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The transcription factor Gcr1 stimulates cell growth by participating in nutrient-responsive gene expression on a global level

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Abstract

Transcriptomic reprogramming is critical to the coordination between growth and cell cycle progression in response to changing extracellular conditions. In Saccharomyces cerevisiae, the transcription factor Gcr1 contributes to this coordination by supporting maximum expression of G1 cyclins in addition to regulating both glucose-induced and glucose-repressed genes. We report here the comprehensive genome-wide expression profiling of gcr1Δ cells. Our data show that reduced expression of ribosomal protein genes in gcr1Δ cells is detectable both 20 min after glucose addition and in steady-state cultures of raffinose-grown cells, showing that this defect is not the result of slow growth or growth on a repressing sugar. However, the large cell phenotype of the gcr1Δ mutant occurs only in the presence of repressing sugars. GCR1 deletion also results in aberrant derepression of numerous glucose repressed loci; glucose-grown gcr1Δ cells actively respire, demonstrating that this global alteration in transcription corresponds to significant changes at the physiological level. These data offer an insight into the coordination of growth and cell division by providing an integrated view of the transcriptomic, phenotypic, and metabolic consequences of GCR1 deletion.

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References

  • Bailey TL, Williams N, Misleh C, Li WW (2006) MEME: discovering and analyzing DNA and protein sequence motifs. Nucleic Acids Res 34:W369–W373

    Article  PubMed  CAS  Google Scholar 

  • Banuelos M, Fraenkel DG (1982) Saccharomyces carlsbergensis fdp mutant and futile cycling of fructose 6-phosphate. Mol Cell Biol 2:921–929

    PubMed  CAS  Google Scholar 

  • Blumberg H, Silver P (1991) A split zinc-finger protein is required for normal yeast growth. Gene 107:101–110

    Article  PubMed  CAS  Google Scholar 

  • Brauer MJ, Saldanha AJ, Dolinski K, Botstein D (2005) Homeostatic adjustment and metabolic remodeling in glucose-limited yeast cultures. Mol Biol Cell 16:2503–2517

    Article  PubMed  CAS  Google Scholar 

  • Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, Gaasterland T, Glenisson P, Holstege FC, Kim IF, Markowitz V, Matese JC, Parkinson H, Robinson A, Sarkans U, Schulze-Kremer S, Stewart J, Taylor R, Vilo J, Vingron M (2001) Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet 29:365–371

    Article  PubMed  CAS  Google Scholar 

  • Buchman AR, Kimmerly WJ, Rine J, Kornberg RD (1988) Two DNA-binding factors recognize specific sequences at silencers, upstream activating sequences, autonomously replicating sequences, and telomeres in Saccharomyces cerevisiae. Mol Cell Biol 8:210–225

    PubMed  CAS  Google Scholar 

  • Cherel I, Thuriaux P (1995) The IFH1 gene product interacts with a fork head protein in Saccharomyces cerevisiae. Yeast 11:261–270

    Article  PubMed  CAS  Google Scholar 

  • Cipollina C, Alberghina L, Porro D, Vai M (2005) SFP1 is involved in cell size modulation in respiro-fermentative growth conditions. Yeast 22:385–399

    Article  PubMed  CAS  Google Scholar 

  • Clifton D, Fraenkel DG (1981) The gcr (glycolysis regulation) mutation of Saccharomyces cerevisiae. J Biol Chem 256:13074–13078

    PubMed  CAS  Google Scholar 

  • Costanzo MC, Hogan JD, Cusick ME, Davis BP, Fancher AM, Hodges PE, Kondu P, Lengieza C, Lew-Smith JE, Lingner C, Roberg-Perez KJ, Tillberg M, Brooks JE, Garrels JI (2000) The yeast proteome database (YPD) and Caenorhabditis elegans proteome database (WormPD): comprehensive resources for the organization and comparison of model organism protein information. Nucleic Acids Res 28:73–76

    Article  PubMed  CAS  Google Scholar 

  • Dabeva MD, Post-Beittenmiller MA, Warner JR (1986) Autogenous regulation of splicing of the transcript of a yeast ribosomal protein gene. Proc Natl Acad Sci USA 83:5854–5857

