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Gene Review

GCN4  -  Gcn4p

Saccharomyces cerevisiae S288c

Synonyms: AAS101, AAS3, ARG9, Amino acid biosynthesis regulatory protein, General control protein GCN4, ...
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Disease relevance of GCN4

  • Using purified GCN4 protein obtained from an overproducing strain of Escherichia coli, we were able to obtain complete protection of all of the repeat elements in these four genes at high GCN4 concentrations [1].
  • We have constructed artificial AP-1 proteins containing elements derived from yeast GCN4 and from the herpes simplex virus activator VP16 [2].
  • DNA-mediated assembly of weakly interacting DNA-binding protein subunits: in vitro recruitment of phage 434 repressor and yeast GCN4 DNA-binding domains [3].
  • The jun oncoprotein, which causes sarcomas in chickens, and the DNA-binding domain of yeast GCN4, which coordinately regulates the expression of amino acid biosynthetic genes, show significant homology [4].
  • The segment of CPC1 similar to the DNA-binding domain of GCN4 also is similar to the DNA-binding domains of the avian sarcoma virus oncogene-encoded v-JUN protein and human c-JUN protein [5].

High impact information on GCN4

  • Like mammalian cells in which activated Ras leads to increased c-Jun synthesis and phosphorylation, the effects in yeast involve increased translation of GCN4 mRNA and a posttranslational event [6].
  • However, this effect on GCN4 translation is different from the response to amino acid or purine starvation [6].
  • Transcriptional activation of HIS3 and HIS4 by Gcn4 is triggered by UV irradiation in a Ras-dependent fashion [6].
  • We show that the yeast S. cerevisiae has a remarkably similar UV response involving the AP-1 factor Gcn4, which is distinct from the DNA damage response [6].
  • The acidic activation domains of the GCN4 and GAL4 proteins are not alpha helical but form beta sheets [7].

Chemical compound and disease context of GCN4

  • In order to understand their specificity, a vector was constructed which permits overexpression in Escherichia coli of those domains of GCN4 that are necessary and sufficient for specific DNA binding i.e. the basic region and the leucine zipper [8].
  • These included such peptides as the d-amino acid- and arginine-substituted Tat-(48-60), the RNA-binding peptides derived from virus proteins, such as HIV-1 Rev, and flock house virus coat proteins, and the DNA binding segments of leucine zipper proteins, such as cancer-related proteins c-Fos and c-Jun, and the yeast transcription factor GCN4 [9].
  • This domain consists of a central cluster rich in serine, threonine and proline (STP cluster) flanked by two negatively charged regions containing bulky hydrophobic residues similar to acidic activation domains of Vp1, the herpes simplex virus virion protein VP16 and transcription factors GCN4 and HAP4 from yeast [10].

Biological context of GCN4


Anatomical context of GCN4

  • Translational derepression of GCN4 was not triggered by misfolding in the endoplasmic reticulum, as expression of the wild type or temperature-sensitive folding mutants of the Na,K-ATPase increased GCN4 translation to the same extent [15].
  • Gcn2p induction of GCN4 translation during carbohydrate limitation enhances storage of amino acids in the vacuoles and facilitates entry into exponential growth during a shift from low-glucose to high-glucose medium [16].
  • Translational activation of GCN4 mRNA in a cell-free system is triggered by uncharged tRNAs [17].
  • Eukaryotic cells respond to starvation by decreasing the rate of general protein synthesis while inducing translation of specific mRNAs encoding transcription factors GCN4 (yeast) or ATF4 (humans) [18].

Associations of GCN4 with chemical compounds

  • A protein complex of translational regulators of GCN4 mRNA is the guanine nucleotide-exchange factor for translation initiation factor 2 in yeast [19].
  • The increase in beta-galactosidase activity induced by PALO was reversed by the addition of arginine and was dependent on GCN4 protein [20].
  • Yeast strains bearing a mutation in any one of the genes GCN1 to GCN4 are defective in derepression of amino acid biosynthetic genes in 10 different pathways under conditions of histidine limitation [21].
  • The ARO3 gene of Saccharomyces cerevisiae codes for the phenylalanine-inhibited 3-deoxy-D-arabinoheptulosonate-7-phosphate synthase (EC and is regulated by the general control system of amino acid biosynthesis through a single GCN4-binding site in its promoter [22].
  • Transcription factor GCN4 for control of amino acid biosynthesis also regulates the expression of the gene for lipoamide dehydrogenase [23].

