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Controlling transcription by destruction: the regulation of yeast Gcn4p stability

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Abstract

The Gcn4 protein, a member of the AP-1 family of transcription factors, is involved in the expression of more than 500 genes in the budding yeast Saccharomyces cerevisiae. A key role of Gcn4p is the increased expression of many amino acid biosynthesis genes in response to amino acid starvation. The accumulation of this transcription activator is mainly induced by efficient translation of the GCN4 ORF and by stabilisation of the Gcn4 protein. Under normal growth conditions, Gcn4p is a highly unstable protein, thereby resembling many eukaryotic transcription factors, including mammalian Jun and Myc proteins. Gcn4p is degraded by ubiquitin-dependent proteolysis mediated by the Skp1/cullin/F-box (SCF) ubiquitin ligase, which recognises specifically phosphorylated substrates. Two cyclin-dependent protein kinases, Pho85p and Srb10p, have crucial functions in regulating Gcn4p phosphorylation and degradation. The past few years have revealed many novel insights into these regulatory processes. Here, we summarise current knowledge about the factors and mechanisms regulating Gcn4p stability.

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References

  • Alarcon-Vargas D, Tansey WP, Ronai Z (2002) Regulation of c-myc stability by selective stress conditions and by MEKK1 requires aa 127–189 of c-myc. Oncogene 21:4384–4391

    Article  CAS  PubMed  Google Scholar 

  • Albrecht G, Mösch HU, Hoffmann B, Reusser U, Braus GH (1998) Monitoring the Gcn4 protein-mediated response in the yeast Saccharomyces cerevisiae. J Biol Chem 273:12696–12702

    Article  CAS  PubMed  Google Scholar 

  • Bai C, et al (1996) SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86:263–274

    CAS  PubMed  Google Scholar 

  • Bell SP, Dutta A (2002) DNA replication in eukaryotic cells. Annu Rev Biochem 71:333–374

    Article  CAS  PubMed  Google Scholar 

  • Blondel M, et al (2000) Nuclear-specific degradation of Far1 is controlled by the localization of the F-box protein Cdc4. EMBO J 19:6085–6097

    Article  CAS  PubMed  Google Scholar 

  • Braus GH (1991) Aromatic amino acid biosynthesis in the yeast Saccharomyces cerevisiae: a model system for the regulation of a eukaryotic biosynthetic pathway. Microbiol Rev 55:349–370

    Google Scholar 

  • Carroll AS, O′Shea EK (2002) Pho85 and signaling environmental conditions. Trends Biochem Sci 27:87–93

    Article  CAS  PubMed  Google Scholar 

  • Cherkasova VA, Hinnebusch AG (2003) Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. Genes Dev 17:859–872

    Article  CAS  PubMed  Google Scholar 

  • Chi Y, et al (2001) Negative regulation of Gcn4 and Msn2 transcription factors by Srb10 cyclin-dependent kinase. Genes Dev 15:1078–1092

    Article  CAS  PubMed  Google Scholar 

  • Ciechanover A, Orian A, Schwartz AL (2000) Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays 22:442–451

    Article  CAS  PubMed  Google Scholar 

  • Conaway RC, Brower CS, Conaway JW (2002) Emerging roles of ubiquitin in transcription regulation. Science 296:1254–1258

    Article  CAS  PubMed  Google Scholar 

  • Craig KL, Tyers M (1999) The F-box: a new motif for ubiquitin dependent proteolysis in cell cycle regulation and signal transduction. Prog Biophys Mol Biol 72:299–328

    Article  CAS  PubMed  Google Scholar 

  • Deshaies RJ (1997) Phosphorylation and proteolysis: partners in the regulation of cell division in budding yeast. Curr Opin Genet Dev 7:7–16

    Article  CAS  PubMed  Google Scholar 

  • Deshaies RJ (1999) SCF and cullin/RING H2-based ubiquitin ligases. Annu Rev Cell Dev Biol 15:435–467

    PubMed  Google Scholar 

  • Deshaies RJ, Chau V, Kirschner M (1995) Ubiquitination of the G1 cyclin Cln2p by a Cdc34p-dependent pathway. EMBO J 14:303–312

