Dataset Information

Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation.

ABSTRACT: 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.

SUBMITTER: Barquilla A

PROVIDER: S-EPMC2567229 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation.

Barquilla Antonio A Crespo José L JL Navarro Miguel M

Proceedings of the National Academy of Sciences of the United States of America 20080916 38

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 ...[more]

PMID: 18796613

Similar Datasets

Project description:TOR kinases integrate environmental and nutritional signals to regulate cell growth in eukaryotic organisms. Here, we describe results from a study combining quantitative proteomics and comparative expression analysis in the budding yeast, S. cerevisiae, to gain insights into TOR function and regulation. We profiled protein abundance changes under conditions of TOR inhibition by rapamycin treatment, and compared this data to existing expression information for corresponding gene products measured under a variety of conditions in yeast. Among proteins showing abundance changes upon rapamycin treatment, almost 90% of them demonstrated homodirectional (i.e., in similar direction) transcriptomic changes under conditions of heat/oxidative stress. Because the known downstream responses regulated by Tor1/2 did not fully explain the extent of overlap between these two conditions, we tested for novel connections between the major regulators of heat/oxidative stress response and the TOR pathway. Specifically, we hypothesized that activation of regulator(s) of heat/oxidative stress responses phenocopied TOR inhibition and sought to identify these putative TOR inhibitor(s). Among the stress regulators tested, we found that cells (hsf1-R206S, F256S and ssa1-3 ssa2-2) constitutively activated for heat shock transcription factor 1, Hsf1, inhibited rapamycin resistance. Further analysis of the hsf1-R206S, F256S allele revealed that these cells also displayed multiple phenotypes consistent with reduced TOR signaling. Among the multiple Hsf1 targets elevated in hsf1-R206S, F256S cells, deletion of PIR3 and YRO2 suppressed the TOR-regulated phenotypes. In contrast to our observations in cells activated for Hsf1, constitutive activation of other regulators of heat/oxidative stress responses, such as Msn2/4 and Hyr1, did not inhibit TOR signaling. Thus, we propose that activated Hsf1 inhibits rapamycin resistance and TOR signaling via elevated expression of specific target genes in S. cerevisiae. Additionally, these results highlight the value of comparative expression analyses between large-scale proteomic and transcriptomic datasets to reveal new regulatory connections.

Dataset Information

Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation.

Publications

Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets