طبية MeSH: | Sirolimus*/pharmacology , TOR Serine-Threonine Kinases*, Biology ; Mechanistic Target of Rapamycin Complex 1 |
| مستخلص: | Rapamycin extends maximal life span and increases resistance to starvation in many organisms. The beneficial effects of rapamycin are thought to be mediated by its inhibitory effects on the mechanistic target of rapamycin complex 1 (mTORC1), although it only partially inhibits the kinase activity of mTORC1. Other mTOR kinase inhibitors have been developed, such as Torin-1, but these readily cross-react with mTORC2. Here, we report the distinct characteristics of a third-generation mTOR inhibitor called RapaLink1. We found that low doses of RapaLink1 inhibited the phosphorylation of all mTORC1 substrates tested, including those whose phosphorylation is sensitive or resistant to inhibition by rapamycin, without affecting mTORC2 activity even after prolonged treatment. Compared with rapamycin, RapaLink1 showed better efficacy for inhibiting mTORC1 and potently blocked cell proliferation and induced autophagy. Moreover, using RapaLink1, we demonstrated that mTORC1 and mTORC2 exerted differential effects on cell glycolysis and glucose uptake. Last, we found that RapaLink1 and rapamycin had opposing effects on starvation resistance in Drosophila . Consistent with the effects of RapaLink1, genetic blockade of mTORC1 activity made flies more sensitive to starvation, reflecting the complexity of the mTORC1 network that extends beyond effects that can be inhibited by rapamycin. These findings extend our understanding of mTOR biology and provide insights into some of the beneficial effects of rapamycin. |
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| معلومات مُعتمدة: | R01 CA221969 United States CA NCI NIH HHS |
| المشرفين على المادة: | EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) EC 2.7.11.1 (TOR Serine-Threonine Kinases) W36ZG6FT64 (Sirolimus) |
| تواريخ الأحداث: | Date Created: 20210921 Date Completed: 20220114 Latest Revision: 20220322 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8580572 |
| DOI: | 10.1126/scisignal.abe0161 |
| PMID: | 34546793 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1937-9145 |
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| DOI: | 10.1126/scisignal.abe0161 |