    CAS  PubMed  Google Scholar 

  • Drury LS, Perkins G, Diffley JF (1997) The Cdc4/34/53 pathway targets Cdc6p for proteolysis in budding yeast. EMBO J 16:5966–5976

    Article  CAS  PubMed  Google Scholar 

  • Drysdale CM, et al (1998) The Gcn4p activation domain interacts specifically in vitro with RNA polymerase II holoenzyme, TFIID, and the Adap–Gcn5p coactivator complex. Mol Cell Biol 18:1711–1724

    CAS  PubMed  Google Scholar 

  • Ebbole DJ, Paluh JL, Plamann M, Sachs MS, Yanofsky C (1991) cpc-1, the general regulatory gene for genes of amino acid biosynthesis in Neurospora crassa, is differentially expressed during the asexual life cycle. Mol Cell Biol 11:928–934

    CAS  PubMed  Google Scholar 

  • Engelberg D, Klein C, Martinetto H, Struhl K, Karin M (1994) The UV response involving the Ras signaling pathway and AP-1 transcription factors is conserved between yeast and mammals. Cell 77:381–390

    CAS  PubMed  Google Scholar 

  • Feldman RM, Correll CC, Kaplan KB, Deshaies RJ (1997) A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 91:221–230

    CAS  PubMed  Google Scholar 

  • Floyd ZE, Trausch-Azar JS, Reinstein E, Ciechanover A, Schwartz AL (2001) The nuclear ubiquitin-proteasome system degrades MyoD. J Biol Chem 276:22468–22475

    Article  CAS  PubMed  Google Scholar 

  • Freedman DA, Levine AJ (1998) Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol Cell Biol 18:7288–7293

    CAS  PubMed  Google Scholar 

  • Galan JM, Peter M (1999) Ubiquitin-dependent degradation of multiple F-box proteins by an autocatalytic mechanism. Proc Natl Acad Sci USA 96:9124–9129

    CAS  PubMed  Google Scholar 

  • Gonzalez F, Delahodde A, Kodadek T, Johnston SA (2002) Recruitment of a 19S proteasome subcomplex to an activated promoter. Science 296:548–550

    Article  CAS  PubMed  Google Scholar 

  • Goossens A, Dever TE, Pascual-Ahuir A, Serrano R (2001) The protein kinase Gcn2p mediates sodium toxicity in yeast. J Biol Chem 276:30753–30760

    Article  CAS  PubMed  Google Scholar 

  • Harding HP, et al (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108

    PubMed  Google Scholar 

  • Harding HP, et al (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633

    CAS  PubMed  Google Scholar 

  • Harper JW, Burton JL, Solomon MJ (2002) The anaphase-promoting complex: it′s not just for mitosis any more. Genes Dev 16:2179–2206

    Article  CAS  PubMed  Google Scholar 

  • Henchoz S, Chi Y, Catarin B, Herskowitz I, Deshaies RJ, Peter M (1997) Phosphorylation- and ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor Far1p in budding yeast. Genes Dev 11:3046–3060

    CAS  PubMed  Google Scholar 

  • Hengartner CJ, et al (1995) Association of an activator with an RNA polymerase II holoenzyme. Genes Dev 9:897–910

    CAS  PubMed  Google Scholar 

  • Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479

    CAS  PubMed  Google Scholar 

  • Hinnebusch AG (1984) Evidence for translational regulation of the activator of general amino acid control in yeast. Proc Natl Acad Sci USA 81:6442–6446

    CAS  PubMed  Google Scholar 

  • Hinnebusch AG (1990) Transcriptional and translational regulation of gene expression in the general control of amino-acid biosynthesis in Saccharomyces cerevisiae. Prog Nucleic Acid Res Mol Biol 38:195–240

    CAS  PubMed  Google Scholar 

  • Hinnebusch AG (1997) Translational regulation of yeast GCN4. A window on factors that control initiator-tRNA binding to the ribosome. J Biol Chem 272:21661–21664

    Article  CAS  PubMed  Google Scholar 

  • Hinnebusch AG, Natarajan K (2002) Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryot Cell 1:22–32

    Article  CAS  PubMed  Google Scholar 

  • Hoffmann B, Valerius O, Andermann M, Braus GH (2001) Transcriptional autoregulation and inhibition of mRNA translation of amino acid regulator gene cpcA of filamentous fungus Aspergillus nidulans. Mol Biol Cell 12:2846–2857

