Tripartite Regulation of Gln3p by TOR, Ure2p, and Phosphatases

Bertram, Paula; Choi, Jae Hyuk; Carvalho, John; Ai, Wandong; Zeng, Chenbo; Chan, Ting‐Fung; Zheng, X.F. Steven

doi:10.1074/jbc.m004235200

Cited by 212 publications

(360 citation statements)

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“…The NDP genes are also regulated by the TOR signaling pathway (Hardwick et al 1999;Shamji et al 2000). Ure2, a component of the TOR signaling cascade, sequesters transcriptional activators such as Gln3 and Gat1 in the cytoplasm, leading to low expression of nitrogen sourceregulated genes (Beck and Hall 1999;Bertram et al 2000). Strains lacking Ure2 specifically cripple the communication between TOR and the NDP genes, without affecting other TOR-dependent pathways.…”

Section: Association Of Rsc With Genes Involved In the Nitrogen Discrmentioning

confidence: 99%

Genome-wide location and regulated recruitment of the RSC nucleosome-remodeling complex

Ng¹,

Robert²,

Young³

et al. 2002

Genes Dev.

255

292

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Genome-wide location analysis indicates that the yeast nucleosome-remodeling complex RSC has ∼700 physiological targets and that the Rsc1 and Rsc2 isoforms of the complex behave indistinguishably. RSC is associated with numerous tRNA promoters, suggesting that the complex is recruited by the RNA polymerase III transcription machinery. At RNA polymerase II promoters, RSC specifically targets several gene classes, including histones, small nucleolar RNAs, the nitrogen discrimination pathway, nonfermentative carbohydrate metabolism, and mitochondrial function. At the histone HTA1/HTB1 promoter, RSC recruitment requires the Hir1 and Hir2 corepressors, and it is associated with transcriptional inactivity. In contrast, RSC binds to promoters involved in carbohydrate metabolism in response to transcriptional activation, but prior to association of the Pol II machinery. Therefore, the RSC complex is generally recruited to Pol III promoters and it is specifically recruited to Pol II promoters by transcriptional activators and repressors.

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Section: Association Of Rsc With Genes Involved In the Nitrogen Discrmentioning

confidence: 99%

Genome-wide location and regulated recruitment of the RSC nucleosome-remodeling complex

Ng¹,

Robert²,

Young³

et al. 2002

Genes Dev.

255

292

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“…Tor1 and Tor2 are thought to control Gln3 intracellular localization by regulating its phosphorylation/dephosphorylation (10,13). The prevailing model posits that active Tor1/2 phosphorylate Tap42 and Tip41 which, in a way not fully understood, results in inactivation of Sit4, one of two phosphoprotein phosphatases suggested to be responsible for Gln3 dephosphorylation (10,13,17,18).…”

mentioning

confidence: 99%

“…Tor1/2 are also suggested by some investigators to be the kinases responsible for Gln3 phosphorylation itself (13,16). Ure2 complexes with phosphorylated Gln3 and prevents its nuclear entry either because (i) the phosphorylated form of Gln3, stabilized in the complex, is unable to enter the nucleus (13) or (ii) Gln3 cannot enter the nucleus when complexed with Ure2 (10). Inactivation of Tor1/2 by rapamycin prevents Tor1/2-mediated phosphorylation reactions and thereby generates the opposite outcomes, i.e.…”

mentioning

confidence: 99%

“…The prevailing model posits that active Tor1/2 phosphorylate Tap42 and Tip41 which, in a way not fully understood, results in inactivation of Sit4, one of two phosphoprotein phosphatases suggested to be responsible for Gln3 dephosphorylation (10,13,17,18). Tor1/2 are also suggested by some investigators to be the kinases responsible for Gln3 phosphorylation itself (13,16). Ure2 complexes with phosphorylated Gln3 and prevents its nuclear entry either because (i) the phosphorylated form of Gln3, stabilized in the complex, is unable to enter the nucleus (13) or (ii) Gln3 cannot enter the nucleus when complexed with Ure2 (10).…”

mentioning

confidence: 99%

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Gln3 Phosphorylation and Intracellular Localization in Nutrient Limitation and Starvation Differ from Those Generated by Rapamycin Inhibition of Tor1/2 in Saccharomyces cerevisiae

Cox

Kulkarni

Tate

et al. 2004

Journal of Biological Chemistry

101

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The ability of the cell to sense environmental conditions and alter gene expression in response to them is critical to its survival. 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. At the other end of that cascade is Gln3, one of two transcriptional activators responsible for most nitrogen catabolic gene expression. When nitrogen is in excess, Tor1/2 are active, and Gln3 is phosphorylated and localizes to the cytoplasm. If Tor1/2 are inhibited by rapamycin or mutation, Gln3 becomes dephosphorylated, accumulates in the nucleus, and mediates nitrogen catabolite repression (NCR)-sensitive transcription. The observations that Gln3 also accumulates in the nuclei of cells provided with poor nitrogen sources or during nitrogen starvation has led to the conclusion that Tor1/2 control intracellular Gln3 localization and NCR-sensitive transcription by regulating Gln3 phosphorylation/dephosphorylation. To test this model, we compared Gln3 phosphorylation states and intracellular localizations under a variety of physiological conditions known to elicit different levels of NCRsensitive transcription. Our data indicate that: (i) observable Gln3 phosphorylation levels do not correlate in a consistent way with the quality or quantity of the nitrogen source provided, the intracellular localization of Gln3, or the capacity to support NCR-sensitive transcription. (ii) Gln3-Myc 13 is hyperphosphorylated during nitrogen and carbon starvation, but this uniform response does not correlate with Gln3 intracellular localization. (iii) Gln3-Myc 13 dephosphorylation and nuclear localization correlate with one another at early but not late times after rapamycin treatment. These data suggest that rapamycin treatment and growth with poor nitrogen sources bring about nuclear accumulation of Gln3 but likely do so by different mechanisms or by a common mechanism involving molecules other than Gln3 and/or other than the levels of Gln3-Myc 13 phosphorylation thus far detected by others and ourselves.