    Article  PubMed  CAS  Google Scholar 

  • David L, Huber W, Granovskaia M, Toedling J, Palm CJ, Bofkin L, Jones T, Davis RW, Steinmetz LM (2006) A high-resolution map of transcription in the yeast genome. Proc Natl Acad Sci USA 103:5320–5325

    Article  PubMed  CAS  Google Scholar 

  • Deminoff SJ, Santangelo GM (2001) Rap1p requires Gcr1p and Gcr2p homodimers to activate ribosomal protein and glycolytic genes, respectively. Genetics 158:133–143

    PubMed  CAS  Google Scholar 

  • Deminoff SJ, Willis KA, Santangelo GM (2003) Coordination between eukaryotic growth and cell cycle progression: RAP1/GCR1 transcriptional activation mediates glucose-dependent CLN function. Recent Res Dev Genet 3:1–16

    CAS  Google Scholar 

  • DeRisi JL, Iyer VR, Brown PO (1997) Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278:680–686

    Article  PubMed  CAS  Google Scholar 

  • Fewell SW, Woolford JL Jr (1999) Ribosomal protein S14 of Saccharomyces cerevisiae regulates its expression by binding to RPS14B pre-mRNA and to 18S rRNA. Mol Cell Biol 19:826–834

    PubMed  CAS  Google Scholar 

  • Fingerman I, Nagaraj V, Norris D, Vershon AK (2003) Sfp1 plays a key role in yeast ribosome biogenesis. Eukaryot Cell 2:1061–1068

    Article  PubMed  CAS  Google Scholar 

  • Gelperin D, Horton L, Beckman J, Hensold J, Lemmon SK (2001) Bms1p, a novel GTP-binding protein, and the related Tsr1p are required for distinct steps of 40S ribosome biogenesis in yeast. RNA 7:1268–1283

    Article  PubMed  CAS  Google Scholar 

  • Hartwell LH (1974) Saccharomyces cerevisiae cell cycle. Bacteriol Rev 38:164–198

    PubMed  CAS  Google Scholar 

  • Hartwell LH, Culotti J, Pringle JR, Reid BJ (1974) Genetic control of the cell division cycle in yeast. Science 183:46–51

    Article  PubMed  CAS  Google Scholar 

  • Henry YA, Lopez MC, Gibbs JM, Chambers A, Kingsman SM, Baker HV, Stanway CA (1994) The yeast protein Gcr1p binds to the PGK UAS and contributes to the activation of transcription of the PGK gene. Mol Gen Genet 245:506–511

    Article  PubMed  CAS  Google Scholar 

  • Hermann-Le Denmat S, Werner M, Sentenac A, Thuriaux P (1994) Suppression of yeast RNA polymerase III mutations by FHL1, a gene coding for a fork head protein involved in rRNA processing. Mol Cell Biol 14:2905–2913

    PubMed  CAS  Google Scholar 

  • Holmberg S, Schjerling P (1996) Cha4p of Saccharomyces cerevisiae activates transcription via serine/threonine response elements. Genetics 144:467–478

    PubMed  CAS  Google Scholar 

  • Ito T, Chiba T, Ozawa R, Yoshida M, Hattori M, Sakaki Y (2001) A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci USA 98:4569–4574

    Article  PubMed  CAS  Google Scholar 

  • Jin SB, Zhao J, Bjork P, Schmekel K, Ljungdahl PO, Wieslander L (2002) Mrd1p is required for processing of pre-rRNA and for maintenance of steady-state levels of 40 S ribosomal subunits in yeast. J Biol Chem 277:18431–18439

    Article  PubMed  CAS  Google Scholar 

  • Johnston GC, Ehrhardt CW, Lorincz A, Carter BL (1979) Regulation of cell size in the yeast Saccharomyces cerevisiae. J Bacteriol 137:1–5

    PubMed  CAS  Google Scholar 

  • Johnston GC, Pringle JR, Hartwell LH (1977) Coordination of growth with cell division in the yeast Saccharomyces cerevisiae. Exp Cell Res 105:79–98

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen P, Nishikawa JL, Breitkreutz BJ, Tyers M (2002) Systematic identification of pathways that couple cell growth and division in yeast. Science 297:395–400

