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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tor proteins are global regulators situated at the top of a signal transduction pathway conserved from yeast to humans. Specific inhibition of the two Saccharomyces cerevisiae Tor proteins by rapamycin alters many cellular processes and the expression of hundreds of genes. Among the regulated genes are those whose expression is activated by the GATA family transcription activator, Gln3. The extent of Gln3 phosphorylation has been thought to determine its intracellular localization, with phosphorylated and dephosphorylated forms accumulating in the cytoplasm and nucleus, respectively. Data presented here demonstrate that rapamycin and the glutamine synthetase inhibitor, methionine sulfoximine (MSX), although eliciting the same outcomes with respect to Gln3-Myc13 nuclear accumulation and nitrogen catabolite repression-sensitive transcription, generate diametrically opposite effects on Gln3-Myc13 phosphorylation. MSX increases Gln3-Myc13 phosphorylation and rapamycin decreases it. Gln3-Myc13 phosphorylation levels are regulated by at least three mechanisms as follows: (i) depends on Snf1 kinase as observed during carbon starvation, (ii) is Snf1-independent as observed during both carbon starvation and MSX treatment, and (iii) is rapamycin-induced dephosphorylation. MSX and rapamycin act additively on Gln3-Myc13 phosphorylation, but MSX clearly predominates. These results suggest that MSX- and rapamycin-inhibited proteins are more likely to function in separate regulatory pathways than they are to function tandemly in a single pathway as thought previously. Furthermore, as we and others have detected thus far, Gln3 phosphorylation/dephosphorylation is not a demonstrably required step in achieving Gln3 nuclear localization and nitrogen catabolite repression-sensitive transcription in response to MSX or rapamycin treatment.
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PMID:Methionine sulfoximine treatment and carbon starvation elicit Snf1-independent phosphorylation of the transcription activator Gln3 in Saccharomyces cerevisiae. 1591 13

Volatile anesthetics including isoflurane affect all cells examined, but their mechanisms of action remain unknown. To investigate the cellular basis of anesthetic action, we are studying Saccharomyces cerevisiae mutants altered in their response to anesthetics. The zzz3-1 mutation renders yeast isoflurane resistant and is an allele of GCN3. Gcn3p functions in the evolutionarily conserved general amino acid control (GCN) pathway that regulates protein synthesis and gene expression in response to nutrient availability through phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha). Hyperphosphorylation of eIF2alpha inhibits translation initiation during amino acid starvation. Isoflurane rapidly (in <15 min) inhibits yeast cell division and amino acid uptake. Unexpectedly, phosphorylation of eIF2alpha decreased dramatically upon initial exposure although hyperphosphorylation occurred later. Translation initiation was inhibited by isoflurane even when eIF2alpha phosphorylation decreased and this inhibition was GCN-independent. Maintenance of inhibition required GCN-dependent hyperphosphorylation of eIF2alpha. Thus, two nutrient-sensitive stages displaying unique features promote isoflurane-induced inhibition of translation initiation. The rapid phase is GCN-independent and apparently has not been recognized previously. The maintenance phase is GCN-dependent and requires inhibition of general translation imparted by enhanced eIF2alpha phosphorylation. Surprisingly, as shown here, the transcription activator Gcn4p does not affect anesthetic response.
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PMID:Inhibition of translation initiation by volatile anesthetics involves nutrient-sensitive GCN-independent and -dependent processes in yeast. 1593 Jan 27

