| Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation. | |
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MedLine Citation:
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PMID: 18796613 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Target of rapamycin (TOR) kinases control cell growth through two functionally distinct multiprotein complexes. TOR complex 1 (TORC1) controls temporal cell growth and is sensitive to rapamycin, whereas TOR complex 2 (TORC2) is rapamycin resistant and regulates spatial cell growth. Here, we identified two TOR orthologues, TbTOR1 and TbTOR2, in the protozoan parasite Trypanosoma brucei, as well as orthologues of the well-known TORC1 and TORC2 partners, KOG1/raptor and AVO3/rictor. TbTOR proteins differ in their functions, subcellular localization, and rapamycin sensitivity. TbTOR1 controls cell growth by regulating cell cycle, nucleolus structure, and protein synthesis, whereas TbTOR2 coordinates cell polarization and cytokinesis. Rapamycin treatment of bloodstream trypanosomes resulted in a pronounced reduction of cell proliferation, with an EC(50) of 152 nM. Unique for a eukaryote, we observed that rapamycin acted exclusively by preventing TORC2 formation, with no effect on TORC1. Our findings on TOR signaling in this protozoan, which is located in a distal position in the eukaryotic cell lineage, highlight the clinical possibilities of rapamycin derivates and provide valuable insights into understanding rapamycin-mediated inhibition of TORC2. |
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Authors:
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Antonio Barquilla; José L Crespo; Miguel Navarro |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-09-16 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 105 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2008 Sep |
Date Detail:
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Created Date: 2008-09-24 Completed Date: 2008-10-22 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 14579-84 Citation Subset: IM |
Affiliation:
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Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Avenida del Conocimiento s/n, 18100 Granada, Spain. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antiprotozoal Agents / pharmacology* Cell Polarity Cell Proliferation / drug effects Cytokinesis / drug effects Immunoprecipitation Intracellular Space / metabolism Multiprotein Complexes / metabolism Protein Biosynthesis Protein-Serine-Threonine Kinases / metabolism* Protozoan Proteins / metabolism* RNA Interference Signal Transduction / drug effects Sirolimus / pharmacology* Transcription Factors / metabolism Trypanosoma brucei brucei / drug effects*, genetics, growth & development*, ultrastructure |
| Grant Support | |
ID/Acronym/Agency:
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55005525//Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Antiprotozoal Agents; 0/Multiprotein Complexes; 0/Protozoan Proteins; 0/Transcription Factors; 53123-88-9/Sirolimus; EC 2.7.11.1/Protein-Serine-Threonine Kinases |
| Comments/Corrections | |
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