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen P, Rupes I, Sharom JR, Schneper L, Broach JR, Tyers M (2004) A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev 18:2491–2505

    Article  PubMed  CAS  Google Scholar 

  • Kief DR, Warner JR (1981) Coordinate control of syntheses of ribosomal ribonucleic acid and ribosomal proteins during nutritional shift-up in Saccharomyces cerevisiae. Mol Cell Biol 1:1007–1015

    PubMed  CAS  Google Scholar 

  • Krogan NJ, Cagney G, Yu H, Zhong G, Guo X, Ignatchenko A, Li J, Pu S, Datta N, Tikuisis AP, Punna T, Peregrin-Alvarez JM, Shales M, Zhang X, Davey M, Robinson MD, Paccanaro A, Bray JE, Sheung A, Beattie B, Richards DP, Canadien V, Lalev A, Mena F, Wong P, Starostine A, Canete MM, Vlasblom J, Wu S, Orsi C, Collins SR, Chandran S, Haw R, Rilstone JJ, Gandi K, Thompson NJ, Musso G, St Onge P, Ghanny S, Lam MH, Butland G, Altaf-Ul AM, Kanaya S, Shilatifard A, O’Shea E, Weissman JS, Ingles CJ, Hughes TR, Parkinson J, Gerstein M, Wodak SJ, Emili A, Greenblatt JF (2006) Global landscape of protein complexes in the yeast Saccharomyces cerevisiae. Nature 440:637–643

    Article  PubMed  CAS  Google Scholar 

  • Lee TI, Rinaldi NJ, Robert F, Odom DT, Bar-Joseph Z, Gerber GK, Hannett NM, Harbison CT, Thompson CM, Simon I, Zeitlinger J, Jennings EG, Murray HL, Gordon DB, Ren B, Wyrick JJ, Tagne JB, Volkert TL, Fraenkel E, Gifford DK, Young RA (2002) Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298:799–804

    Article  PubMed  CAS  Google Scholar 

  • Li B, Vilardell J, Warner JR (1996) An RNA structure involved in feedback regulation of splicing and of translation is critical for biological fitness. Proc Natl Acad Sci USA 93:1596–1600

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Paulovich AG, Woolford JL Jr (1995) Feedback inhibition of the yeast ribosomal protein gene CRY2 is mediated by the nucleotide sequence and secondary structure of CRY2 pre-mRNA. Mol Cell Biol 15:6454–6464

    PubMed  CAS  Google Scholar 

  • Lieb JD, Liu X, Botstein D, Brown PO (2001) Promoter-specific binding of Rap1 revealed by genome-wide maps of protein-DNA association. Nat Genet 28:327–334

    Article  PubMed  CAS  Google Scholar 

  • Lodi T, Donnini C, Ferrero I (1991) Catabolite repression by galactose in overexpressed GAL4 strains of Saccharomyces cerevisiae. J Gen Microbiol 137:1039–1044

    PubMed  CAS  Google Scholar 

  • Lopez MC, Baker HV (2000) Understanding the growth phenotype of the yeast gcr1 mutant in terms of global genomic expression patterns. J Bacteriol 182:4970–4978

    Article  PubMed  CAS  Google Scholar 

  • Lu J, Kobayashi R, Brill SJ (1996) Characterization of a high mobility group 1/2 homolog in yeast. J Biol Chem 271:33678–33685

    Article  PubMed  CAS  Google Scholar 

  • MacIsaac KD, Wang T, Gordon DB, Gifford DK, Stormo GD, Fraenkel E (2006) An improved map of conserved regulatory sites for Saccharomyces cerevisiae. BMC Bioinformatics 7:113

    Article  PubMed  CAS  Google Scholar 

  • Mager WH, Planta RJ (1991) Coordinate expression of ribosomal protein genes in yeast as a function of cellular growth rate. Mol Cell Biochem 104:181–187

    Article  PubMed  CAS  Google Scholar 

  • Measday V, Moore L, Ogas J, Tyers M, Andrews B (1994) The PCL2 (ORFD)-PHO85 cyclin-dependent kinase complex: a cell cycle regulator in yeast. Science 266:1391–1395