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“…The TOR proteins are protein kinases (Alarcon et al, 1999) and are members of the phosphatidylinositol kinase-related kinase superfamily (Helliwell et al, 1994), which includes the DNA-PK, ATM, ATR, MEC1, and TEL1 proteins, all of which regulate cell-cycle progression (reviewed in Keith and Schreiber, 1995;Kuruvilla and Schreiber, 1999). Several downstream effectors of TOR have been identified in yeast including the catalytic subunits of PP2A, TAP42p (which regulates PP2A activity), Gln3p, and Ure2p (Di Como and Arndt, 1996;Beck and Hall, 1999;Bertram et al, 2000).Levels of yeast mRNAs are dramatically altered upon entry into diauxic shift. Microarray analysis of mRNA expression in yeast shows that nearly 20% of all yeast mRNAs are downregulated and that nearly 14% are up-regulated at least twofold upon entering the diauxic shift (DeRisi et al, 1997).…”

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confidence: 99%

The Target of Rapamycin Signaling Pathway Regulates mRNA Turnover in the YeastSaccharomyces cerevisiae

Albig

Decker

2001

MBoC

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The target of rapamycin (TOR) signaling pathway is an important mechanism by which cell growth is regulated by nutrient availability in eukaryotes. We provide evidence that the TOR signaling pathway controls mRNA turnover in Saccharomyces cerevisiae. During nutrient limitation (diauxic shift) or after treatment with rapamycin (a specific inhibitor of TOR), multiple mRNAs were destabilized, whereas the decay of other mRNAs was unaffected. Our findings suggest that the regulation of mRNA decay by the TOR pathway may play a significant role in controlling gene expression in response to nutrient depletion. The inhibition of the TOR pathway accelerated the major mRNA decay mechanism in yeast, the deadenylation-dependent decapping pathway. Of the destabilized mRNAs, two different responses to rapamycin were observed. Some mRNAs were destabilized rapidly, while others were affected only after prolonged exposure. Our data suggest that the mRNAs that respond rapidly are destabilized because they have short poly(A) tails prematurely either as a result of rapid deadenylation or reduced polyadenylation. In contrast, the mRNAs that respond slowly are destabilized by rapid decapping. In summary, the control of mRNA turnover by the TOR pathway is complex in that it specifically regulates the decay of some mRNAs and not others and that it appears to control decay by multiple mechanisms. INTRODUCTIONIt is estimated that most of the microorganisms in the environment exist in conditions in which nutrients are limiting (Lewis and Gattie, 1991). Nutrient availability is very important in controlling cell division, growth, and physiology in microorganisms as well as in multicellular organisms. One critical response in yeast to glucose limitation is the switch from fermentation to respiration, which is termed the diauxic shift. At the diauxic shift, major changes in gene expression are induced (reviewed in Werner-Washburne et al., 1996) including a general repression of translation (Fuge et al., 1994) and extensive changes in the abundance of mRNAs (DeRisi et al., 1997). The target of rapamycin (TOR) signaling pathway senses external nutrient availability and is involved in mediating the changes in gene expression induced at the diauxic shift (reviewed in Cutler et al., 1999;Dennis et al., 1999;Thomas and Hall 1999;Cardenas et al., 1999). Rapamycin artificially induces a starvation-like state in yeast (Barbet et al., 1996) by first forming a complex with the yeast FK506 binding protein, FKBP. This complex then binds to and represses the activity of the TOR1 and TOR2proteins (Heitman et al., 1991). The TOR signaling transduction pathway is conserved among yeast, flies, and mammals. In mammalian cells, the TOR protein homolog mTOR/ FRAP/RAFT1 also coordinates nutrient and mitogenic signals to control cell growth and cell-cycle progression (reviewed in Cutler et al., 1999;Thomas and Hall, 1999). The Drosophila TOR homolog dTOR also senses nutrient availability (Oldham et al., 2000;Zhang et al., 2000). The TOR proteins are protein kinases...

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Tripartite Regulation of Gln3p by TOR, Ure2p, and Phosphatases

Cited by 212 publications

References 34 publications

Genome-wide location and regulated recruitment of the RSC nucleosome-remodeling complex

Genome-wide location and regulated recruitment of the RSC nucleosome-remodeling complex

Gln3 Phosphorylation and Intracellular Localization in Nutrient Limitation and Starvation Differ from Those Generated by Rapamycin Inhibition of Tor1/2 in Saccharomyces cerevisiae

The Target of Rapamycin Signaling Pathway Regulates mRNA Turnover in the YeastSaccharomyces cerevisiae

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