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Gene Review

CUP1-1  -  Cup1-1p

Saccharomyces cerevisiae S288c

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Disease relevance of CUP1-1

  • Expression vectors have been constructed in which the mouse mammary tumor virus gag-pro frameshift region is placed upstream of the lacZ gene or the CUP1 gene so that the reporters are in the -1 frame relative to the initiation codon [1].
  • We now report that nucleosome loss activates the expression of two additional promoters that are normally induced by independent mechanisms: CUP1 (induced by heavy-metal toxicity) and HIS3 (induced by amino acid starvation) [2].
  • Yeast (CUP1) and mammalian (HMT-1A) metallothioneins (MTs) have been efficiently expressed in Escherichia coli as fusions to the outer membrane protein LamB [3].
  • Strains with fewer copies of the CUP1 loci showed hypersensitivity to sulfomethuron methyl [4].

High impact information on CUP1-1

  • This activation is specific since other regulated genes (GAL10, PHO5, CUP1) are repressed and induced normally in these cells [5].
  • Most CUP1 transcripts made by DeltaCTD Pol II were degraded but could be stabilized by deletion of the XRN1 gene [6].
  • The upstream-activating sequence (UAS) of the CUP1 promoter was sufficient to drive Cu2+ inducible transcription without Srb4 and heat shock inducible transcription without the CTD [6].
  • Furthermore, protection against oxidative stress conferred by CUP1 in a (sod1)delta strain requires HSF-mediated CUP1 transcription [7].
  • We demonstrate that transcription of the Saccharomyces cerevisiae MT gene CUP1 is strongly activated by the superoxide anion generator menadione [7].

Chemical compound and disease context of CUP1-1

  • A large cassette, 4.6 x 10(3) bases (4.6 kb) in length, containing an inducible expression system (the yeast CUP1 promoter fused to the Escherichia coli lacZ structural gene) and a bacterial neomycin-resistance gene (neo) has been cloned into the noncoding region of a GAL1-regulated Ty1 retrotransposon [8].

Biological context of CUP1-1

  • Upon addition of CuSO4, mRNA levels of CTR3 were rapidly reduced to eightfold the original basal level whereas the Ace1p-mediated transcriptional activation of CUP1 was rapid and potent but transient [9].
  • Induction requires the ACE1 gene product, which binds to specific sites in the promoter region of the CUP1 gene [10].
  • In this study, we found that deleting the entire coding sequence of the ACE1 gene resulted in a decrease in basal-level transcription of CUP1 to low but detectable levels and conferred a copper-sensitive phenotype to the cells [10].
  • In vivo dimethyl sulfate footprinting analysis of the CUP1 promoter demonstrated transient occupation of the metal response elements by Ace1p which paralleled CUP1 mRNA expression [9].
  • The presence of multiple copies of the ACE2 gene enhanced expression of an unlinked CUP1-lacZ fusion integrated in the yeast genome and resulted in an increase in the steady-state levels of CUP1 mRNA in an ace1-deletion background [10].

Anatomical context of CUP1-1

  • Reversion of the cup1 growth phenotype by a pAPI-CUP1 chimera indicates that pAPI is transported to the vacuole by a post-translational mechanism [11].

Associations of CUP1-1 with chemical compounds

  • Instead, we found that the PDR13 null mutant could not express CUP1 or CRS5 metallothionein at wild-type levels when subjected to high Cu(2+) stress [12].
  • Although a carboxyl-terminal HSF transcriptional activation domain is critical for the activation of CUP1 transcription in response to both heat shock stress and glucose starvation, this region is dispensable for transient heat shock activation of at least two genes encoding members of the S. cerevisiae hsp70 family [13].
  • Cadmium-resistant Saccharomyces cerevisiae strain 301N exhibits high basal as well as cadmium-induced expression of the CUP1 metallothionein gene [14].
  • Overexpression of the GPD1 gene encoding glycerol-3-phosphate dehydrogenase, ENA1 encoding sodium ion efflux protein, and CUP1 encoding copper metallothionein conferred high salt stress tolerance to yeast cells, and our selection of candidate genes for the creation of stress-tolerant yeast strains based on the transcriptome data was validated [15].
  • We observed that the deficiency of Sod1 increases the expression of both Cup1 (a metallothionein) and Ycf1 (a vacuolar glutathione S-conjugate pump), proteins involved with protection against cadmium [16].