    CAS  PubMed  Google Scholar 

  • Hsiung YG, Chang HC, Pellequer JL, La Valle R, Lanker S, Wittenberg C (2001) F-box protein Grr1 interacts with phosphorylated targets via the cationic surface of its leucine-rich repeat. Mol Cell Biol 21:2506–2520

    Article  CAS  PubMed  Google Scholar 

  • Jackson PK, Eldridge AG (2002) The SCF ubiquitin ligase: an extended look. Mol Cell 9:923–925

    CAS  PubMed  Google Scholar 

  • Jackson PK, et al (2000) The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol 10:429–439

    CAS  PubMed  Google Scholar 

  • Jaquenoud M, Gulli MP, Peter K, Peter M (1998) The Cdc42p effector Gic2p is targeted for ubiquitin-dependent degradation by the SCF–Grr1 complex. EMBO J 17:5360–5373

    Article  CAS  PubMed  Google Scholar 

  • Jia MH, et al (2000) Global expression profiling of yeast treated with an inhibitor of amino acid biosynthesis, sulfometuron methyl. Physiol Genomics 3:83–92

    CAS  PubMed  Google Scholar 

  • Kaffman A, Rank NM, O′Shea EK (1998) Phosphorylation regulates association of the transcription factor Pho4 with its import receptor Pse1/Kap121. Genes Dev 12:2673–2683

    CAS  PubMed  Google Scholar 

  • Kornitzer D, Ciechanover A (2000) Modes of regulation of ubiquitin-mediated protein degradation. J Cell Physiol 182:1–11

    CAS  PubMed  Google Scholar 

  • Kornitzer D, Raboy B, Kulka RG, Fink GR (1994) Regulated degradation of the transcription factor Gcn4. EMBO J 13:6021–6030

    CAS  PubMed  Google Scholar 

  • Lassot I, et al (2001) ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Mol Cell Biol 21:2192–2202

    Article  CAS  PubMed  Google Scholar 

  • Li FN, Johnston M (1997) Grr1 of Saccharomyces cerevisiae is connected to the ubiquitin proteolysis machinery through Skp1: coupling glucose sensing to gene expression and the cell cycle. EMBO J 16:5629–5638

    PubMed  Google Scholar 

  • Lo RS, Massague J (1999) Ubiquitin-dependent degradation of TGF-beta-activated smad2. Nat Cell Biol 1:472–478

    Google Scholar 

  • Marbach I, Licht R, Frohnmeyer H, Engelberg D (2001) Gcn2 mediates Gcn4 activation in response to glucose stimulation or UV radiation not via GCN4 translation. J Biol Chem 276:16944–16951

    Article  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Meimoun A, et al (2000) Degradation of the transcription factor Gcn4 requires the kinase Pho85 and the SCF(CDC4) ubiquitin-ligase complex. Mol Biol Cell 11:915–927

    CAS  PubMed  Google Scholar 

  • Moffat J, Huang D, Andrews B (2000) Functions of Pho85 cyclin-dependent kinases in budding yeast. Prog Cell Cycle Res 4:97–106

    CAS  PubMed  Google Scholar 

  • Molinari E, Gilman M, Natesan S (1999) Proteasome-mediated degradation of transcriptional activators correlates with activation domain potency in vivo. EMBO J 18:6439–6447

    Article  CAS  PubMed  Google Scholar 

  • Mueller PP, Hinnebusch AG (1986) Multiple upstream AUG codons mediate translational control of GCN4. Cell 45:201–207

    CAS  PubMed  Google Scholar 

  • Musti AM, Treier M, Bohmann D (1997) Reduced ubiquitin-dependent degradation of c-Jun after phosphorylation by MAP kinases. Science 275:400–402

    Article  CAS  PubMed  Google Scholar 

  • Natarajan K, et al (2001) Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast. Mol Cell Biol 21:4347–4368

    CAS  PubMed  Google Scholar 

  • Nishizawa M, Kawasumi M, Fujino M, Toh-e A (1998) Phosphorylation of sic1, a cyclin-dependent kinase (Cdk) inhibitor, by Cdk including Pho85 kinase is required for its prompt degradation. Mol Biol Cell 9:2393–2405

