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Gene Review

Max  -  Max protein

Mus musculus

Synonyms: AA960152, AI875693, Myc-associated factor X, Myc-binding novel HLH/LZ protein, Myn, ...
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Disease relevance of Max

  • Analysis of the DNA-binding activities of Myc/Max/Mad network complexes during induced differentiation of U-937 monoblasts and F9 teratocarcinoma cells [1].
  • Regulation of murine Max (Myn) parallels the regulation of c-Myc in differentiating murine erythroleukemia cells [2].
  • An exception is P19 embryonal carcinoma cells, where Mnt is expressed and in a complex with Max, but Myc proteins are not detected [3].
  • For this strategy we selected the Heb HLH and Max Zip regions as molecular scaffolds for the randomization process and displayed the two resulting molecular repertoires on lambda phage capsids [4].
  • However, cell toxicity was observed only in COLO320 DM and A-431 cells when the HSV-TK gene promoted by the Myc/Max binding sequence was introduced [5].

High impact information on Max


Biological context of Max

  • In addition, Myc/Max heterodimers, but not Max homodimers, bind to the EFII enhancer sequence in vitro [10].
  • We suggest that the c-Myc HLH/LZ domain induces apoptosis by specific interaction with cellular factors different to Max [11].
  • We have studied the phenotype of dominant-negative mutants of c-Myc and Max in microinjection experiments [11].
  • c-Myc and Mad each form heterodimers with Max that bind the same E-box related DNA sequences [12].
  • Thus, dMax is a widely expressed, naturally occurring protein, with the capacity to bind most members of the Myc/Max superfamily; dMax has little effect on Inr-mediated repression by c-Myc, but can significantly decrease E-box-mediated events promoting proliferation and cell survival [13].

Anatomical context of Max

  • Max mutants with a deleted or mutated basic region inhibited DNA synthesis in serum-stimulated 3T3-L1 mouse fibroblasts [11].
  • Using Western blot (immunoblot) and immunoprecipitation analysis, we have identified a variant form of Max protein (16 to 17 kDa), termed dMax, in detergent nuclear extracts of murine B-lymphoma cells, normal B lymphocytes, and NIH 3T3 fibroblasts [14].
  • Immunoprecipitation experiments confirmed that Max was also phosphorylated in NIH-3T3 cells, demonstrating that Max phosphorylation may have an important physiological function [15].
  • Loss of Max function in the mouse resulted in generalized developmental arrest of both embryonic and extraembryonic tissues at early postimplantation (approximately E5.5-6.5), coincident with loss or dilution of maternal Max stores in the expanding embryo in vivo and in blastocyst outgrowths in vitro [9].
  • Max RNA is expressed in quiescent BALB/c 3T3 cells and is modestly increased 3 h after addition of serum to the quiescent cells [16].

Associations of Max with chemical compounds

  • In contrast to Myc RNA, Max RNA does not decline immediately upon induction of differentiation of HL60 cells by dimethyl sulfoxide, and only a modest decrease of Max RNA was observed 72 h after induction of differentiation [16].
  • The basic helix-loop-helix/leucine zipper region, the casein kinase II phosphorylation sites and the nuclear localization signal sequence are 100% conserved in all vertebrate Max proteins characterized to date [17].
  • However, injection of the HSV-TK gene promoted by the Myc/Max binding sequence and aciclovir administration into mice could achieve significant tumor regression only in COLO320 DM and A-431 cells [5].
  • A buried salt bridge involving a histidine on the Max LZ and two glutamate residues on the c-Myc LZ is observed at the interface of the heterodimeric LZ [18].

Physical interactions of Max

  • Max protein forms specific DNA-binding dimeric complexes with itself and with proteins of the c-myc gene family [19].
  • Mnt interacts with Max in vivo and functions as a transcriptional repressor of reporter genes containing promoter-proximal CACGTG sites [3].

Other interactions of Max

  • The Myc proteins, as heterodimers with Max protein, have been shown to function as activators of transcription through an E-box DNA-binding element, CACGTG [10].
  • c-Myc and Max transregulate the mouse ornithine decarboxylase promoter through interaction with two downstream CACGTG motifs [20].
  • Our findings suggest that the precise temporal regulation of Myc/Max/Mad network proteins is critical for determining cellular behavior [21].
  • Mga, a dual-specificity transcription factor that interacts with Max and contains a T-domain DNA-binding motif [22].
  • In contrast, the p22/Myn-L and p21/Myn-S protein isoforms down-regulate in monophasic fashion [2].

Analytical, diagnostic and therapeutic context of Max

  • The past two decades of gene targeting experiments have allowed us to make significant strides towards understanding how the Myc/Max/Mad network influences multiple aspects of cellular behavior during development [23].
  • Affinity chromatography confirmed that YY1 associates with c-Myc but not with Max [24].
  • By deletion analysis and site-directed mutagenesis, the inhibitory domain was localized to a CKII phosphorylation site in the amino terminus of Max [15].
  • Omomyc sequestered Myc in complexes with low DNA binding efficiency, preventing binding to Max and inhibiting Myc transcriptional activator function [25].
  • These results suggest that gene therapy using the HSV-TK gene promoted by the Myc/Max binding sequence can be an attractive approach for treatment against tumor cells expressing high levels of c-myc [5].


