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Gene Review

MAC1  -  Mac1p

Saccharomyces cerevisiae S288c

Synonyms: CUA1, Metal-binding activator 1, YM9711.11C, YMR021C
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Disease relevance of MAC1

  • N-terminal fusions of Mac1 with the herpes simplex VP16 activation domain were used to show that residues 1-159 in Mac1 constitute the minimal DNA binding domain [1].

High impact information on MAC1

  • First, MAC1 is involved in basal level transcription of FRE1, encoding a plasma membrane component associated with both Cu(II) and Fe(III) reduction [2].
  • Second, MAC1 is involved in the H2O2-induced transcription of CTT1, encoding the cytosolic catalase [2].
  • Here we report the identification of a nuclear protein from S. cerevisiae, MAC1, whose N-terminal region is highly similar to the copper and DNA binding domains of ACE1 and AMT1 [2].
  • Loss-of-function mutants of MAC1 have a defect in the plasma membrane Cu(II) and Fe(III) reductase activity, are slow growing, respiratory deficient, and hypersensitive to heat and exposure to cadmium, zinc, lead and H2O2 [2].
  • We have identified two target genes of MAC1 whose altered expression in mutants of MAC1 can account for some of the observed mutant phenotypes [2].

Biological context of MAC1

  • From the three Mac1-responsive elements in FRE7, a new consensus sequence for Mac1 binding can be established as TTTGC(T/G)C(A/G) [3].
  • Spacing between Mac1-responsive sites is important as shown by the attenuated expression of FRE7 and CTR1 when two elements are separated by over 100 base pairs [3].
  • Taken together, the data reported here and in earlier investigations indicate that GRISEA is an ortholog of the yeast transcription factor MAC1 and suggest at least a partial conservation of the molecular machinery involved in the control of cellular copper homeostasis in eukaryotes [4].
  • GRISEA, a copper-modulated transcription factor from Podospora anserina involved in senescence and morphogenesis, is an ortholog of MAC1 in Saccharomyces cerevisiae [4].
  • Mac1p-dependent transcriptional activation is negatively regulated by copper [5].

Anatomical context of MAC1

  • The macrophages were characterized by their capacity to phagocytose yeasts and by the presence of nonspecific esterases, of Fc receptors, and of specific antigens (MAC1 ...). In vitro, these macrophages were fully activated and were tumoricidal against different tumor cell lines [6].
  • The Gal4/Mac1p hybrid exhibits transactivation activity that is repressed in cells cultured in the presence of copper salts and derepressed in cells with reduced copper uptake [7].
  • These results suggest that CUC-1 and CUA-1 constitute a copper trafficking pathway similar to the yeast counterparts in intestinal and hypodermal cells, and CUA-1 may have a different function in pharyngeal muscle [8].

Associations of MAC1 with chemical compounds

  • The data indicate that the signal resulting from copper deprivation is transduced via the Cys-rich motif of MAC1 encompassing residues 264-279 [9].
  • Two additional MAC1 mutations exhibiting constitutive activity were in-frame deletions encompassing portions C1 [10].
  • Yeast one-hybrid analysis demonstrates that the copper-dependent transcriptional activity in Mac1p resides primarily in a cysteine-rich element encompassing residues 264-279 [5].
  • The protein phosphatase domain in MAC1, which is unique to fungal adenylate cyclases, interacted with a MAP kinase kinase and a Ser/Thr kinase [11].
  • The yeast transcription factor Mac1 binds to DNA in a modular fashion [12].

Physical interactions of MAC1

  • A positive transcription factor, Mac1p binds via its N-terminal domain to GCTC elements in the promoters of CTR1 and FRE1, encoding a copper permease and metal reductase, respectively [5].

Regulatory relationships of MAC1

  • The yeast Fre1p/Fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated Mac1p activator [13].
  • These studies (i) demonstrate that the nutritional and toxic copper metalloregulatory transcription factors Mac1p and Ace1p must sense and respond to copper ions in a dynamic fashion to appropriately regulate copper ion homeostasis and (ii) establish the requirement for a wild-type Mac1p for survival in the presence of toxic copper levels [14].

Other interactions of MAC1

  • Two elements are critical for Mac1-dependent FRE7 expression [3].
  • RESULTS: Genes in the upstream group encoded the regulator of copper transport, MAC1, and two copper transporters, CTR1 and CCC2 [15].
  • Under copper-limiting conditions, yeast cells harbouring deletions of the MAC1, CTR1 and CTR3 genes were defective in amine oxidase activity [16].
  • Evidence for (Mac1p)2.DNA ternary complex formation in Mac1p-dependent transactivation at the CTR1 promoter [17].
  • Two of the last three newly identified Mac1 target genes have no known function; the third, YFR055w, is homologous to cystathionine gamma-lyase encoded by CYS3 [18].