    Article  PubMed  CAS  Google Scholar 

  • Menon BB, Sarma NJ, Pasula S, Deminoff SJ, Willis KA, Barbara KE, Andrews B, Santangelo GM (2005) Reverse recruitment: the Nup84 nuclear pore subcomplex mediates Rap1/Gcr1/Gcr2 transcriptional activation. Proc Natl Acad Sci USA 102:5749–5754

    Article  PubMed  CAS  Google Scholar 

  • Mizuta K, Warner JR (1994) Continued functioning of the secretory pathway is essential for ribosome synthesis. Mol Cell Biol 14:2493–2502

    PubMed  CAS  Google Scholar 

  • Nash R, Tokiwa G, Anand S, Erickson K, Futcher AB (1988) The WHI1+ gene of Saccharomyces cerevisiae tethers cell division to cell size and is a cyclin homolog. EMBO J 7:4335–4346

    PubMed  CAS  Google Scholar 

  • Parviz F, Heideman W (1998) Growth-independent regulation of CLN3 mRNA levels by nutrients in Saccharomyces cerevisiae. J Bacteriol 180:225–230

    PubMed  CAS  Google Scholar 

  • Polakis ES, Bartley W (1965) Changes in the enzyme activities of Saccharomyces cerevisiae during aerobic growth on different carbon sources. Biochem J 97:284–297

    PubMed  CAS  Google Scholar 

  • Polakis ES, Bartley W (1966) Changes in the intracellular concentrations of adenosine phosphates and nicotinamide nucleotides during the aerobic growth cycle of yeast on different carbon sources. Biochem J 99:521–533

    PubMed  CAS  Google Scholar 

  • Popolo L, Vanoni M, Alberghina L (1982) Control of the yeast cell cycle by protein synthesis. Exp Cell Res 142:69–78

    Article  PubMed  CAS  Google Scholar 

  • Prescott EM, Osheim YN, Jones HS, Alen CM, Roan JG, Reeder RH, Beyer AL, Proudfoot NJ (2004) Transcriptional termination by RNA polymerase I requires the small subunit Rpa12p. Proc Natl Acad Sci USA 101:6068–6073

    Article  PubMed  CAS  Google Scholar 

  • Presutti C, Ciafre SA, Bozzoni I (1991) The ribosomal protein L2 in S. cerevisiae controls the level of accumulation of its own mRNA. EMBO J 10:2215–2221

    PubMed  CAS  Google Scholar 

  • Robinson MD, Grigull J, Mohammad N, Hughes TR (2002) FunSpec: a web-based cluster interpreter for yeast. BMC Bioinformatics 3:35

    Article  PubMed  Google Scholar 

  • Samanta MP, Tongprasit W, Sethi H, Chin CS, Stolc V (2006) Global identification of noncoding RNAs in Saccharomyces cerevisiae by modulating an essential RNA processing pathway. Proc Natl Acad Sci USA 103:4192–4197

    Article  PubMed  CAS  Google Scholar 

  • Santangelo GM (2006) Glucose signaling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 70:253–282

    Article  PubMed  CAS  Google Scholar 

  • Santangelo GM, Tornow J (1990) Efficient transcription of the glycolytic gene ADH1 and three translational component genes requires the GCR1 product, which can act through TUF/GRF/RAP binding sites. Mol Cell Biol 10:859–862

    PubMed  CAS  Google Scholar 

  • Sasaki H, Uemura H (2005) Influence of low glycolytic activities in gcr1 and gcr2 mutants on the expression of other metabolic pathway genes in Saccharomyces cerevisiae. Yeast 22:111–127

    Article  PubMed  CAS  Google Scholar 

  • Sherman F (2002) Getting started with yeast. Methods Enzymol 350:3–41

    Article  PubMed  CAS  Google Scholar 

  • Slonim DK (2002) From patterns to pathways: gene expression data analysis comes of age. Nat Genet 21:5–9

    Google Scholar 

  • Southern E, Mir K, Shchepinov M (1999) Molecular interactions on microarrays. Nat Genet 21:5–9

    Article  PubMed  CAS  Google Scholar 

  • Stoppani AO (1951) Pyruvate metabolism in Saccharomyces cerevisiae. Nature 167:653–654