  1. Analysis of the DNA-binding activities of Myc/Max/Mad network complexes during induced differentiation of U-937 monoblasts and F9 teratocarcinoma cells. Larsson, L.G., Bahram, F., Burkhardt, H., Lüscher, B. Oncogene (1997) [Pubmed]
  2. Regulation of murine Max (Myn) parallels the regulation of c-Myc in differentiating murine erythroleukemia cells. Dunn, B.K., Cogliati, T., Cultraro, C.M., Bar-Ner, M., Segal, S. Cell Growth Differ. (1994) [Pubmed]
  3. Mnt: a novel Max-interacting protein and Myc antagonist. Hurlin, P.J., Qúeva, C., Eisenman, R.N. Curr. Top. Microbiol. Immunol. (1997) [Pubmed]
  4. Molecular recognition in helix-loop-helix and helix-loop-helix-leucine zipper domains. Design of repertoires and selection of high affinity ligands for natural proteins. Ciarapica, R., Rosati, J., Cesareni, G., Nasi, S. J. Biol. Chem. (2003) [Pubmed]
  5. Inhibition of tumor growth by direct intratumoral gene transfer of herpes simplex virus thymidine kinase gene with DNA-liposome complexes. Sugaya, S., Fujita, K., Kikuchi, A., Ueda, H., Takakuwa, K., Kodama, S., Tanaka, K. Hum. Gene Ther. (1996) [Pubmed]
  6. Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Ayer, D.E., Lawrence, Q.A., Eisenman, R.N. Cell (1995) [Pubmed]
  7. Association of Myn, the murine homolog of max, with c-Myc stimulates methylation-sensitive DNA binding and ras cotransformation. Prendergast, G.C., Lawe, D., Ziff, E.B. Cell (1991) [Pubmed]
  8. Recognition by Max of its cognate DNA through a dimeric b/HLH/Z domain. Ferré-D'Amaré, A.R., Prendergast, G.C., Ziff, E.B., Burley, S.K. Nature (1993) [Pubmed]
  9. Essential role for Max in early embryonic growth and development. Shen-Li, H., O'Hagan, R.C., Hou, H., Horner, J.W., Lee, H.W., DePinho, R.A. Genes Dev. (2000) [Pubmed]
  10. The alternatively initiated c-Myc proteins differentially regulate transcription through a noncanonical DNA-binding site. Hann, S.R., Dixit, M., Sears, R.C., Sealy, L. Genes Dev. (1994) [Pubmed]
  11. Induction of apoptosis by the c-Myc helix-loop-helix/leucine zipper domain in mouse 3T3-L1 fibroblasts. Kohlhuber, F., Hermeking, H., Graessmann, A., Eick, D. J. Biol. Chem. (1995) [Pubmed]
  12. Regulation of Myc and Mad during epidermal differentiation and HPV-associated tumorigenesis. Hurlin, P.J., Foley, K.P., Ayer, D.E., Eisenman, R.N., Hanahan, D., Arbeit, J.M. Oncogene (1995) [Pubmed]
  13. Differential effects of the widely expressed dMax splice variant of Max on E-box vs initiator element-mediated regulation by c-Myc. FitzGerald, M.J., Arsura, M., Bellas, R.E., Yang, W., Wu, M., Chin, L., Mann, K.K., DePinho, R.A., Sonenshein, G.E. Oncogene (1999) [Pubmed]
  14. Variant Max protein, derived by alternative splicing, associates with c-Myc in vivo and inhibits transactivation. Arsura, M., Deshpande, A., Hann, S.R., Sonenshein, G.E. Mol. Cell. Biol. (1995) [Pubmed]
  15. Casein kinase II inhibits the DNA-binding activity of Max homodimers but not Myc/Max heterodimers. Berberich, S.J., Cole, M.D. Genes Dev. (1992) [Pubmed]
  16. Expression, regulation, and chromosomal localization of the Max gene. Wagner, A.J., Le Beau, M.M., Diaz, M.O., Hay, N. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  17. Structural analysis of the chicken max gene. Sollenberger, K.G., Kao, T.L., Taparowsky, E.J. Oncogene (1994) [Pubmed]
  18. Insights into the mechanism of heterodimerization from the 1H-NMR solution structure of the c-Myc-Max heterodimeric leucine zipper. Lavigne, P., Crump, M.P., Gagné, S.M., Hodges, R.S., Kay, C.M., Sykes, B.D. J. Mol. Biol. (1998) [Pubmed]
  19. Transfected wild-type and mutant max regulate cell growth and differentiation of murine erythroleukemia cells. Cogliati, T., Dunn, B.K., Bar-Ner, M., Cultraro, C.M., Segal, S. Oncogene (1993) [Pubmed]
  20. c-Myc and Max transregulate the mouse ornithine decarboxylase promoter through interaction with two downstream CACGTG motifs. Tobias, K.E., Shor, J., Kahana, C. Oncogene (1995) [Pubmed]
  21. Analysis of Myc/Max/Mad network members in adipogenesis: inhibition of the proliferative burst and differentiation by ectopically expressed Mad1. Pulverer, B., Sommer, A., McArthur, G.A., Eisenman, R.N., Lüscher, B. J. Cell. Physiol. (2000) [Pubmed]
  22. Mga, a dual-specificity transcription factor that interacts with Max and contains a T-domain DNA-binding motif. Hurlin, P.J., Steingrìmsson, E., Copeland, N.G., Jenkins, N.A., Eisenman, R.N. EMBO J. (1999) [Pubmed]
  23. Lessons learned from Myc/Max/Mad knockout mice. Pirity, M., Blanck, J.K., Schreiber-Agus, N. Curr. Top. Microbiol. Immunol. (2006) [Pubmed]
  24. Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc. Shrivastava, A., Saleque, S., Kalpana, G.V., Artandi, S., Goff, S.P., Calame, K. Science (1993) [Pubmed]
  25. Design and properties of a Myc derivative that efficiently homodimerizes. Soucek, L., Helmer-Citterich, M., Sacco, A., Jucker, R., Cesareni, G., Nasi, S. Oncogene (1998) [Pubmed]
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