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
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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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    • "For example, the homologs of the core components of TORC2 in animals, such as SIN1 and RICTOR, are missing in plants (Xiong and Sheen, 2014). The disruption of TOR function has been lethal in all examined eukaryotic organisms, which has prevented definition of the TOR functions (Barbet et al., 1996; Zhang et al., 2000; Weisman and Choder, 2001; Menand et al., 2002; Murakami et al., 2004; Ren et al., 2011). Progress in this respect was not made until the discovery of rapamycin, which can repress TORC1 activity in yeast and animals very efficiently (Heitman et al., 1991; Chiu et al., 1994; Sabatini et al., 1994). "
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    ABSTRACT: Target of rapamycin (TOR) acts as a master regulator to control cell growth by integrating nutrient, energy, and growth factors in all eukaryotic species. TOR plays an evolutionarily conserved role in regulating the transcription of genes associated with anabolic and catabolic processes in Arabidopsis, but little is known about the functions of TOR in photosynthesis and phytohormone signaling, which are unique features of plants. In this study, AZD8055 (AZD) was screened as the strongest active-site TOR inhibitor (asTORi) in Arabidopsis compared with TORIN1 and KU63794 (KU). Gene expression profiles were evaluated using RNA-seq after treating Arabidopsis seedlings with AZD. More than three-fold differentially expressed genes (DEGs) were identified in AZD-treated plants relative to rapamycin-treated plants in previous studies. Most of the DEGs and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in cell wall elongation, ribosome biogenesis, and cell autophagy were common to both AZD- and rapamycin-treated samples, but AZD displayed much broader and more efficient inhibition of TOR compared with rapamycin. Importantly, the suppression of TOR by AZD resulted in remodeling of the expression profile of the genes associated with photosynthesis and various phytohormones, indicating that TOR plays a crucial role in modulating photosynthesis and phytohormone signaling in Arabidopsis. These newly identified DEGs expand the understanding of TOR signaling in plants. This study elucidates the novel functions of TOR in photosynthesis and phytohormone signaling and provides a platform to study the downstream targets of TOR in Arabidopsis.
    Frontiers in Plant Science 10/2015; 6:677. DOI:10.3389/fpls.2015.00677 · 3.95 Impact Factor
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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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