TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell 7:25-42

Department of Biochemistry, University of Basel, Switzerland.
Molecular Biology of the Cell (Impact Factor: 4.47). 02/1996; 7(1):25-42. DOI: 10.1091/mbc.7.1.25
Source: PubMed


Saccharomyces cerevisiae cells treated with the immunosuppressant rapamycin or depleted for the targets of rapamycin TOR1 and TOR2 arrest growth in the early G1 phase of the cell cycle. Loss of TOR function also causes an early inhibition of translation initiation and induces several other physiological changes characteristic of starved cells entering stationary phase (G0). A G1 cyclin mRNA whose translational control is altered by substitution of the UBI4 5' leader region (UBI4 is normally translated under starvation conditions) suppresses the rapamycin-induced G1 arrest and confers starvation sensitivity. These results suggest that the block in translation initiation is a direct consequence of loss of TOR function and the cause of the G1 arrest. We propose that the TORs, two related phosphatidylinositol kinase homologues, are part of a novel signaling pathway that activates eIF-4E-dependent protein synthesis and, thereby, G1 progression in response to nutrient availability. Such a pathway may constitute a checkpoint that prevents early G1 progression and growth in the absence of nutrients.

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Available from: Stephen B Helliwell, Oct 07, 2015
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    • "Similarly, specific inactivation of TORC2 with rapamycin in AVO3 DCT TOR1-1 cells caused a pronounced depolarization of the actin cytoskeleton in less than 30 min of treatment (Figure 4D). Acute inhibition of TORC1 leads to cellcycle arrest in G 1 (Barbet et al., 1996). Remarkably, in our experiments, rapamycin inhibition of TORC2 triggered a rapid cell-cycle arrest in G 2 /M (Figure 4E). "
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    ABSTRACT: Target of Rapamycin (TOR) plays central roles in the regulation of eukaryote growth as the hub of two essential multiprotein complexes: TORC1, which is rapamycin-sensitive, and the lesser characterized TORC2, which is not. TORC2 is a key regulator of lipid biosynthesis and Akt-mediated survival signaling. In spite of its importance, its structure and the molecular basis of its rapamycin insensitivity are unknown. Using crosslinking-mass spectrometry and electron microscopy, we determined the architecture of TORC2. TORC2 displays a rhomboid shape with pseudo-2-fold symmetry and a prominent central cavity. Our data indicate that the C-terminal part of Avo3, a subunit unique to TORC2, is close to the FKBP12-rapamycin-binding domain of Tor2. Removal of this sequence generated a FKBP12-rapamycin-sensitive TORC2 variant, which provides a powerful tool for deciphering TORC2 function in vivo. Using this variant, we demonstrate a role for TORC2 in G2/M cell-cycle progression. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 05/2015; 58(6). DOI:10.1016/j.molcel.2015.04.031 · 14.02 Impact Factor
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    • "Staining of intracellular glycogen was performed with iodine vapor as previously described (Barbet et al., 1996). "
    Dataset: 3475-3
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    • "Rapamycin is a lipophilic macrocyclic lactone that inhibits TORC1 (Zheng et al., 1995; Wullschleger et al., 2006) and hence mimics nutrient starvation. TORC1 activity promotes the transition from G1 to S as rapamycin-treated cells accumulate in G1 (Barbet et al., 1996). Recent evidence, however, has demonstrated that TORC1 also influences the G2/M transition by regulating Cdc5 localization (Nakashima et al., 2008). "
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    ABSTRACT: Cells challenged with DNA damage activate checkpoints to arrest the cell cycle and allow time for repair. Successful repair coupled to subsequent checkpoint inactivation is referred to as recovery. When DNA damage cannot be repaired, a choice between permanent arrest and cycling in the presence of damage (checkpoint adaptation) must be made. While permanent arrest jeopardizes future lineages, continued proliferation is associated with the risk of genome instability. We demonstrate that nutritional signaling through target of rapamycin complex 1 (TORC1) influences the outcome of this decision. Rapamycin-mediated TORC1 inhibition prevents checkpoint adaptation via both Cdc5 inactivation and autophagy induction. Preventing adaptation results in increased cell viability and hence proliferative potential. In accordance, the ability of rapamycin to increase longevity is dependent upon the DNA damage checkpoint. The crosstalk between TORC1 and the DNA damage checkpoint may have important implications in terms of therapeutic alternatives for diseases associated with genome instability.
    Cell Reports 09/2014; 9(1). DOI:10.1016/j.celrep.2014.08.053 · 8.36 Impact Factor
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