The retinoblastoma gene product (RB) is an important regulator of E2F activity. RB recruits a number of proteins, including HDACs, SWI/SNF complex, lysine methyl transferase (SUV39H1) and DNA methyltransferase (DNMT1), all of which negatively regulate E2F activity with RB. Here, we show that RB interacts with PRMT2, a member of the protein arginine methyltransferase family, to regulate E2F activity. PRMT2 directly bound and interacted with RB through its AdoMet binding domain, in contrast to other PRMT proteins, including PRMT1, PRMT3 and PRMT4. In reporter assays, PRMT2 repressed E2F1 transcriptional activity in an RB-dependent manner. PRMT2 formed a ternary complex with E2F1 in the presence of RB. To further explore the role of endogenous PRMT2 in the regulation of E2F activity, the PRMT2 gene was ablated in mice by gene targeting. Compared with PRMT2(+/+) mouse embryonic fibroblasts (MEFs), PRMT2(-/-) MEFs demonstrated increased E2F activity and early S phase entry following release of serum starvation. Vascular injury to PRMT2(-/-) arteries results in a hyperplastic response, consistent with increased G1-S phase progression. Taken together, these findings demonstrate a novel mechanism for the regulation of E2F activity by a member of the protein arginine methyltransferase family.
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PMID:The arginine methyltransferase PRMT2 binds RB and regulates E2F function. 1661 19

Recently, we have shown implication of Brm, the catalytic subunit of the SWI/SNF chromatin remodeling complex, in repression of cyclin A expression in quiescent cells. Here, we have examined the fate of cells lacking Brm throughout the cycle. We find that despite elevated levels of cyclins A and E, these cells can respond to serum starvation, however, without reaching a canonical G(0) phase as they continue to express high levels of c-Myc and have an abnormally large average size. The response to serum starvation can be correlated with increased levels of Rb proteins p130 and p107 as well as increased association of p27 with the cyclin-dependent kinases, possibly compensating for the higher levels of G(1) cyclins by reducing their associated kinase activity. After serum stimulation, reentry into the cycle occurs normally, but the S phase is delayed and shorter. In addition, the M phase has an increased duration, and we observed frequent faulty chromosome segregation events in anaphase. Altogether, our data suggest that cells can partially overcome the absence of Brm by activating several compensatory mechanisms to control the cell cycle. However, they remain profoundly affected, unable to enter a canonical quiescent state, presenting a shorter S phase, and finally unable to perform correct chromosome segregation.
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PMID:Role for Brm in cell growth control. 1670 29

Intracellular localization of Saccharomyces cerevisiae GATA family transcription activator, Gln3, is used as a downstream readout of rapamycin-inhibited Tor1,2 control of Tap42 and Sit4 activities. Gln3 is cytoplasmic in cells provided with repressive nitrogen sources such as glutamine and is nuclear in cells growing with a derepressive nitrogen source such as proline or those treated with rapamycin or methionine sulfoximine (Msx). Although gross Gln3-Myc13 phosphorylation levels in wild type cells do not correlate with nitrogen source-determined intracellular Gln3-Myc13 localization, the phosphorylation levels are markedly influenced by several environmental perturbations. Msx treatment increases Snf1-independent Gln3-Myc13 phosphorylation, whereas carbon starvation increases both Snf1-dependent and -independent Gln3-Myc13 phosphorylation. Here we demonstrate that a broad spectrum of environmental stresses (temperature, osmotic, and oxidative) increase Gln3-Myc13 phosphorylation. In parallel, these stresses elicit rapid (<5 min for NaCl) Gln3-Myc13 relocalization from the nucleus to the cytoplasm. The response of Gln3-Myc13 localization to stressful conditions can completely overwhelm its response to nitrogen source quality or inhibitor-generated disruption of the Tor1,2 signal transduction pathway. Adding NaCl to cells cultured under conditions in which Gln3-Myc13 is normally nuclear, i.e. proline-grown, nitrogen-starved, Msx-, caffeine-, and rapamycin-treated wild type cells, or ure2Delta cells, results in its prompt relocalization to the cytoplasm. Together these data identify a major new level of regulation to which Gln3 responds, and adds a new dimension to mechanistic studies of the regulation of this transcription factor.
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PMID:Stress-responsive Gln3 localization in Saccharomyces cerevisiae is separable from and can overwhelm nitrogen source regulation. 1743 49