Physical interactions of GCN4

  • The complete functional ARO3 promoter comprises 231 base pairs and contains only one TGACTA binding site for the general control activator protein GCN4 [24].
  • Induction of GCN4 translation in amino acid-starved cells involves the inhibition of initiator tRNA(Met) binding to eukaryotic translation initiation factor 2 (eIF2) in response to eIF2 phosphorylation by protein kinase GCN2 [25].
  • For example, the histone acetyltransferase GCN5 is part of a yeast multiprotein complex that is recruited by the DNA-binding activator protein GCN4 (refs 1-3) [26].
  • GCN3 mRNA contains no leader AUG codons, and no potential GCN4 binding sites were found in GCN3 5' noncoding DNA [27].
  • GCN4 protein binds specifically to the 20 bp region of the HIS3 gene that is critical for transcriptional regulation in vivo and contains the TGACTC sequence common to coregulated genes [28].

Regulatory relationships of GCN4

  • In Saccharomyces cerevisiae, phosphorylation of the alpha subunit of translation initiation factor 2 (eIF-2) by protein kinase GCN2 stimulates translation of GCN4 mRNA [19].
  • Both the GCN2 and GCN3 products appear to stimulate translation of GCN4 mRNA in response to amino acid starvation, because a recessive mutation in either gene blocked derepression of GCN4-lacZ fusion enzyme levels but did not reduce the fusion transcript level relative to that in wild-type cells grown in the same conditions [29].
  • The amount of GCN4 protein present in repressed wild-type cells therefore seems to contribute to a basal level of ARO3 gene expression [24].
  • The GCD1 product appears to inhibit translation of GCN4 mRNA because under certain growth conditions, the gcd1-101 mutation led to derepression of the GCN4-lacZ fusion enzyme level in the absence of any increase in the fusion transcript level [29].
  • We have isolated and characterized the GCD6 and GCD7 genes and shown that their products are required to repress GCN4 translation under nonstarvation conditions [30].

Other interactions of GCN4

  • We show that the gcd11 mutations specifically alter regulation of GCN4 expression at the translational level, without altering the scanning mechanism for protein synthesis initiation [31].
  • We describe here 17 dominant GCN2 mutations that lead to derepression of GCN4 expression in the absence of amino acid starvation [14].
  • However, strains containing gcn4 mutations are unable to grow in medium containing aminotriazole because they lack the GCN4 transcriptional activator protein necessary for the coordinate induction of HIS3 and other amino acid biosynthetic genes [32].
  • The general control activator protein GCN4 is essential for a basal level of ARO3 gene expression in Saccharomyces cerevisiae [24].
  • In strains overproducing GCN4 protein, the translational control completely overrode transcriptional activation of CPA1 by general amino acid control [20].

