A Biochemical and Biological Analysis of Myc Superfamily Interactions

  • N. Schreiber-Agus
  • L. Alland
  • R. Muhle
  • J. Goltz
  • K. Chen
  • L. Stevens
  • D. Stein
  • R. A. DePinho
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 224)


Members of the myc family of nuclear proto-oncogenes (c-, N- and L-myc) play central roles in the control of normal growth and development and in genetic pathways linked to cellular transformation and apoptotic cell death (for reviews see [19, 40]). Accumulating structural, biochemical, and genetic evidence affords the view that the function of Myc family oncoproteins in these diverse processes relates in part to their roles as sequence-specific transcription factors (for reviews see [31, 58]). Myc family proteins possess a multi-functional amino-terminal domain with transactivation potential [32], a region rich in basic amino acid residues responsible for sequence-specific DNA binding activity to the E-box consensus CACGTG [8], and a carboxy-terminal α-helical domain required for dimerization with another basic region helix-loop-helix/leucine zipper (bHLH/LZ) protein, Max [9, 43]. Many of the biochemical and biological activities of Myc appear to be highly dependent upon its association with Max [1, 2, 9, 35, 43). In addition to its key role as an obligate partner in transactivation-competent Myc/Max complexes, Max may also repress Myc-responsive genes through the formation of transactivation-inert complexes that are capable of binding the Myc/Max recognition sequence [5, 10, 33, 35, 39, 41, 44, 65]. These complexes include Max/Max homodimers, and the heterodimers Mad/Max [5, 29] and Mxil/Max [65].


Albert Einstein College Repression Domain Cell BioI Calcium Phosphate Precipitation Method Early Passage Culture 
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  1. 1.
    Amati B, Littlewood TD, Evan GI, Land H (1993a) The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max. EMBO J. 12: 5083–5087PubMedCentralPubMedGoogle Scholar
  2. 2.
    Amati B, Brooks MW, Levy M, Littlewood TD, Evan GI, Land, H (1993b) Oncogenic activity of the c-Myc protein requires dimerization with Max. Cell 72:233–245PubMedCrossRefGoogle Scholar
  3. 3.
    Amati B, Land H (1994) Myc-Max-Mad: a transcription factor network controlling cell cycle progression, differentiation and death. Curr. Opin. Genet. Dev. 4:102–108PubMedCrossRefGoogle Scholar
  4. 4.
    Ayer DE, Eisenman RN (1993) A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation. Genes Dev. 7:2110–2119PubMedCrossRefGoogle Scholar
  5. 5.
    Ayer DE, Kretzner L, Eisenman RN (1993) Mad: a heterodimeric partner for Max that antagonizes Myc transcriptional activity. Cell 72:211–222PubMedCrossRefGoogle Scholar
  6. 6.
    Ayer DE, Lawrence QA, Eisenman RN (1995) The amino-terminus of Mad mediates ternary complex formation with mammalian homologs of the yeast repressor Sin3 and is required for Mad:Max transcriptional repression. Cell 80:767–776PubMedCrossRefGoogle Scholar
  7. 7.
    Bello-Fernandez C, Packham G, Cleveland JL (1993) The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc. Nat’l Acad. Sci. USA 90:7804–7808CrossRefGoogle Scholar
  8. 8.
    Blackwell TK, Kretzner L, Blackwood EM, Eisenman RN, Weintraub H (1990) Sequence-specific DNA binding by the c-myc protein. Science 250:1149–1151PubMedCrossRefGoogle Scholar
  9. 9.
    Blackwood EM, Eisenman RN (1991) Max: A helix-loop-helix zipper protein that forms a sequence-specific DNA binding complex with Myc. Science 251:1211–1217PubMedCrossRefGoogle Scholar
  10. 10.
    Blackwood EM, Luscher B, Eisenman RN (1992) Myc and Max associate in vivo. Genes Dev. 6:71–80PubMedCrossRefGoogle Scholar
  11. 11.
    Charron J, Malynn B, Fisher P, Stewart V, Jeannotte L, Goff SP, Robertson L, Alt FW (1992) Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene. Genes Dev. 6:2248–2257PubMedCrossRefGoogle Scholar
  12. 12.
    Chen J, Willingham T, Margraf LF, Schreiber-Agus N, DePinho RA, Nisen PD (1995) Effects of the Myc oncogene antagonist, MAD, on proliferation, cell cycling and the malignant phenotype of human brain tumor cells. Nature Med. 1:638–643PubMedCrossRefGoogle Scholar
  13. 13.
