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Chemical­‐genetic approach to identify new TOR effectors

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Defense Thèse de doctorat : Univ. Genève, 2012 - Sc. 4431 - 2012/06/13
Abstract The TOR kinases are central regulators of cell growth and extremely well conserved throughout the eukaryotic kingdom. The model organism Saccharomyces cerevisiae possesses two paralogous genes encoding TOR kinases: TOR1 and TOR2. They form the catalytic core of two distinct multi-protein complexes TORC1 and TORC2. The projects of this thesis pursued two goals: identification of new TOR-inhibitors and characterization of phosphorylation events downstream of TORC1 and TORC2. A novel label-free mass-spectrometry approach was applied to quantify changes in abundance of phosphopeptides after TORC1 inhibition by rapamycin. More than 100 TORC1-dependent phosphorylation events were identified. To get a better understanding of TORC2-signalling, a high-throughput chemical screen for new small molecule TOR-inhibitors was performed. Finally, a compound that putatively targeted TORC1 and TORC2 was characterized: BHS345. This molecule was confirmed to be a potent and yeast-permeable TOR-inhibitor in vivo and in vitro.
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URN: urn:nbn:ch:unige-230790
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STAHL, Michael. Chemical­‐genetic approach to identify new TOR effectors. Université de Genève. Thèse, 2012. https://archive-ouverte.unige.ch/unige:23079

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Deposited on : 2012-10-01

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