Proceedings of the National Academy of Sciences - PNAS, 2010-03, Vol.107 (10), p.4764-4769
2010
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- Autor(en) / Beteiligte
- Titel
- Cholesterol trafficking is required for mTOR activation in endothelial cells
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2010-03, Vol.107 (10), p.4764-4769
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2010
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Mammalian target of rapamycin (mTOR) constitutes a nodal point of a signaling network that regulates cell growth and proliferation in response to various environmental cues ranging from growth factor stimulation to nutrients to stress. Whether mTOR is also affected by cholesterol homeostasis, however, has remained unknown. We report that blockade of cholesterol trafficking through lysosome by a newly identified inhibitor of angiogenesis, itraconazole, leads to inhibition of mTOR activity in endothelial cells. Inhibition of mTOR by itraconazole but not rapamycin can be partially restored by extracellular cholesterol delivered by cyclodextrin. Moreover, other known inhibitors of endosomal/lysosomal cholesterol trafficking as well as siRNA knockdown of Niemann-Pick disease type C (NPC) 1 and NPC2 also cause inhibition of mTOR in endothelial cells. In addition, both the accumulation of cholesterol in the lysosome and inhibition of mTOR caused by itraconazole can be reversed by thapsigarin. These observations suggest that mTOR is likely to be involved in sensing membrane sterol concentrations in endothelial cells, and the cholesterol trafficking pathway is a promising target for the discovery of inhibitors of angiogenesis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.0910872107Titel-ID: cdi_pubmed_primary_20176935
- Format
- –
- Schlagworte
- Androstenes - pharmacology, Angiogenesis, Biological Sciences, Biological Transport, Blotting, Western, Carrier Proteins - genetics, Carrier Proteins - metabolism, Cell Cycle - drug effects, Cell growth, Cell Line, Cell lines, Cell membranes, Cell Proliferation - drug effects, Cholesterol, Cholesterol - metabolism, Cholesterol - pharmacology, Cholesterols, Cyclin-Dependent Kinase Inhibitor p21 - metabolism, Cyclin-Dependent Kinase Inhibitor p27 - metabolism, Cyclodextrins - pharmacology, Endothelial cells, Endothelial Cells - cytology, Endothelial Cells - drug effects, Endothelial Cells - metabolism, Enzyme Inhibitors - pharmacology, Homeostasis, Humans, Imipramine - pharmacology, Intracellular Signaling Peptides and Proteins - metabolism, Itraconazole - pharmacology, Lysosomes, Mechanistic Target of Rapamycin Complex 1, Membrane Glycoproteins - genetics, Membrane Glycoproteins - metabolism, Membranes, Metabolic disorders, Multiprotein Complexes, Phosphorylation, Physiological regulation, Protein-Serine-Threonine Kinases - metabolism, Proteins, Ribonucleic acid, RNA, RNA Interference, Thapsigargin - pharmacology, TOR Serine-Threonine Kinases, Transcription Factors - metabolism