This chapter describes phenotypic assays on specific and general aspects of translation using yeast Saccharomyces cerevisiae as a model eukaryote. To study the effect on start codon selection stringency, a his4(-) or his4-lacZ allele altering the first AUG to AUU is employed. Mutations relaxing the stringent selection confer the His(+) phenotype in the his4(-) strain background or increase expression from his4-lacZ compared to that from wild-type HIS4-lacZ (Sui(-) phenotype). Translation of the Gcn4p transcription activator is strictly regulated by amino acid availability depending on upstream ORF (uORF) elements in the GCN4 mRNA leader. Mutations reducing the eIF2/GTP/Met-tRNA(i)(Met) complex level or the rate of its binding to the 40S subunit derepress GCN4 translation by allowing ribosomes to bypass inhibitory uORFs in the absence of the starvation signal (Gcd(-) phenotype). Mutations impairing scanning or AUG recognition generally impair translational GCN4 induction during amino acid starvation (Gcn(-) phenotype). Different amino acid analogs or amino acid enzyme inhibitors are used to study Gcd(-) or Gcn(-) phenotypes. The method of polysome profiling is also described to gain an ultimate "phenotypic" proof for translation defects.
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PMID:Yeast phenotypic assays on translational control. 1791 21

Transcription of the arginine biosynthetic gene ARG1 is activated by Gcn4p, a transcription factor induced by starvation for any amino acid. Previously, we showed that Gcn4p binding stimulates the recruitment of Mcm1p and co-activator SWI/SNF to ARG1 in cells via Gcn4p induction through amino acid starvation. Here, we report that Gcn4p binding is reduced by point mutations of the Mcm1p binding site and increased by overexpression of Mcm1p. This result suggests that Mcm1p plays a positive role in recruiting activator Gcn4p to ARG1, similar to the previously described cooperative interaction of Mcm1p with sequence-specific transcription factors at their promoters. In addition, the mutational analysis of Mcm1p binding sites showed that recruitment of the co-activator SWI/SNF correlated more closely with binding of Mcm1p than of Gcn4p at ARG1. Consistent with this, SWI/SNF co-immunoprecipitated with Mcm1p, but not with Gcn4p. These results support that Mcm1p increases the SWI/SNF recruitment at ARG1, a Gcn4p target promoter. The interaction between Mcm1p and SWI/SNF was abolished in a snf2 deletion strain containing an intact SWI/SNF sub-complex, suggesting that Mcm1p targets the catalytic subunit, which has ATPase activity, during SWI/SNF recruitment. We propose that Mcm1p contributes to active transcription at the ARG1 promoter by increasing the binding of the activator Gcn4p and by recruiting the co-activator complex SWI/SNF at ARG1 under Gcn4p-induced conditions.
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PMID:Mcm1p binding sites in ARG1 positively regulate Gcn4p binding and SWI/SNF recruitment. 1923 44

Tumor cells undergoing serum starvation in vitro partially mimic metabolically stressed cells trying to adjust to a changed environment in vivo by inducing signal transduction and gene expression so that the tumor continues to grow. Our hypothesis is that the changes in protein and phosphoprotein levels after serum starvation may reflect the adapted phenotype of the tumor, which could be targeted for therapy. We used reverse-phase protein microarrays to interrogate five high-grade glioma cell lines and seven adenocarcinoma cell lines for differences in the level of 81 proteins and 25 phosphoproteins. All cell lines were studied in the well-fed condition of growth with 10% FBS and the starved condition of 0.5% FBS. Protein expression levels were normalized to beta-actin and trichotomized as increased (+1, upper 75th quartile), decreased (-1, lowest 25th quartile), or unchanged (0, others) to focus on the patterns of the biggest (and hopefully most robust) changes in protein and phosphoprotein levels. We examined these trichotomized values to better understand Starved-Fed differences among the cell lines and thereby gain better/clearer insight into the effects of serum starvation on potential cellular responses. In general, the expression of proteins and phosphoproteins 24 h after FBS starvation increased more often in glioma lines than in adenocarcinoma lines, which appeared to have fewer increased protein scores and more decreased scores. Many of the proteins increased in gliomas were downstream targets of the PTEN-PI-3 kinase-AKT, EGFR-MAPK-Stat, and transcription activator-polyamine signaling pathways. In adenocarcinomas, the expression of proteins and phosphoproteins generally increased in apoptosis pathways, while there were minor fluctuations in the other pathways above. Contrawise, gliomas become resistant to apoptosis after 24 h of serum starvation and upregulate transcription activators and polyamines more so than adenocarciomas.
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PMID:Different changes in protein and phosphoprotein levels result from serum starvation of high-grade glioma and adenocarcinoma cell lines. 1989 63