    Chin L, Schreiber-Agus N, Pellicer I, Chen K, Lee HW, Dudast M, Cordon-Cardo C, DePinho RA (1995) Contrasting roles for Myc and Mad proteins in cellular growth and differentiation. Proc. Natl. Acad. Sci. USA 92:8488–8492PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Cowell IG (1994) Repression versus activation in the control of gene transcription. Trends Biochem. Sci. 19:38–42PubMedCrossRefGoogle Scholar
  15. 15.
    Davis AC, Wims M, Sports GD, Hann S, Bradley A (1993) A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev. 7:671–682PubMedCrossRefGoogle Scholar
  16. 16.
    DePinho RA, Schreiber-Agus N, Alt FW (1991) myc family oncogenes in the development of normal and neoplastic cells. Adv. Cancer Res. 57:1–46PubMedCrossRefGoogle Scholar
  17. 17.
    Devereux J, Haeberli P, Smithies O (1984) A comprhensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 12:387–395PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Edelhoff S, Ayer DE, Zervos AS, Steingrimsson E, Jenkins NA, Copeland NG, Eisenman RN, Brent R, Disteche CM (1994) Mapping of two genes encoding members of a distinct subfamily of MAX interacting proteins: MAD to human chromosome 2 and mouse chromosome 6, and MXI1 to human chromosome 10 and mouse chromosome 19. Oncogene 9:665–668PubMedGoogle Scholar
  19. 19.
    Evan, GI, Littlewood TD (1993) The role of c-myc in cell growth. Current Biol. 3:44–49CrossRefGoogle Scholar
  20. 20.
    Fields S, Song O (1989) A novel genetic system to detect protein-protein interactions. Nature 340:245–246PubMedCrossRefGoogle Scholar
  21. 21.
    Galaktionov K, Chen X, Beach D (1996) Cdc25 cell cycle phosphatase as a target of c-myc. Nature 382:511–517PubMedCrossRefGoogle Scholar
  22. 22.
    Gallant P, Shiio Y, Cheng PF, Parkhurst SM, Eisenman RN (1996) Myc and Max Homologs in Drosophila. Science 274:1523–1527PubMedCrossRefGoogle Scholar
  23. 23.
    Gu W, Bhatia K, Magrath, IT, Dang CV, Dalla-Favera R (1994) Binding and suppression of the Myc transcriptional activation domain by pl07. Science 264:251–254PubMedCrossRefGoogle Scholar
  24. 24.
    Halleck MS, Pownall S, Harder KW, Duncan AM, Jirik FR, Schlegel RA (1995) A widely distributed putative mammalian transcriptional regulator containing multiple paired amphipathic helices, with similarity to yeast SIN3. Genomics 26:403–406PubMedCrossRefGoogle Scholar
  25. 25.
    Harper SE, Qiu Y, Sharp PA (1996) Sin3 corepressor function in Myc-induced transcription and transformation. Proc. Natl. Acad. Sci. USA 93:8536–8540PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Hateboer G, Timmers HT, Rustgi AK, Billaud M, van’t Veer LJ, Bernards R (1993) TATA-binding protein and the retinoblastoma gene product bind to overlapping epitpoes on c-Myc and adenovirus E1A protein. Proc. Natl. Acad. Sci. U.S.A. 90:8489–8493PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Horlein AJ, Naar AM, Heinze T, Torchia J, Gloss B, Korokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, Rosenfeld MG (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear co-repressor. Nature 377:397–404PubMedCrossRefGoogle Scholar
  28. 28.
    Hurlin PJ, Foley KP, Ayer DE, Eisenman RN, Hanahan D, Arbeit JM (1995) Regulation of Myc and Mad during epidermal differentiaion and HPV-associated tumorigenesis. Oncogene 11:2487–2501PubMedGoogle Scholar
  29. 29.
    Hurlin PJ, Queva C, Koskinen PJ, Steingrimsson E, Ayer DE, Copeland NG, Jenkins NA, Eisenman RN (1996) Mad3 and Mad4: novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation. EMBO J. 14:5646–5659Google Scholar
  30. 30.
    Kasten MM, Ayer DE, Stillman DJ (1996) SIN3-dependent transcriptional repression by interaction with the Mad1 DNA-binding protein. Mol. Cell. Biol. 16:4215–4221.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Kato GJ, Dang CV (1992) Function of the c-Myc oncoprotein. FASEB 6:3065–3072Google Scholar
  32. 32.
    Kato GJ, Barret J, Villa-Garcia M, Dang CV (1990) An amino-terminal c-Myc domain required for neoplastic transformation activates transcription. Mol. Cell. Biol. 10:5914–5920PubMedCentralPubMedGoogle Scholar
  33. 33.