Analytical, diagnostic and therapeutic context of GCN4


  1. GCN4 protein, a positive transcription factor in yeast, binds general control promoters at all 5' TGACTC 3' sequences. Arndt, K., Fink, G.R. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  2. Artificial oncoproteins: modified versions of the yeast bZip protein GCN4 induce cellular transformation. Nishizawa, M., Fu, S.L., Kataoka, K., Vogt, P.K. Oncogene (2003) [Pubmed]
  3. DNA-mediated assembly of weakly interacting DNA-binding protein subunits: in vitro recruitment of phage 434 repressor and yeast GCN4 DNA-binding domains. Guarnaccia, C., Raman, B., Zahariev, S., Simoncsits, A., Pongor, S. Nucleic Acids Res. (2004) [Pubmed]
  4. The DNA-binding domains of the jun oncoprotein and the yeast GCN4 transcriptional activator protein are functionally homologous. Struhl, K. Cell (1987) [Pubmed]
  5. 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. Paluh, J.L., Orbach, M.J., Legerton, T.L., Yanofsky, C. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  6. The UV response involving the Ras signaling pathway and AP-1 transcription factors is conserved between yeast and mammals. Engelberg, D., Klein, C., Martinetto, H., Struhl, K., Karin, M. Cell (1994) [Pubmed]
  7. The acidic activation domains of the GCN4 and GAL4 proteins are not alpha helical but form beta sheets. Van Hoy, M., Leuther, K.K., Kodadek, T., Johnston, S.A. Cell (1993) [Pubmed]
  8. Identification of three residues in the basic regions of the bZIP proteins GCN4, C/EBP and TAF-1 that are involved in specific DNA binding. Suckow, M., von Wilcken-Bergmann, B., Müller-Hill, B. EMBO J. (1993) [Pubmed]
  9. Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. Futaki, S., Suzuki, T., Ohashi, W., Yagami, T., Tanaka, S., Ueda, K., Sugiura, Y. J. Biol. Chem. (2001) [Pubmed]
  10. PvAlf, an embryo-specific acidic transcriptional activator enhances gene expression from phaseolin and phytohemagglutinin promoters. Bobb, A.J., Eiben, H.G., Bustos, M.M. Plant J. (1995) [Pubmed]
  11. Multiple global regulators control HIS4 transcription in yeast. Arndt, K.T., Styles, C., Fink, G.R. Science (1987) [Pubmed]
  12. Mutations in the structural genes for eukaryotic initiation factors 2 alpha and 2 beta of Saccharomyces cerevisiae disrupt translational control of GCN4 mRNA. Williams, N.P., Hinnebusch, A.G., Donahue, T.F. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  13. Translation of the yeast transcriptional activator GCN4 is stimulated by purine limitation: implications for activation of the protein kinase GCN2. Rolfes, R.J., Hinnebusch, A.G. Mol. Cell. Biol. (1993) [Pubmed]
  14. Mutations activating the yeast eIF-2 alpha kinase GCN2: isolation of alleles altering the domain related to histidyl-tRNA synthetases. Ramirez, M., Wek, R.C., Vazquez de Aldana, C.R., Jackson, B.M., Freeman, B., Hinnebusch, A.G. Mol. Cell. Biol. (1992) [Pubmed]
  15. Heterologous expression of membrane and soluble proteins derepresses GCN4 mRNA translation in the yeast Saccharomyces cerevisiae. Steffensen, L., Pedersen, P.A. Eukaryotic Cell (2006) [Pubmed]
  16. Glucose limitation induces GCN4 translation by activation of Gcn2 protein kinase. Yang, R., Wek, S.A., Wek, R.C. Mol. Cell. Biol. (2000) [Pubmed]
  17. Translational activation of GCN4 mRNA in a cell-free system is triggered by uncharged tRNAs. Krupitza, G., Thireos, G. Mol. Cell. Biol. (1990) [Pubmed]
  18. Study of translational control of eukaryotic gene expression using yeast. Hinnebusch, A.G., Asano, K., Olsen, D.S., Phan, L., Nielsen, K.H., Valásek, L. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  19. A protein complex of translational regulators of GCN4 mRNA is the guanine nucleotide-exchange factor for translation initiation factor 2 in yeast. Cigan, A.M., Bushman, J.L., Boal, T.R., Hinnebusch, A.G. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  20. Arginine restriction induced by delta-N-(phosphonacetyl)-L-ornithine signals increased expression of HIS3, TRP5, CPA1, and CPA2 in Saccharomyces cerevisiae. Kinney, D.M., Lusty, C.J. Mol. Cell. Biol. (1989) [Pubmed]