Two important nutrient-sensing and regulatory pathways, the general amino acid control (GAAC) and the target of rapamycin (TOR), participate in the control of yeast growth and metabolism during changes in nutrient availability. Amino acid starvation activates the GAAC through Gcn2p phosphorylation of translation factor eIF2 and preferential translation of GCN4, a transcription activator. TOR senses nitrogen availability and regulates transcription factors such as Gln3p. We used microarray analyses to address the integration of the GAAC and TOR pathways in directing the yeast transcriptome during amino acid starvation and rapamycin treatment. We found that GAAC is a major effector of the TOR pathway, with Gcn4p and Gln3p each inducing a similar number of genes during rapamycin treatment. Although Gcn4p activates a common core of 57 genes, the GAAC directs significant variations in the transcriptome during different stresses. In addition to inducing amino acid biosynthetic genes, Gcn4p in conjunction with Gln3p activates genes required for the assimilation of secondary nitrogen sources such as gamma-aminobutyric acid (GABA). Gcn2p activation upon shifting to secondary nitrogen sources is suggested to occur by means of a dual mechanism. First, Gcn2p is induced by the release of TOR repression through a mechanism involving Sit4p protein phosphatase. Second, this eIF2 kinase is activated by select uncharged tRNAs, which were shown to accumulate during the shift to the GABA medium. This study highlights the mechanisms by which the GAAC and TOR pathways are integrated to recognize changing nitrogen availability and direct the transcriptome for optimal growth adaptation.
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PMID:Integration of general amino acid control and target of rapamycin (TOR) regulatory pathways in nitrogen assimilation in yeast. 2023 14

BRM is an ATPase component of the SWI/SNF complex that regulates chromatin remodeling and cell proliferation and is considered a tumor suppressor. In this study we characterized transcripts from the Smarca2 gene that encodes the BRM protein. We found that the human Smarca2 gene (hSmarca2), like its mouse counterpart (mSmarca2), also initiated a short transcript from intron 27 of the long transcript. We name the long and short transcripts as Smarca2-a and Smarca2-b, respectively. Like its human counterpart, mSmarca2-a also underwent alternative splicing at the 54-bp exon 29. The hSmarca2-b had two alternative initiation sites and underwent alternative splicing at three different 3' sites of exon 1 and at exons 2, 3 and/or 5. We identified nine hSmarca2-b mRNA variants that might produce five different proteins. mSmarca2-b also underwent alternative splicing at exon 3 and/or exon 5, besides alternatively retaining part of intron 1 in exon 1. Smarca2-b was expressed more abundantly than Smarca2-a in many cell lines and was more sensitive to serum starvation. Moreover, cyclin D1 also regulated the expression of both Smarca2-a and Smarca2-b in a complex manner. These data suggest that the functions of the Smarca2 gene may be very complex, not just simply inhibiting cell proliferation, and in certain situations may be elicited mainly by expressing the much less known Smarca2-b, not the better studied Smarca2-a and its products BRM proteins.
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PMID:Complex alternative splicing of the smarca2 gene suggests the importance of smarca2-B variants. 2181 17


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