    Kato GJ, Lee WMF, Chen L, Dang CV (1992) Max: functional domains and interaction with c-Myc. Genes Dev. 6:81–92PubMedCrossRefGoogle Scholar
  34. 34.
    Koskinen PJ, Ayer DE, Eisenman RN (1995) Repression of Myc-Ras cotransformation by Mad is mediated by multiple protein-protein interactions. Cell Growth Diff. 6:623–629PubMedGoogle Scholar
  35. 35.
    Kretzner L, Blackwood EM, Eisenman RN (1992) Myc and Max proteins possess distinct transcriptional activities. Nature (London) 359:426–429CrossRefGoogle Scholar
  36. 36.
    Lahoz EG, Xu L, Schreiber-Agus N, DePinho RA (1994) Suppression of Myc, but not E1a, transformation activity by Max-associated proteins, Mad and Mxi1. Proc. Natl. Acad. Sci. USA 91:5503–5507PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Land H, Parada LF, Weinberg RA (1983) Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature (London) 304:596–602CrossRefGoogle Scholar
  38. 38.
    Larsson LG, Pettersson M, Oberg F, Nilsson K, Luscher B (1994) Expression of mad, mxil, max and c-myc during induced differentiation of hematopoietic cells: opposite regulation of mad and myc. Oncogene 9:1247–1252PubMedGoogle Scholar
  39. 39.
    Makela TP, Koskinen PJ, Vastrik I, Alitalo K (1992) Alternative forms of Max as enhancers or suppressors of Myc-Ras cotransformation. Science 256:373–376PubMedCrossRefGoogle Scholar
  40. 40.
    Morgenbesser SD, DePinho RA (1994) Use of transgenic mice to study myc family gene function in normal mammalian development and in cancer. Seminars in Cancer Biol. 5:21–36Google Scholar
  41. 41.
    Mukherjee B, Morgenbesser SD, DePinho RA (1992) Myc-family oncoproteins function through a common pathway to transform normal cells in culture: cross interference by Max and trans-acting dominant mutants. Genes Dev. 6:1480–1492PubMedCrossRefGoogle Scholar
  42. 42.
    Nasmyth K, Stillman D, Kipling D (1987) Both positive and negative regulators of HO transcription are required for mother-cell-specific mating-type switching in yeast. Cell 48:579–587PubMedCrossRefGoogle Scholar
  43. 43.
    Prendergast GC, Lawe D, Ziff EB (1991) Association of Myn, the murine homolog of Max, with c-Myc stimulates methylation-sensitive DNA Binding and Ras cotransformation. Cell 65:395–407PubMedCrossRefGoogle Scholar
  44. 44.
    Prendergast GC, Hopewell R, Gorham BJ, Ziff EB (1992) Biphasic effect of Max on Myc cotransformation activity and dependence on amino- and carboxy-terminal Max functions. Genes Dev. 6:2429–2439PubMedCrossRefGoogle Scholar
  45. 45.
    Rao G, Alland L, Guida P, Schreiber-Agus N, Chen K, Chin L, Rochelle JM, Seldin MF, Skoultchi AS, DePinho RA (1996) Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression domain of the Myc antagonist Mxi. Oncogene 12:1165–1172PubMedGoogle Scholar
  46. 46.
    Roussel MF, Ashmun RA, Sherr CJ, Eisenman RN, Ayer DE (1996) Inhibition of cell proliferation by the Mad1 transcriptional repressor. Mol. Cell Biol. 16:2796–2801PubMedCentralPubMedGoogle Scholar
  47. 47.
    Roy B, Reisman, D (1995) Inducible expression of Mad accelerates growth arrest of serum deprived human glioblastoma cells. Cell Biol. Intl. 19:307–313.CrossRefGoogle Scholar
  48. 48.
    Rubin GM, (1988) Drosophila melanogaster as an experimental organism. Science 243:1453–1459CrossRefGoogle Scholar
  49. 49.
    Sawai SA, Shimono K, Yakamatsu Y, Palmes C, Hanaoka K, Kondoh H (1993) Defects of embryonic organogenesis resulting from targetd disruption of the N-myc gene in the mouse. Development 117:1445–1455PubMedGoogle Scholar
  50. 50.
    Schreiber-Agus N, Chin L, Chen K, Torres R, Thomson C, Sacchettini JC, DePinho RA (1994) Evolutionary relationships and functional conservation among vertebrate Max-associated proteins: the zebra fish homolog of Mxi1. Oncogene 9:3167–3177PubMedGoogle Scholar
  51. 51.