Physical interactions of CUP1-1

  • In studies with the bathocuproine Cu(I) chelator, the Cu(I) ions bound to Crs5 were kinetically more labile than the Cu(I) binding to Cup1 [17].
  • We show that removal of Gal11 from the yeast transcription complex can affect activation from the CUP1 UAS in a manner dependent on its genomic context [18].
  • A single binding site for ACE1 is present in the SOD1 promoter region, as demonstrated by DNase I protection and methylation interference experiments, and is highly homologous to a high-affinity ACE1 binding site in the CUP1 promoter [19].
  • Limited proteolysis assays show that HSF adopts a distinct protease-sensitive conformation when bound to the CUP1 HSE1, providing evidence that the HSE influences DNA-bound HSF conformation [20].

Regulatory relationships of CUP1-1

  • When copper ions are present in the sample, the Ace1 protein activates the cup1 promoter located upstream from the gfpuv gene in plasmid pYEX-GFPuv, thus inducing the production of GFPuv [21].
  • Histone H2A and Spt10 cooperate to regulate induction and autoregulation of the CUP1 metallothionein [22].
  • RESULTS: Fusions with Med2 or Pgd1 activated CUP1 independently of TFIIE [23].
  • A gene encoding the yeast ubiquitin was chemically synthesized and expressed in yeast under regulatory control of the copper metallothionein (CUP1) promoter [24].

Other interactions of CUP1-1

  • Strains with a complete deletion of the ACE1 gene, the copper-dependent activator of CUP1 transcription, are hypersensitive to copper [25].
  • Analysis of a Mac1p mutant, refractile for copper-dependent repression of the Cu(I) transport genes, showed an aberrant pattern of CUP1 expression and copper sensitivity [9].
  • In addition, these mutations are capable of suppressing certain alterations in the conserved PyAG trinucleotide at the 3' splice junction, as detected by an ACT1-CUP1 splicing reporter system [26].
  • Targeted histone acetylation at the yeast CUP1 promoter requires the transcriptional activator, the TATA boxes, and the putative histone acetylase encoded by SPT10 [27].
  • These CUP1 and HIS3 promoter activities are increased similarly from either episomal or genomic constructs [2].