  21. Association of RAP1 binding sites with stringent control of ribosomal protein gene transcription in Saccharomyces cerevisiae. Moehle, C.M., Hinnebusch, A.G. Mol. Cell. Biol. (1991) [Pubmed]
  22. Activation and repression of the yeast ARO3 gene by global transcription factors. Künzler, M., Springer, C., Braus, G.H. Mol. Microbiol. (1995) [Pubmed]
  23. Transcription factor GCN4 for control of amino acid biosynthesis also regulates the expression of the gene for lipoamide dehydrogenase. Zaman, Z., Bowman, S.B., Kornfeld, G.D., Brown, A.J., Dawes, I.W. Biochem. J. (1999) [Pubmed]
  24. The general control activator protein GCN4 is essential for a basal level of ARO3 gene expression in Saccharomyces cerevisiae. Paravicini, G., Mösch, H.U., Schmidheini, T., Braus, G. Mol. Cell. Biol. (1989) [Pubmed]
  25. Defects in tRNA processing and nuclear export induce GCN4 translation independently of phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Qiu, H., Hu, C., Anderson, J., Björk, G.R., Sarkar, S., Hopper, A.K., Hinnebusch, A.G. Mol. Cell. Biol. (2000) [Pubmed]
  26. Global histone acetylation and deacetylation in yeast. Vogelauer, M., Wu, J., Suka, N., Grunstein, M. Nature (2000) [Pubmed]
  27. Molecular analysis of GCN3, a translational activator of GCN4: evidence for posttranslational control of GCN3 regulatory function. Hannig, E.M., Hinnebusch, A.G. Mol. Cell. Biol. (1988) [Pubmed]
  28. GCN4 protein, synthesized in vitro, binds HIS3 regulatory sequences: implications for general control of amino acid biosynthetic genes in yeast. Hope, I.A., Struhl, K. Cell (1985) [Pubmed]
  29. A hierarchy of trans-acting factors modulates translation of an activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. Hinnebusch, A.G. Mol. Cell. Biol. (1985) [Pubmed]
  30. Evidence that GCD6 and GCD7, translational regulators of GCN4, are subunits of the guanine nucleotide exchange factor for eIF-2 in Saccharomyces cerevisiae. Bushman, J.L., Asuru, A.I., Matts, R.L., Hinnebusch, A.G. Mol. Cell. Biol. (1993) [Pubmed]
  31. Mutations in GCD11, the structural gene for eIF-2 gamma in yeast, alter translational regulation of GCN4 and the selection of the start site for protein synthesis. Dorris, D.R., Erickson, F.L., Hannig, E.M. EMBO J. (1995) [Pubmed]
  32. ATR1, a Saccharomyces cerevisiae gene encoding a transmembrane protein required for aminotriazole resistance. Kanazawa, S., Driscoll, M., Struhl, K. Mol. Cell. Biol. (1988) [Pubmed]
  33. Negative regulatory gene for general control of amino acid biosynthesis in Saccharomyces cerevisiae. Myers, P.L., Skvirsky, R.C., Greenberg, M.L., Greer, H. Mol. Cell. Biol. (1986) [Pubmed]
  34. Transcriptional regulation of the one-carbon metabolism regulon in Saccharomyces cerevisiae by Bas1p. Subramanian, M., Qiao, W.B., Khanam, N., Wilkins, O., Der, S.D., Lalich, J.D., Bognar, A.L. Mol. Microbiol. (2005) [Pubmed]
  35. Functional dissection of a eukaryotic transcriptional activator protein, GCN4 of yeast. Hope, I.A., Struhl, K. Cell (1986) [Pubmed]
  36. Folding transition in the DNA-binding domain of GCN4 on specific binding to DNA. Weiss, M.A., Ellenberger, T., Wobbe, C.R., Lee, J.P., Harrison, S.C., Struhl, K. Nature (1990) [Pubmed]
  37. A flexible domain is essential for the large step size and processivity of myosin VI. Rock, R.S., Ramamurthy, B., Dunn, A.R., Beccafico, S., Rami, B.R., Morris, C., Spink, B.J., Franzini-Armstrong, C., Spudich, J.A., Sweeney, H.L. Mol. Cell (2005) [Pubmed]
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