    Schreiber-Agus N, Chin L, Chen K, Torres R, Rao G, Guida P, Skoultchi AI, DePinho RA (1995) An amino-terminal domain of Mxil mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell 80:777–786PubMedCrossRefGoogle Scholar
  52. 52.
    Schreiber-Agus N, Stein D, Chen K, Goltz JS, Stevens L, DePinho RA (1997)Drosophila Myc is oncogenic in mammalian cells and plays a role in the diminutive phenotype. Proc. Natl. Acad. Sci., U.S.A., in pressGoogle Scholar
  53. 53.
    Shrivastava A, Saleque S, Kalpana GV, Artandi S, Goff SP, Calame K (1993) Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc. Science 262:1889–1892PubMedCrossRefGoogle Scholar
  54. 54.
    Stanton BR, Perkins A, Tessarollo L, Sassoon D, Parada L (1992) Loss of N-myc function results in embryonic lethality and failure of the epithelial component of the embryo to develop. Genes Dev. 6:2235–2247PubMedCrossRefGoogle Scholar
  55. 55.
    Sternberg PW, Stern MJ, Clark I, Herskowitz I (1987) Activation of the yeast HO gene by release from multiple negative controls. Cell 48:567–577PubMedCrossRefGoogle Scholar
  56. 56.
    Strich R, Slater MR, Esposito RE (1989) Identification of negative regulatory genes that govern the expression of early meiotic genes in yeast. Proc. Natl. Acad. Sci. U.S.A. 86:10018–10022PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Taunton J, Hassig CA, Schreiber SL (1996) A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272:408–411PubMedCrossRefGoogle Scholar
  58. 58.
    Torres R, Schreiber-Agus N, Morgenbesser SD, DePinho RA (1992) Myc and Max: a putative transcriptional complex in search of a cellular target. Curr. Opin. Cell Biol. 4:468–474PubMedCrossRefGoogle Scholar
  59. 59.
    Vastrik I, Kaipainen A, Penttila TL, Lymboussakis A, Alitalo R, Parvinen M, Alitalo K (1995) Expression of the mad gene during cell differentiation in vivo and its inhibition of cell growth in vitro. J. Cell Biol. 128:1197–1208PubMedCrossRefGoogle Scholar
  60. 60.
    Vidal M, Strich R, Esposito RE, Gaber RF (1991) RPD1 (SIN3/UME4) is required for maximal activation and repression of diverse yeast genes. Mol. Cell. Biol. 11:6306–6316PubMedCentralPubMedGoogle Scholar
  61. 61.
    Vojtek AB, Hollenberg SM, Cooper JA (1993) Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74:205–214PubMedCrossRefGoogle Scholar
  62. 62.
    Wang H, Clark I, Nicholson PR, Herskowitz I, Stillman DJ (1990) The Saccharomyces cerevisiae SIN3 gene, a negative regulator of HO, contains four paired amphipathic helix motifs. Mol. Cell. Biol. 10:5927–5936PubMedCentralPubMedGoogle Scholar
  63. 63.
    Wang H, Stillman DJ (1993) Transcriptional repression in Saccharomyces cerevisiae by a SIN3-LexA fusion protein. Mol. Cell. Biol. 13:1805–1814PubMedCentralPubMedGoogle Scholar
  64. 64.
    Wechsler DS, Hawkins AL, Li X, Jabs EW, Griffin CA, Dang CV (1994) Localization of the human Mxil transcription factor gene (MXI1) to chromosome 10q24-q25. Genomics 21:669–672PubMedCrossRefGoogle Scholar
  65. 65.
    Zervos AS, Gyuris J, Brent R (1993) Mxil, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell 72:223–232PubMedCrossRefGoogle Scholar
  66. 66.
    Zimmerman KA, Yancopoulos GD, Collum RG, Smith RK, Kohl NE, Denis KA, Nau MM, Witte ON, Toran-Allerand D, Gee CE, Minna JD, Alt FW (1986) Differential expression of myc family genes during murine development. Nature (London) 319:780–783CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • N. Schreiber-Agus
    • 1
  • L. Alland
    • 1
  • R. Muhle
    • 1
  • J. Goltz
    • 2
  • K. Chen
    • 1
  • L. Stevens
    • 3
  • D. Stein
    • 2
  • R. A. DePinho
    • 1
  1. 1.Dept. of Microbiology and ImmunologyAlbert Einstein College of MedicineBronxUSA
  2. 2.Dept. of Molecular GeneticsAlbert Einstein College of MedicineBronxUSA
  3. 3.Dept. of Developmental and Molecular BiologyAlbert Einstein College of MedicineBronxUSA

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