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Gene Review

MET4  -  Met4p

Saccharomyces cerevisiae S288c

Synonyms: Methionine-requiring protein 4, N2177, Transcriptional activator of sulfur metabolism MET4, YNL103W
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High impact information on MET4

  • The critical target of SCF(Met30) is the transcription factor Met4, as deletion of MET4 suppresses the lethality of met30 mutants [1].
  • However, transcriptional repression of Met4 target genes correlates with Cdc34/SCF(Met30)-dependent ubiquitination of Met4 [1].
  • In yeast, the activator Met4 is inhibited by the SCF(Met30) ubiquitin ligase, which recognizes and oligo-ubiquitylates Met4 [2].
  • In the latter growth condition, oligo-ubiquitylated Met4 is not recruited to MET gene promoters, but is recruited to the SAM genes, which are required for production of S-adenosylmethionine, an unstable metabolite that is not present in rich medium [2].
  • Here, we demonstrate that in minimal media, Met4 is ubiquitylated and rapidly degraded in response to methionine excess, whereas in rich media, Met4 is oligo-ubiquitylated but remains stable [2].

Biological context of MET4


Associations of MET4 with chemical compounds


Physical interactions of MET4


Regulatory relationships of MET4

  • Over-expression of MET4 resulted in leaky expression from the otherwise tightly regulated MET3 promoter under its control [4].
  • Transcriptional studies showed that MET4 was regulated by the general amino acid control and hence by another bZIP protein encoded by GCN4 [4].
  • The requirement for Met4 in regulating GSH1 expression is lost in the absence of the centromere-binding protein Cbf1 [9].

Other interactions of MET4

  • In this paper, we demonstrate that other pathways are used to recruit Met4p on the 5' upstream region of the two genes, MET3 and MET28 [15].
  • The obtained results suggest that the binding of CBF1 to its cognate sequences increases the ability of MET4 to stimulate transcription of the MET genes [3].
  • A mutation in the MET4 gene abolishes transcription of both genes MET16 and MET25 [16].
  • The use of LexA-MET4 fusion proteins also reveals that the leucine zipper of MET4 is required for the recognition of the MET25 promoter [3].
  • Furthermore, yeast cells exposed to the xenobiotic 1-chloro-2,4-dintrobenzene are rapidly depleted of glutathione, accumulate oxidized thioredoxins, and elicit the Yap1/Met4-dependent transcriptional response of GSH1 [9].
  • We further demonstrated that Met32 is part of the Cbf1-Met4 complex bound to Cbf1-recruiting promoter elements and that Met31/32 are required for formation of a stable Met4-Cbf1 transcription complex [17].

Analytical, diagnostic and therapeutic context of MET4


  1. Regulation of transcription by ubiquitination without proteolysis: Cdc34/SCF(Met30)-mediated inactivation of the transcription factor Met4. Kaiser, P., Flick, K., Wittenberg, C., Reed, S.I. Cell (2000) [Pubmed]
  2. Dual regulation of the met4 transcription factor by ubiquitin-dependent degradation and inhibition of promoter recruitment. Kuras, L., Rouillon, A., Lee, T., Barbey, R., Tyers, M., Thomas, D. Mol. Cell (2002) [Pubmed]
  3. MET4, a leucine zipper protein, and centromere-binding factor 1 are both required for transcriptional activation of sulfur metabolism in Saccharomyces cerevisiae. Thomas, D., Jacquemin, I., Surdin-Kerjan, Y. Mol. Cell. Biol. (1992) [Pubmed]
  4. The general amino acid control regulates MET4, which encodes a methionine-pathway-specific transcriptional activator of Saccharomyces cerevisiae. Mountain, H.A., Byström, A.S., Korch, C. Mol. Microbiol. (1993) [Pubmed]
  5. Total deletion of yeast LEU4: further evidence for a second alpha-isopropylmalate synthase and evidence for tight LEU4-MET4 linkage. Chang, L.F., Gatzek, P.R., Kohlhaw, G.B. Gene (1985) [Pubmed]
  6. Molecular cloning and genetic mapping of the DNA topoisomerase II gene of Saccharomyces cerevisiae. Voelkel-Meiman, K., DiNardo, S., Sternglanz, R. Gene (1986) [Pubmed]
  7. Metabolism of sulfur amino acids in Saccharomyces cerevisiae. Thomas, D., Surdin-Kerjan, Y. Microbiol. Mol. Biol. Rev. (1997) [Pubmed]
  8. Antifungal azoxybacilin exhibits activity by inhibiting gene expression of sulfite reductase. Aoki, Y., Yamamoto, M., Hosseini-Mazinani, S.M., Koshikawa, N., Sugimoto, K., Arisawa, M. Antimicrob. Agents Chemother. (1996) [Pubmed]
  9. Coupling of the transcriptional regulation of glutathione biosynthesis to the availability of glutathione and methionine via the Met4 and Yap1 transcription factors. Wheeler, G.L., Trotter, E.W., Dawes, I.W., Grant, C.M. J. Biol. Chem. (2003) [Pubmed]
  10. Exposure of Saccharomyces cerevisiae to acetaldehyde induces sulfur amino acid metabolism and polyamine transporter genes, which depend on Met4p and Haa1p transcription factors, respectively. Aranda, A., del Olmo, M.L. Appl. Environ. Microbiol. (2004) [Pubmed]
  11. Sulfur sparing in the yeast proteome in response to sulfur demand. Fauchon, M., Lagniel, G., Aude, J.C., Lombardia, L., Soularue, P., Petat, C., Marguerie, G., Sentenac, A., Werner, M., Labarre, J. Mol. Cell (2002) [Pubmed]
  12. Assembly of a bZIP-bHLH transcription activation complex: formation of the yeast Cbf1-Met4-Met28 complex is regulated through Met28 stimulation of Cbf1 DNA binding. Kuras, L., Barbey, R., Thomas, D. EMBO J. (1997) [Pubmed]
  13. Proteolysis-independent regulation of the transcription factor Met4 by a single Lys 48-linked ubiquitin chain. Flick, K., Ouni, I., Wohlschlegel, J.A., Capati, C., McDonald, W.H., Yates, J.R., Kaiser, P. Nat. Cell Biol. (2004) [Pubmed]
  14. Met30p, a yeast transcriptional inhibitor that responds to S-adenosylmethionine, is an essential protein with WD40 repeats. Thomas, D., Kuras, L., Barbey, R., Cherest, H., Blaiseau, P.L., Surdin-Kerjan, Y. Mol. Cell. Biol. (1995) [Pubmed]
  15. Multiple transcriptional activation complexes tether the yeast activator Met4 to DNA. Blaiseau, P.L., Thomas, D. EMBO J. (1998) [Pubmed]
  16. Gene-enzyme relationship in the sulfate assimilation pathway of Saccharomyces cerevisiae. Study of the 3'-phosphoadenylylsulfate reductase structural gene. Thomas, D., Barbey, R., Surdin-Kerjan, Y. J. Biol. Chem. (1990) [Pubmed]
  17. A dominant suppressor mutation of the met30 cell cycle defect suggests regulation of the Saccharomyces cerevisiae Met4-Cbf1 transcription complex by Met32. Su, N.Y., Ouni, I., Papagiannis, C.V., Kaiser, P. J. Biol. Chem. (2008) [Pubmed]
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