    CAS  PubMed  Google Scholar 

  • Ohta T, Michel JJ, Schottelius AJ, Xiong Y (1999) ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol Cell 3:535–541

    CAS  PubMed  Google Scholar 

  • Okazaki K, Sagata N (1995) The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells. EMBO J 14:5048–5059

    CAS  PubMed  Google Scholar 

  • Paluh JL, Orbach MJ, Legerton TL, Yanofsky C (1988) The cross-pathway control gene of Neurospora crassa, cpc-1, encodes a protein similar to GCN4 of yeast and the DNA-binding domain of the oncogene v-jun-encoded protein. Proc Natl Acad Sci USA 85:3728–3732

    CAS  PubMed  Google Scholar 

  • Patton EE, Peyraud C, Rouillon A, Surdin-Kerjan Y, Tyers M, Thomas D (2000) SCF(Met30)-mediated control of the transcriptional activator Met4 is required for the G(1)-S transition. EMBO J 19:1613–1624

    Article  CAS  PubMed  Google Scholar 

  • Peters JM (1998) SCF and APC: the Yin and Yang of cell cycle regulated proteolysis. Curr Opin Cell Biol 10:759–768.

    Google Scholar 

  • Peters JM (2002) The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol Cell 9:931–943

    CAS  PubMed  Google Scholar 

  • Peter M, Herskowitz I (1994) Direct inhibition of the yeast cyclin-dependent kinase Cdc28-Cln by Far1. Science 265:1228–1231

    CAS  PubMed  Google Scholar 

  • Pries R, Bömeke K, Irniger S, Grundmann O, Braus GH (2002) Amino acid-dependent Gcn4p stability regulation occurs exclusively in the yeast nucleus. Eukaryot Cell 1:663–672

    Article  CAS  PubMed  Google Scholar 

  • Salghetti SE, Kim SY, Tansey WP (1999) Destruction of Myc by ubiquitin-mediated proteolysis: cancer-associated and transforming mutations stabilize Myc. EMBO J 18:717–726

    Article  CAS  PubMed  Google Scholar 

  • Salghetti SE, Caudy AA, Chenoweth JG, Tansey WP (2001) Regulation of transcriptional activation domain function by ubiquitin. Science 293:1651–1653

    Article  CAS  PubMed  Google Scholar 

  • Schneider KR, Smith RL, O′Shea EK (1994) Phosphate-regulated inactivation of the kinase PHO80–PHO85 by the CDK inhibitor PHO81. Science 266:122–126

    CAS  PubMed  Google Scholar 

  • Schwob E, Bohm T, Mendenhall MD, Nasmyth K (1994) The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae. Cell 79:233–244

    CAS  PubMed  Google Scholar 

  • Seol JH, et al (1999) Cdc53/cullin and the essential Hrt1 RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34. Genes Dev 13:1614–1626

    CAS  PubMed  Google Scholar 

  • Shemer R, Meimoun A, Holtzman T, Kornitzer D (2002) Regulation of the transcription factor Gcn4 by Pho85 cyclin PCL5. Mol Cell Biol 22:5395–5404

    Article  CAS  PubMed  Google Scholar 

  • Shimada Y, Gulli MP, Peter M (2000) Nuclear sequestration of the exchange factor Cdc24 by Far1 regulates cell polarity during yeast mating. Nat Cell Biol 2:117–124

    Google Scholar 

  • Siu F, Bain PJ, LeBlanc-Chaffin R, Chen H, Kilberg MS (2002) ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. J Biol Chem 277:24120–24127

    Article  CAS  PubMed  Google Scholar 

  • Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW (1997) F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91:209–219

    CAS  PubMed  Google Scholar 

  • Skowyra D, et al (1999) Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1. Science 284:662–665

    Article  CAS  PubMed  Google Scholar 

  • Struhl K (1987) The DNA-binding domains of the jun oncoprotein and the yeast GCN4 transcriptional activator protein are functionally homologous. Cell 50:841–846

    CAS  PubMed  Google Scholar 

  • Tansey WP (2001) Transcriptional activation: risky business. Genes Dev 15:1045–1050