Analytical, diagnostic and therapeutic context of MAC1

  • Immunofluorescence studies indicate that Mac1p contains two nuclear localization signals, one each in the N- and C-terminal halves of the protein [5].
  • The transcription activity of Mac1 is rapidly inhibited in the copper-replete cells, whereas chromatin immunoprecipitation studies showed only partial copper-induced loss of DNA binding [19].


  1. Mapping of the DNA binding domain of the copper-responsive transcription factor Mac1 from Saccharomyces cerevisiae. Jensen, L.T., Posewitz, M.C., Srinivasan, C., Winge, D.R. J. Biol. Chem. (1998) [Pubmed]
  2. MAC1, a nuclear regulatory protein related to Cu-dependent transcription factors is involved in Cu/Fe utilization and stress resistance in yeast. Jungmann, J., Reins, H.A., Lee, J., Romeo, A., Hassett, R., Kosman, D., Jentsch, S. EMBO J. (1993) [Pubmed]
  3. Metalloregulation of FRE1 and FRE2 homologs in Saccharomyces cerevisiae. Martins, L.J., Jensen, L.T., Simon, J.R., Keller, G.L., Winge, D.R., Simons, J.R. J. Biol. Chem. (1998) [Pubmed]
  4. GRISEA, a copper-modulated transcription factor from Podospora anserina involved in senescence and morphogenesis, is an ortholog of MAC1 in Saccharomyces cerevisiae. Borghouts, C., Osiewacz, H.D. Mol. Gen. Genet. (1998) [Pubmed]
  5. Structure-function analysis of the protein-binding domains of Mac1p, a copper-dependent transcriptional activator of copper uptake in Saccharomyces cerevisiae. Serpe, M., Joshi, A., Kosman, D.J. J. Biol. Chem. (1999) [Pubmed]
  6. Immunotherapy of cancer: experimental approach with activated macrophages proliferating in culture. Bartholeyns, J., Lombard, Y., Dumont, S., Hartmann, D., Chokry, M., Giaimis, J., Kaufmann, S., Poindron, P. Cancer Detect. Prev. (1988) [Pubmed]
  7. Copper-mediated repression of the activation domain in the yeast Mac1p transcription factor. Graden, J.A., Winge, D.R. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  8. Identification of the copper chaperone, CUC-1, in Caenorhabditis elegans: tissue specific co-expression with the copper transporting ATPase, CUA-1. Wakabayashi, T., Nakamura, N., Sambongi, Y., Wada, Y., Oka, T., Futai, M. FEBS Lett. (1998) [Pubmed]
  9. Homeostatic regulation of copper uptake in yeast via direct binding of MAC1 protein to upstream regulatory sequences of FRE1 and CTR1. Yamaguchi-Iwai, Y., Serpe, M., Haile, D., Yang, W., Kosman, D.J., Klausner, R.D., Dancis, A. J. Biol. Chem. (1997) [Pubmed]
  10. Functional independence of the two cysteine-rich activation domains in the yeast Mac1 transcription factor. Keller, G., Gross, C., Kelleher, M., Winge, D.R. J. Biol. Chem. (2000) [Pubmed]
  11. Identification of proteins that interact with two regulators of appressorium development, adenylate cyclase and cAMP-dependent protein kinase A, in the rice blast fungus Magnaporthe grisea. Kulkarni, R.D., Dean, R.A. Mol. Genet. Genomics (2004) [Pubmed]
  12. The yeast transcription factor Mac1 binds to DNA in a modular fashion. Jamison McDaniels, C.P., Jensen, L.T., Srinivasan, C., Winge, D.R., Tullius, T.D. J. Biol. Chem. (1999) [Pubmed]
  13. The yeast Fre1p/Fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated Mac1p activator. Georgatsou, E., Mavrogiannis, L.A., Fragiadakis, G.S., Alexandraki, D. J. Biol. Chem. (1997) [Pubmed]
  14. 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]
  15. Genetic analysis of iron uptake in the yeast Saccharomyces cerevisiae. Dancis, A. J. Pediatr. (1998) [Pubmed]
  16. Mechanisms of copper loading on the Schizosaccharomyces pombe copper amine oxidase 1 expressed in Saccharomyces cerevisiae. Laliberté, J., Labbé, S. Microbiology (Reading, Engl.) (2006) [Pubmed]
  17. Evidence for (Mac1p)2.DNA ternary complex formation in Mac1p-dependent transactivation at the CTR1 promoter. Joshi, A., Serpe, M., Kosman, D.J. J. Biol. Chem. (1999) [Pubmed]
  18. Identification of the copper regulon in Saccharomyces cerevisiae by DNA microarrays. Gross, C., Kelleher, M., Iyer, V.R., Brown, P.O., Winge, D.R. J. Biol. Chem. (2000) [Pubmed]
  19. Independent metalloregulation of Ace1 and Mac1 in Saccharomyces cerevisiae. Keller, G., Bird, A., Winge, D.R. Eukaryotic Cell (2005) [Pubmed]
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