    Article  PubMed  CAS  Google Scholar 

  • Tokiwa G, Tyers M, Volpe T, Futcher B (1994) Inhibition of G1 cyclin activity by the Ras/cAMP pathway in yeast. Nature 371:342–345

    Article  PubMed  CAS  Google Scholar 

  • Tornow J, Zeng X, Gao W, Santangelo GM (1993) GCR1, a transcriptional activator in Saccharomyces cerevisiae, complexes with RAP1 and can function without its DNA binding domain. EMBO J 12:2431–2437

    PubMed  CAS  Google Scholar 

  • Tsuno A, Miyoshi K, Tsujii R, Miyakawa T, Mizuta K (2000) RRS1, a conserved essential gene, encodes a novel regulatory protein required for ribosome biogenesis in Saccharomyces cerevisiae. Mol Cell Biol 20:2066–2074

    Article  PubMed  CAS  Google Scholar 

  • Turkel S, Turgut T, Lopez MC, Uemura H, Baker HV (2003) Mutations in GCR1 affect SUC2 gene expression in Saccharomyces cerevisiae. Mol Genet Genomics 268:825–831

    PubMed  CAS  Google Scholar 

  • Wang Y, Pierce M, Schneper L, Guldal CG, Zhang X, Tavazoie S, Broach JR (2004) Ras and Gpa2 mediate one branch of a redundant glucose signaling pathway in yeast. PLoS Biol 2:610–622

    CAS  Google Scholar 

  • Warner JR (1999) The economics of ribosome biosynthesis in yeast. Trends Biochem Sci 24:437–440

    Article  PubMed  CAS  Google Scholar 

  • Wegierski T, Billy E, Nasr F, Filipowicz W (2001) Bms1p, a G-domain-containing protein, associates with Rcl1p and is required for 18S rRNA biogenesis in yeast. RNA 7:1254–1267

    Article  PubMed  CAS  Google Scholar 

  • Willis KA, Barbara KE, Menon BB, Moffat J, Andrews B, Santangelo GM (2003) The global transcriptional activator of Saccharomyces cerevisiae, Gcr1p, mediates the response to glucose by stimulating protein synthesis and CLN-dependent cell cycle progression. Genetics 165:1017–1029

    PubMed  CAS  Google Scholar 

  • Wu K, Wu P, Aris JP (2001) Nucleolar protein Nop12p participates in synthesis of 25S rRNA in Saccharomyces cerevisiae. Nucleic Acids Res 29:2938–2949

    Article  PubMed  CAS  Google Scholar 

  • Wu LF, Hughes TR, Davierwala AP, Robinson MD, Stoughton R, Altschuler SJ (2002) Large-scale prediction of Saccharomyces cerevisiae gene function using overlapping transcriptional clusters. Nat Genet 31:255–265

    Article  PubMed  CAS  Google Scholar 

  • Xu Z, Norris D (1998) The SFP1 gene product of Saccharomyces cerevisiae regulates G2/M transitions during the mitotic cell cycle and DNA-damage response. Genetics 150:1419–1428

    PubMed  CAS  Google Scholar 

  • Zeng X, Deminoff SJ, Santangelo GM (1997) Specialized Rap1p/Gcr1p Transcriptional Activation Through Gcr1p DNA Contacts Requires Gcr2p, as Does Hyperphosphorylation of Gcr1p. Genetics 147:493–505

    PubMed  CAS  Google Scholar 

  • Zhu J, Zhang MQ (1999) SCPD: a promoter database of the yeast Saccharomyces cerevisiae. Bioinformatics 15:607–611

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Kristina Clarke, Nicole Thompson and Baobin Kang for outstanding technical support and other members of the Santangelo lab and USM yeast group for helpful suggestions and comments. This work was supported by a National Institutes of Health Grant RR16476 to G.M.S.

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Correspondence to George M. Santangelo.

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Communicated by S. Hohmann.

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Barbara, K.E., Haley, T.M., Willis, K.A. et al. The transcription factor Gcr1 stimulates cell growth by participating in nutrient-responsive gene expression on a global level. Mol Genet Genomics 277, 171–188 (2007). https://doi.org/10.1007/s00438-006-0182-0

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