    Article  CAS  PubMed  Google Scholar 

  • Toh-e A, Nishizawa M (2001) Structure and function of cyclin-dependent Pho85 kinase of Saccharomyces cerevisiae. J Gen Appl Microbiol 47:107–117

    CAS  PubMed  Google Scholar 

  • Toh-e A, Tanaka K, Uesono Y, Wickner RB (1988) PHO85, a negative regulator of the PHO system, is a homolog of the protein kinase gene, CDC28, of Saccharomyces cerevisiae. Mol Gen Genet 214:162–164

    CAS  PubMed  Google Scholar 

  • Treier M, Staszewski LM, Bohmann D (1994) Ubiquitin-dependent c-Jun degradation in vivo is mediated by the delta domain. Cell 78:787–798

    CAS  PubMed  Google Scholar 

  • Tyers M, Jorgensen P (2000) Proteolysis and the cell cycle: with this RING I do thee destroy. Curr Opin Genet Dev 10:54–64

    Article  CAS  PubMed  Google Scholar 

  • Uesono Y, Tanaka K, Toh-e A (1987) Negative regulators of the PHO system in Saccharomyces cerevisiae: isolation and structural characterization of PHO85. Nucleic Acids Res 15:10299–10309

    CAS  PubMed  Google Scholar 

  • Utley RT, et al (1998) Transcriptional activators direct histone acetyltransferase complexes to nucleosomes. Nature 394:498–502

    CAS  PubMed  Google Scholar 

  • Valenzuela L, Aranda C, Gonzalez A (2001) TOR modulates GCN4-dependent expression of genes turned on by nitrogen limitation. J Bacteriol 183:2331–2334

    Article  CAS  PubMed  Google Scholar 

  • Vandel L, Kouzarides T (1999) Residues phosphorylated by TFIIH are required for E2F-1 degradation during S-phase. EMBO J 18:4280–4291

    Article  CAS  PubMed  Google Scholar 

  • Verma R, Feldman RM, Deshaies RJ (1997) SIC1 is ubiquitinated in vitro by a pathway that requires CDC4, CDC34, and cyclin/CDK activities. Mol Biol Cell 8:1427–1437

    CAS  PubMed  Google Scholar 

  • Wang P, Larson TG, Chen CH, Pawlyk DM, Clark JA, Nuss DL (1998) Cloning and characterization of a general amino acid control transcriptional activator from the chestnut blight fungus Cryphonectria parasitica. Fungal Genet Biol 23:81–94

    Article  CAS  PubMed  Google Scholar 

  • Wanke C et al. (1997) The Aspergillus niger GCN4 homologue, cpcA, is transcriptionally regulated and encodes an unusual leucine zipper. Mol Microbiol 23:23–33

    CAS  PubMed  Google Scholar 

  • Willems AR, Goh T, Taylor L, Chernushevich I, Shevchenko A, Tyers M (1999) SCF ubiquitin protein ligases and phosphorylation-dependent proteolysis. Philos Trans R Soc Lond B Biol Sci 354:1533–1550

    Article  CAS  PubMed  Google Scholar 

  • Yang R, Wek SA, Wek RC (2000) Glucose limitation induces GCN4 translation by activation of Gcn2 protein kinase. Mol Cell Biol 20:2706–2717

    Article  CAS  PubMed  Google Scholar 

  • Zachariae W, Nasmyth K (1999) Whose end is destruction: cell division and the anaphase-promoting complex. Genes Dev 13:2039–2058

    CAS  PubMed  Google Scholar 

  • Zheng N, et al (2002) Structure of the Cul1-Rbx1-Skp1-F box-Skp2 SCF ubiquitin ligase complex. Nature 416:703–709

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Ralph Pries and Katrin Bömeke for helpful discussions and comments on the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie and the Volkswagen-Stiftung.

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  1. Institute of Microbiology and Genetics, Georg-August-University, Grisebachstrasse 8, 37077, Göttingen, Germany

    Stefan Irniger & Gerhard H. Braus

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Correspondence to Gerhard H. Braus.

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Communicated by K. Esser and S. Hohmann

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Irniger, S., Braus, G.H. Controlling transcription by destruction: the regulation of yeast Gcn4p stability. Curr Genet 44, 8–18 (2003). https://doi.org/10.1007/s00294-003-0422-3

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