The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors

Beck, Thomas W.; Hall, Michael N.

doi:10.1038/45287

Cited by 880 publications

(1,167 citation statements)

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“…To address this possibility, we examined whether CPZ changes the expression of speciWc genes or the levels of glycogen, which are under the control of TORC1. Gln3p is the transcription activator of nitrogen catabolic genes, which is translocated into the nucleus under low nitrogen conditions or in response to TORC1 inhibition by rapamycin (Beck and Hall 1999). A wild type strain containing a genomically integrated myc-tagged GLN3 allele was treated with CPZ (100 M) or rapamycin (1 g/ml; »1 M) for 30 min and 60 min (data not shown) and Gln3p localization was visualized by indirect immunoXuorescence.…”

Section: Inhibition Of Translation Initiation Occurs In a Prototrophimentioning

confidence: 99%

Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells

et al. 2007

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Chlorpromazine (CPZ) is a small permeable cationic amphiphilic molecule that inserts into membrane bilayers and binds to anionic lipids such as poly-phosphoinositides (PIs). Since PIs play important roles in many cellular processes, including signaling and membrane traYcking pathways, it has been proposed that CPZ aVects cellular growth functions by preventing the recruitment of proteins with speciWc PI-binding domains. In this study, we have investigated the biological eVects of CPZ in the yeast Saccharomyces cerevisiae. We screened a collection of approximately 4,800 gene knockout mutants, and found that mutants defective in membrane traYcking between the late-Golgi and endosomal compartments are highly sensitive to CPZ. Microscopy and transport analyses revealed that CPZ aVects membrane structure of organelles, blocks membrane transport and activates the unfolded protein response (UPR). In addition, CPZ-treatment induces phosphorylation of the translation initiation factor (eIF2 ), which reduces the general rate of protein synthesis and stimulates the production of Gcn4p, a major transcription factor that is activated in response to environmental stresses. Altogether, our results reveal that membrane stress within the cells rapidly activates an important gene expression program, which is followed by a general inhibition of protein synthesis. Remarkably, the increase of phosphorylated eIF2 and protein synthesis inhibition were also detected in CPZ-treated NIH-3T3 Wbroblasts, suggesting the existence of a conserved mechanism of translational regulation that operates during a membrane stress.

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Section: Inhibition Of Translation Initiation Occurs In a Prototrophimentioning

confidence: 99%

Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells

et al. 2007

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“…A connection between the retrograde pathway and nitrogen metabolism has recently been uncovered by the finding that the target of rapamycin (TOR) kinase pathway in yeast also involves the RTG genes (Komeili et al, 2000;Shamji et al, 2000). The TOR kinase pathway promotes the formation of a complex between Gln3p, a transcription factor that controls the expression of genes required for the utilization of poor nitrogen sources (Mitchell and Magasanik, 1984;Courchesne and Magasanik, 1988;Coschigano and Magasanik, 1991;Blinder et al, 1996), and Ure2p, a negative regulator of Gln3p (Beck and Hall, 1999). When the TOR kinase pathway is inhibited by rapamycin, or when cells are grown on a poor nitrogen source such as urea, Rtg1p and Rtg3p translocate from the cytoplasm to the nucleus in an Rtg2p-dependent manner to activate target gene expression (Komeili et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

RTG-dependent Mitochondria-to-Nucleus Signaling Is Regulated by MKS1 and Is Linked to Formation of Yeast Prion [URE3]

