Disease relevance of TOR1

• However, the hypersensitivity of a tor1 null mutant to this drug was rescued neither by sorbitol nor by adenine, which was found to outcompete caffeine effects specially on mutants in the PKC pathway [1].

High impact information on TOR1

• We now show that an intact kinase domain is required for the G1 cell cycle functions of both proteins, for the ability of a mutation in a neighboring FKBP12-rapamycin-binding domain of the TOR1 protein to inhibit the growth of yeast cells when overexpressed, and for the essential function of the TOR2 protein [2].
• TCP20 overexpression does not restore growth in a tor1 tor2 double mutant [3].
• We conclude either that DRR1 (alone or in combination with DRR2) acts as a target of FKBP12-rapamycin complexes or that a missense mutation in DRR1 allows it to compensate for the function of the normal drug target [4].
• Genomic disruption of DRR1 in a mutant haploid strain restored drug sensitivity and demonstrated that the gene encodes a nonessential function [4].
• Mutant copies of DRR1 and DRR2 were cloned from genomic YCp50 libraries by their ability to confer drug resistance in wild-type cells [4].

Biological context of TOR1

• The Saccharomyces cerevisiae targets of rapamycin, TOR1 and TOR2, signal activation of cell growth in response to nutrient availability [5].
• Retrograde response to mitochondrial dysfunction is separable from TOR1/2 regulation of retrograde gene expression [6].
• We report here that yeast TOR1 has an intrinsic protein kinase activity capable of phosphorylating PHAS-1, and this activity is abolished by an active site mutation and inhibited by FKBP12-rapamycin or wortmannin [7].
• Three genes clustered within 22 kb (YJR059w, YJR061w and TOR1) have counterparts arranged within 15 kb on the left arm of chromosome XI [8].
• As with its role in cell cycle progression, both the N-terminal and C-terminal regions, as well as the kinase domain of Tor1p, are required for rescue of dna2 mutants [9].

Anatomical context of TOR1

• Using immunogold electron microscopy, we observed that Tor2p, as well as Tor1p, localizes in punctate clusters to regions adjacent to the plasma membrane and within the cell interior, often in association with characteristic membranous tracks [10].
• Subcellular fractionation and immunofluorescence studies showed that Tor1p and Tor2p associate with the plasma membrane and a second fraction that is distinct from Golgi, vacuoles, mitochondria, and nucleus and may represent vesicular structures [11].

Associations of TOR1 with chemical compounds

• Additionally, the transcriptional programme elicited by caffeine resembled that of rapamycin, a potent inhibitor of the TOR1/2 kinases [1].
• The TOR1 (S1972A) mutant protein retained Rm sensitivity (RmS), whereas both the Thr and Asp substitutions conferred RmR [12].
• The fission yeast TOR homolog, tor1+, is required for the response to starvation and other stresses via a conserved serine [13].
• It has been reported recently that both NCR-sensitive and retrograde gene expression is negatively regulated by glutamine and induced by treating cells with the Tor1/2 inhibitor, rapamycin [14].
• In Saccharomyces cerevisiae, the Tor1/2 serine/threonine kinases are global regulators situated at the top of a signal cascade reported to receive and transmit nutritional signals associated with the nitrogen supply of the cell [15].

Other interactions of TOR1

• The TOR1 and TOR2 kinases (TOR) control cytoplasmic protein synthesis and degradation through the conserved TAP42 protein [16].
• Fourth, TOR1, similar to ENA1, is required for growth under saline stress conditions [17].
• Mutation of AGGGG sequence at position -116 to -112 caused a high drop in PRX1 expression under respiratory conditions and in strains containing deletions of TOR1 or RAS2, confirming the finding that this sequence is a STRE [18].
• We also showed that Lst8p, a component of the TOR1/2 complexes and a negative regulator of the RTG pathway, has multiple roles in the regulation of RTG- and NCR-sensitive genes [6].
• When cells are transferred from a good to a poor nitrogen source (glutamine to proline) or treated with rapamycin, an inhibitor of the protein kinases Tor1/2, Gln3 (NCR-sensitive transcription activator) moves from the cytoplasm into the nucleus [19].

Analytical, diagnostic and therapeutic context of TOR1

• RmS correlated with the ability to interact with FKBP12-Rm in a two-hybrid assay: both wild-type TOR1 and the S1972A mutant retained the ability to interact with FKBP12-Rm, whereas the S1972T, S1972D and S1972R mutants failed to interact [12].
• Using site-directed mutagenesis, we replaced the Ser1972 residue of TOR1 with either a conservative residue, Ala, an alternative potential phosphorylation site, Thr, or Asp to mimic phosphorylation [12].
• Here, we show by northern blot and reporter gene (beta-galactosidase) assays that deletion of genes encoding Tor1p and Ras2p resulted in increased PRX1 expression, indicating that these proteins are also mediators of the glucose repression effect [18].

References