Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control

Department of Molecular Biology and National Centers of Competence in Research and Frontiers in Genetics and Chemical Biology, University of Geneva, Geneva, CH-1211, Switzerland.
Genetics (Impact Factor: 5.96). 12/2011; 189(4):1177-201. DOI: 10.1534/genetics.111.133363
Source: PubMed


TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin used in three different therapeutic areas. The yeast Saccharomyces cerevisiae has played a prominent role in both the discovery of TOR and the elucidation of its function. Here we review the TOR signaling network in S. cerevisiae.

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Available from: Robbie Loewith, Apr 01, 2014
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    • "rRNA production in S. cerevisiae is downregulated in response to gradual exhaustion of nutrients during saturating growth and upon acute shift to various low-nutrient conditions (Conrad et al., 2014). Although there are regulatory differences between the respective starvation responses (Klosinska et al., 2011), most involve signaling by TOR kinase, a conserved regulator of cell growth and ribosome biogenesis (Loewith and Hall, 2011). Inhibition of TOR kinase by rapamycin leads to reduced rRNA expression, increased rDNA stability, and enhanced Sir2 binding in the rDNA (Ha and Huh, 2011). "
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    ABSTRACT: Repetitive DNA arrays are important structural features of eukaryotic genomes that are often heterochromatinized to suppress repeat instability. It is unclear, however, whether all repeats within an array are equally subject to heterochromatin formation and gene silencing. Here, we show that in starving Saccharomyces cerevisiae, silencing of reporter genes within the ribosomal DNA (rDNA) array is less pronounced in outer repeats compared with inner repeats. This position effect is linked to the starvation-induced contraction of the nucleolus. We show that the chromatin regulators condensin and Hmo1 redistribute within the rDNA upon starvation; that Hmo1, like condensin, is required for nucleolar contraction; and that the position effect partially depends on both proteins. Starvation-induced nucleolar contraction and differential desilencing of the outer rDNA repeats may provide a mechanism to activate rDNA-encoded RNAPII transcription units without causing general rDNA instability.
    Full-text · Article · Jan 2016 · Cell Reports
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    • "TOR proteins are best known for roles in the nutrient-dependent signaling pathways underlying cell growth, proliferation, and survival (Weisman et al., 2014). TOR genes, which have been isolated in all eukaryotes investigated, form two functionally distinct complexes, TORC1 (CRTC1) and TORC2 (CRTC2); both have been the focus of metabolic and cancer studies for many years (Wullschleger et al., 2006; Loewith and Hall, 2011; Natarajan et al., 2013). Regulation of transcription of gluconeogenic genes, such as PEPCK and G6Pase, is controlled by AMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2), which acts by specifying targets for the transcription factor CREB in response to glucagon (Koo et al., 2005). "
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    ABSTRACT: Growth and meat quality traits play important roles in the evaluation of cattle productivity and are influenced by genetic and environmental factors. CRTC2 is a recently discovered gene related to obesity that may influence fat deposition. The aim of the current study was to detect polymorphisms of bovine CRTC2 and explore their relationships to growth and meat quality in Qinchuan cattle. Three single nucleotide polymorphisms (SNPs); g.3001 C>T; g.3034 G>A; and g.3467 T>C, were identified from sequencing results of 422 Qinchuan cattle. The genotypic distributions of both g.3034 G>A and g.3467 T>C mutations were in agreement with Hardy-Weinberg equilibrium, (P < 0.05), while the T3001C mutation was not (P > 0.05), based on χ(2) test analysis. The SNPs g.3001 C>T and g.3034 G>A are missense mutations (Ser/Phe and Ser/Thr respectively). Additionally, SNPs g.3034 G>A and g.3467 T>C showed a medium polymorphism level (0.25 < PIC< 0.50), whereas g.3001 C>T showed a low polymorphism level (PIC < 0.25). These three SNPs were significantly associated with several growth and meat quality traits in the Qinchuan cattle population (P < 0.05 or P < 0.01). Collectively, these results demonstrate that CRTC2 is involved in the regulation of cattle growth and meat quality, and suggest that CRTC2 is a potential candidate gene for marker-assisted selection in future breeding development programs for Qinchuan cattle.
    Preview · Article · Oct 2015 · Genetics and molecular research: GMR
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    • "The core adaptor proteins of TORC1 are Raptor and LST8, whereas LST8, Rictor and Sin1 are the conserved components of TORC2. Removing either of the proteins from a cell destabilizes the TORC2 complex and inhibits its kinase activity (Frias et al., 2006;Jacinto et al., 2006Jacinto et al., , 2004Kim et al., 2002;Loewith et al., 2002;Sarbassov et al., 2004).Since its original discovery in screens for rapamycin suppressors (Heitman et al., 1991;Sabatini et al., 1994), TOR has been extensively studied in the context of TORC1, and has been shown to stimulate key anabolic cellular processes and inhibit the degradative pathway of autophagy (reviewed inDibble and Manning, 2013;Loewith and Hall, 2011;Soulard et al., 2009) with crucial roles in metabolic diseases, cancer and aging (Cornu et al., 2014;Sabatini, 2006;Zoncu et al., 2011). TORC1 is widely regarded as the central node in cell growth control; its activity is dependent on growth factors and nutrient availability, and it is generally shut down in times of stress (Li et al., 2010;Reiling and Sabatini, 2006;Sancak et al., 2010;Sengupta et al., 2010;Urban et al., 2007). "
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    ABSTRACT: The kinase TOR is found in two complexes, TORC1, involved in growth control, and TORC2 with less well defined roles. Here, we ask whether TORC2 has a role in sustaining cellular stress. We show that TORC2 inhibition in Drosophila melanogaster leads to a reduced tolerance to heat stress, whereas sensitivity to other stresses is not affected. Accordingly, we show that upon heat stress, both in the animal and Drosophila cultured S2 cells, TORC2 is activated and is required for the stability of its known target Akt/PKB. We show that the phosphorylation of the stress activated protein kinases is not modulated by TORC2, nor is the heat-induced upregulation of heat shock proteins. Instead, we show, both in vivo and in cultured cells, that TORC2 is required for the assembly of heat-induced cytoprotective ribonucleoprotein particles, the pro-survival stress granules. These granules are formed in response to protein translation inhibition imposed by heat stress that appears less efficient in the absence of TORC2 function. We propose that TORC2 mediates heat resistance in Drosophila by promoting the cell autonomous formation of stress granules. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Jun 2015 · Journal of Cell Science
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