Sekito¹

2002

Molecular Biology of the Cell

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An important function of the RTG signaling pathway is maintenance of intracellular glutamate supplies in yeast cells with dysfunctional mitochondria. Herein, we report that MKS1 is a negative regulator of the RTG pathway, acting between Rtg2p, a proximal sensor of mitochondrial function, and the bHLH transcription factors Rtg1p and Rtg3p. In mks1⌬ cells, RTG target gene expression is constitutive, bypassing the requirement for Rtg2p, and is no longer repressible by glutamate. We show further that Mks1p is a phosphoprotein whose phosphorylation pattern parallels that of Rtg3p in response to activation of the RTG pathway, and that Mks1p is in a complex with Rtg2p. MKS1 was previously implicated in the formation of [URE3], an inactive prion form of a negative regulator of the nitrogen catabolite repression pathway, Ure2p. rtg⌬ mutations induce [URE3] and can do so independently of MKS1. We find that glutamate suppresses [URE3] formation, suggesting that the Mks1p effect on the formation of [URE3] can occur indirectly via regulation of the RTG pathway. INTRODUCTIONCells are able to monitor and respond to the functional state of their organelles. In animal cells, for example, compromises in mitochondrial function or certain external cues can lead to increased expression of genes encoding components of the mitochondrial oxidative phosphorylation apparatus and, in some instances, lead to a general increase in the biogenesis of mitochondria (Lunardi and Attardi, 1991;Scarpulla, 1997;Biswas et al., 1999;Heddi et al., 1999;Murdock et al., 1999;Wu et al., 1999;Amuthan et al., 2001). These events are controlled, in part, by transcriptional activators and coactivators whose targets include nuclear genes encoding mitochondrial proteins.Yeast cells also respond to mitochondrial dysfunction by altering the expression of a subset of nuclear genes (Parikh et al., 1987(Parikh et al., , 1989. This response, called retrograde regulation, functions to better adapt cells to the mitochondrial defects. In derepressed, respiratory-deficient cells, such as those that have lost their mitochondrial DNA ( petites), the expression of genes involved in anaplerotic pathways, small molecule transport, peroxisomal activities, and stress responses is up-regulated (Liao et al., 1991;Liu and Butow, 1999;Hallstrom and Moye-Rowley, 2000;Traven et al., 2000;Epstein et al., 2001). In many cases, these changes in gene expression reflect activities that would compensate for the block in the tricarboxylic acid (TCA) cycle caused by the respiratory defect. Expression of a number of these retrograde responsive genes, such as CIT2, DLD3, and PDH1 encoding, respectively, a glyoxylate cycle isoform of citrate synthase, a cytosolic d-lactate dehydrogenase, and a protein involved in propionate metabolism, is controlled by RTG1, RTG2, and RTG3. Rtg1p and Rtg3p are basic helix-loop-helix transcription factors (Jia et al., 1997), and Rtg2p is a cytoplasmic protein with an N-terminal ATP-binding domain similar to that of the actin/sugar kinase/hsp70 superfamily (Bork...

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“…Although RAD24 and RAD25 appear to be functionally redundant, Rad25p has only marginal effects on resistance to UV resistance (Ford et al, 1994). In S. cerevisiae, the 14-3-3 proteins (Bmh1p and Bmh2p) are proposed to play a role in several signalling cascades, including the cAMP-dependent RAS-MAPK and TOR signalling pathways and vesicular transport (Beck and Hall, 1999;Bertram et al, 1998;Gelperin et al, 1995;Roberts et al, 1997;Roth et al, 1999). In the RAS-MAPK pathway, 14-3-3 proteins are essential for subsequent cell elongation, possibly by interacting with Ste20p (Roberts et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…In the RAS-MAPK pathway, 14-3-3 proteins are essential for subsequent cell elongation, possibly by interacting with Ste20p (Roberts et al, 1997). In the TOR pathway, Bmhp plays a role in rapamycin resistance as well as nutrient regulation, perhaps by sequestering Msn2p (Beck and Hall, 1999;Bertram et al, 1998). Although the 14-3-3 proteins are highly conserved in S. cerevisiae and Sz.…”

Section: Introductionmentioning

confidence: 99%

The Candida albicans 14‐3‐3 gene, BMH1, is essential for growth

Cognetti

Davis

Sturtevant

2001

Yeast

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The 14-3-3 proteins are a family of conserved small acidic proteins that have been implicated in playing major roles in a wide variety of signalling cascades. In Saccharomyces cerevisiae, the 14-3-3 genes (BMH1 and BMH2) are essential for normal pseudohyphal induction and normal bud cell development. The Bmh proteins function in the cAMPdependent RAS/MAPK and rapamycin-sensitive signalling cascades. Deletion of only one BMH gene demonstrates no phenotypic differences under normal growth conditions. Strains deleted of both BMH1 and BMH2 are either non-viable or demonstrate sensitivity to environmental stresses. In Schizosaccharomyces pombe, the BMH homologues (RAD24 and RAD25) are essential for cell cycle control after DNA damage and deletion of both genes renders the cell inviable. The 14-3-3 gene in Candida albicans (BMH1) was identified using a novel adherence assay and differential display RT-PCR. Unlike other yeasts, C. albicans has only one 14-3-3 gene (BMH1). It was not possible to construct double knockouts by routine methods. These results suggested that the C. albicans BMH1 gene is essential. The essentiality of C. albicans BMH1 was confirmed by a PCR disruption technique. The C. albicans bmh1D/BMH1 heterozygotes exhibit growth and morphogenetic defects. Therefore, the BMH1 gene in C. albicans (Accession No. AF038154) is an excellent candidate to improve our understanding of the coordinate regulation of cell cycle and morphogenesis.

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The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors

Cited by 880 publications

References 23 publications

Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells

Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells

RTG-dependent Mitochondria-to-Nucleus Signaling Is Regulated by MKS1 and Is Linked to Formation of Yeast Prion [URE3]

The Candida albicans 14‐3‐3 gene, BMH1, is essential for growth

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