Analytical, diagnostic and therapeutic context of CUP1-1


  1. A genetic screen identifies cellular factors involved in retroviral -1 frameshifting. Lee, S.I., Umen, J.G., Varmus, H.E. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  2. Nucleosome loss activates CUP1 and HIS3 promoters to fully induced levels in the yeast Saccharomyces cerevisiae. Durrin, L.K., Mann, R.K., Grunstein, M. Mol. Cell. Biol. (1992) [Pubmed]
  3. Metalloadsorption by Escherichia coli cells displaying yeast and mammalian metallothioneins anchored to the outer membrane protein LamB. Sousa, C., Kotrba, P., Ruml, T., Cebolla, A., De Lorenzo, V. J. Bacteriol. (1998) [Pubmed]
  4. Microarray karyotyping of commercial wine yeast strains reveals shared, as well as unique, genomic signatures. Dunn, B., Levine, R.P., Sherlock, G. BMC Genomics (2005) [Pubmed]
  5. Extremely conserved histone H4 N terminus is dispensable for growth but essential for repressing the silent mating loci in yeast. Kayne, P.S., Kim, U.J., Han, M., Mullen, J.R., Yoshizaki, F., Grunstein, M. Cell (1988) [Pubmed]
  6. Activated transcription independent of the RNA polymerase II holoenzyme in budding yeast. McNeil, J.B., Agah, H., Bentley, D. Genes Dev. (1998) [Pubmed]
  7. Oxidative stress induced heat shock factor phosphorylation and HSF-dependent activation of yeast metallothionein gene transcription. Liu, X.D., Thiele, D.J. Genes Dev. (1996) [Pubmed]
  8. Application of Ty1 for cloned gene insertion: amplification of a large regulated expression cassette in Saccharomyces cerevisiae. Lee, F.W., Da Silva, N.A. Appl. Microbiol. Biotechnol. (1996) [Pubmed]
  9. Dynamic regulation of copper uptake and detoxification genes in Saccharomyces cerevisiae. Peña, M.M., Koch, K.A., Thiele, D.J. Mol. Cell. Biol. (1998) [Pubmed]
  10. ACE2, an activator of yeast metallothionein expression which is homologous to SWI5. Butler, G., Thiele, D.J. Mol. Cell. Biol. (1991) [Pubmed]
  11. Yeast aminopeptidase I is post-translationally sorted from the cytosol to the vacuole by a mechanism mediated by its bipartite N-terminal extension. Seguí-Real, B., Martinez, M., Sandoval, I.V. EMBO J. (1995) [Pubmed]
  12. The role of PDR13 in tolerance to high copper stress in budding yeast. Kim, D.Y., Song, W.Y., Yang, Y.Y., Lee, Y. FEBS Lett. (2001) [Pubmed]
  13. Heat shock transcription factor activates yeast metallothionein gene expression in response to heat and glucose starvation via distinct signalling pathways. Tamai, K.T., Liu, X., Silar, P., Sosinowski, T., Thiele, D.J. Mol. Cell. Biol. (1994) [Pubmed]
  14. Mutated yeast heat shock transcription factor exhibits elevated basal transcriptional activation and confers metal resistance. Sewell, A.K., Yokoya, F., Yu, W., Miyagawa, T., Murayama, T., Winge, D.R. J. Biol. Chem. (1995) [Pubmed]
  15. Comparative analysis of transcriptional responses to saline stress in the laboratory and brewing strains of Saccharomyces cerevisiae with DNA microarray. Hirasawa, T., Nakakura, Y., Yoshikawa, K., Ashitani, K., Nagahisa, K., Furusawa, C., Katakura, Y., Shimizu, H., Shioya, S. Appl. Microbiol. Biotechnol. (2006) [Pubmed]
  16. The effect of superoxide dismutase deficiency on cadmium stress. Adamis, P.D., Gomes, D.S., Pereira, M.D., Freire de Mesquita, J., Pinto, M.L., Panek, A.D., Eleutherio, E.C. J. Biochem. Mol. Toxicol. (2004) [Pubmed]
  17. Enhanced effectiveness of copper ion buffering by CUP1 metallothionein compared with CRS5 metallothionein in Saccharomyces cerevisiae. Jensen, L.T., Howard, W.R., Strain, J.J., Winge, D.R., Culotta, V.C. J. Biol. Chem. (1996) [Pubmed]
  18. The CUP1 upstream repeated element renders CUP1 promoter activation insensitive to mutations in the RNA polymerase II transcription complex. Badi, L., Barberis, A. Nucleic Acids Res. (2002) [Pubmed]
  19. ACE1, a copper-dependent transcription factor, activates expression of the yeast copper, zinc superoxide dismutase gene. Gralla, E.B., Thiele, D.J., Silar, P., Valentine, J.S. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  20. Heat shock element architecture is an important determinant in the temperature and transactivation domain requirements for heat shock transcription factor. Santoro, N., Johansson, N., Thiele, D.J. Mol. Cell. Biol. (1998) [Pubmed]
  21. Fluorescence-based sensing system for copper using genetically engineered living yeast cells. Shetty, R.S., Deo, S.K., Liu, Y., Daunert, S. Biotechnol. Bioeng. (2004) [Pubmed]
  22. Histone H2A and Spt10 cooperate to regulate induction and autoregulation of the CUP1 metallothionein. Kuo, H.C., Moore, J.D., Krebs, J.E. J. Biol. Chem. (2005) [Pubmed]
  23. Artificial recruitment of certain Mediator components affects requirement of basal transcription factor IIE. Sakurai, H., Fukasawa, T. Genes Cells (2003) [Pubmed]
  24. Chemical synthesis and expression of a cassette adapted ubiquitin gene. Ecker, D.J., Khan, M.I., Marsh, J., Butt, T.R., Crooke, S.T. J. Biol. Chem. (1987) [Pubmed]
  25. Heat shock transcription factor activates transcription of the yeast metallothionein gene. Silar, P., Butler, G., Thiele, D.J. Mol. Cell. Biol. (1991) [Pubmed]
  26. Extensive genetic interactions between PRP8 and PRP17/CDC40, two yeast genes involved in pre-mRNA splicing and cell cycle progression. Ben-Yehuda, S., Russell, C.S., Dix, I., Beggs, J.D., Kupiec, M. Genetics (2000) [Pubmed]
  27. Targeted histone acetylation at the yeast CUP1 promoter requires the transcriptional activator, the TATA boxes, and the putative histone acetylase encoded by SPT10. Shen, C.H., Leblanc, B.P., Neal, C., Akhavan, R., Clark, D.J. Mol. Cell. Biol. (2002) [Pubmed]
  28. Ubp8p, a histone deubiquitinase whose association with SAGA is mediated by Sgf11p, differentially regulates lysine 4 methylation of histone H3 in vivo. Shukla, A., Stanojevic, N., Duan, Z., Sen, P., Bhaumik, S.R. Mol. Cell. Biol. (2006) [Pubmed]
  29. A new family of polymorphic metallothionein-encoding genes MTH1 (CUP1) and MTH2 in Saccharomyces cerevisiae. Naumov, G.I., Naumova, E.S., Turakainen, H., Korhola, M. Gene (1992) [Pubmed]
  30. Identification and functional expression of tahA, a filamentous fungal gene involved in copper trafficking to the secretory pathway in Trametes versicolor. Uldschmid, A., Engel, M., Dombi, R., Marbach, K. Microbiology (Reading, Engl.) (2002) [Pubmed]
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