Myc Target Genes in Cell Proliferation and Programmed Cell Death

  • Chi V. Dang
  • Linda A. Lee
Part of the Medical Intelligence Unit book series (MIU.LANDES)


In the previous chapters, we reviewed the dissection of the c-Myc molecule and its structural organization that typifies a transcription factor. c-Myc function is regulated by a complicated network of proteins that developed through millions of years of evolution and is likely to include a large repertoire of interacting proteins. Yet, the mechanism by which c-Myc or its retroviral counterpart v-Myc transforms cells remains largely unknown. Clues to the molecular basis of c-Myc mediated cellular transformation may be revealed by studies that attempt to identify target genes and events linking the deregulated expression of Myc and transformed phenotypes.


Initiator Element Murine Erythroleukemia Cell Syrian Hamster Embryo Cell Cdc2 Gene Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Prendergast GC, Cole MD. Posttranscriptional regulation of cellular gene expression by the c-myc oncogene. Mol Cell Biol 1989; 9: 124–34.PubMedGoogle Scholar
  2. 2.
    Prendergast GC, Diamond LE, Dahl D, Cole MD. The c-mycregulated gene mrl encodes plasminogen activator inhibitor 1. Mol Cell Biol 1990; 10: 1265–9.PubMedGoogle Scholar
  3. 3.
    Gibson AW, Ye R, Johnston RN, Browder LW. A possible role for c-Myc oncoproteins in post-transcriptional regulation of ribosomal RNA. Oncogene 1992; 7: 2363–7.PubMedGoogle Scholar
  4. 4.
    Riccio A, Pedone PV, Lund LR, Olesen T, Olsen HS, Andreasen PA. Transforming growth factor beta 1-responsive element: closely associated binding sites for USF and CCAAT-binding transcription factor-nuclear factor I in the type 1 plasminogen activator inhibitor gene. Mol Cell Biol 1992; 12: 1846–55.PubMedGoogle Scholar
  5. 5.
    Yang BS, Geddes TJ, Pogulis RJ, de Crombrugghe B, Freytag SO. Transcriptional suppression of cellular gene expression by c-Myc. Mol Cell Biol 1991; 11: 2291–5.PubMedGoogle Scholar
  6. 6.
    Yang BS, Gilbert JD, Freytag SO. Overexpression of Myc suppresses CCAAT transcription factor/nuclear factor 1-dependent promoters in vivo. Mol Cell Biol 1993; 13: 3093–102.PubMedGoogle Scholar
  7. 7.
    Schmidt A, Setoyama C, de Crombrugghe B. Regulation of a collagen gene promoter by the product of viral mos oncogene. Nature 1985; 314: 286–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Slack JL, Parker MI, Robinson VR, Bornstein P. Regulation of collagen I gene expression by ras. Mol Cell Biol 1992; 12: 4714–23.PubMedGoogle Scholar
  9. 9.
    Setoyama C, Liau G, de Crombrugghe B. Pleiotropic mutants of NIH 3T3 cells with altered regulation in the expression of both type I collagen and fibronectin. Cell 1985; 41: 201–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Eizenberg O, Oren M. Reduced levels of alpha 1 (I) collagen mRNA in cells immortalized by mutant p53 or transformed by ras. Biochim Biophys Acta 1991; 1129: 34–42.PubMedCrossRefGoogle Scholar
  11. 11.
    Frankfort BJ, Gelman IH. Identification of novel cellular genes transcriptionally suppressed by v-src. Biochem Biophys Res Commun 1995; 206: 916–26.PubMedCrossRefGoogle Scholar
  12. 12.
    Hampton LL, Worland PJ, Yu B, Thorgeirsson SS, Huggett AC. Expression of growth-related genes during tumor progression in v-raf-transformed rat liver epithelial cells. Cancer Res 1990; 50: 7460–7.PubMedGoogle Scholar
  13. 13.
    Schuur ER, Kruse U, Iacovoni JS, Vogt PK. Nuclear factor 1 interferes with transformation by nuclear oncogenes. Cell Growth Differ 1995; 6: 219–27.PubMedGoogle Scholar
  14. 14.
    Lim A, Greenspan DS, Smith BD. Expression of alpha 2 type I collagen in W8 cells increases cell adhesion and decreases colony formation in soft agar. Matrix Biol 1994; 14: 21–30.PubMedCrossRefGoogle Scholar
  15. 15.
    Wiseman RW, Montgomery JC, Hosoi J, et al. Identification of genes associated with tumor suppression in Syrian hamster embryo cells. [Review]. Environ Health Perspect 1991; 93: 105–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Filers M, Picard D, Yamamoto KR, Bishop JM. Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells. Nature 1989; 340: 66–8.CrossRefGoogle Scholar
  17. 17.
    Eilers M, Schirm S, Bishop JM. The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J 1991; 10: 133–41.PubMedGoogle Scholar
  18. 18.
    Eschenfeldt WH, Berger SL. The human prothymosin alpha gene is polymorphic and induced upon growth stimulation: evidence using a cloned cDNA. Proc Natl Acad Sci USA 1986; 83: 9403–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Sburlati AR, Manrow RE, Berger SL. Prothymosin alpha antisense oligomers inhibit myeloma cell division. Proc Natl Acad Sci USA 1991; 88: 253–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Manrow RE, Sburlati AR, Hanover JA, Berger SL. Nuclear targeting of prothymosin alpha. J Biol Chem 1991; 266: 3916–24.PubMedGoogle Scholar
  21. 21.
    Gaubatz S, Meichle A, Eilers M. An E-box element localized in the first intron mediates regulation of the prothymosin alpha gene by c-myc. Mol Cell Biol 1994; 14: 3853–62.PubMedGoogle Scholar
  22. 22.
    Meichle A, Philipp A, Eilers M. The functions of Myc proteins. [Review]. Biochim Biophys Acta 1992; 1114: 129–46.PubMedGoogle Scholar
  23. 23.
    Gaubatz S, Imho fA, Dosch R, et al. Transcriptional activation by Myc is under negative control by the transcription factor AP-2. EMBO J 1995; 14: 1508–19.PubMedGoogle Scholar
  24. 24.
    Tavtigian SV, Zabludoff SD, Wold BJ. Cloning of mid-G(1) serum response genes and identification of a subset regulated by conditional myc expression. Mol Biol Cell 1994; 5: 375–88.PubMedGoogle Scholar
  25. 25.
    Benvenisty N, Leder A, Kuo A, Leder P. An embryonically expressed gene is a target for c-Myc regulation via the c-Myc-binding sequence. Genes Dev 1992; 6: 2513–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Benvenisty N, Ornitz DM, Bennett GL, et al. Brain tumours and lymphomas in transgenic mice that carry HTLV-I LTR/c-myc and Ig/tax genes. Oncogene 1992; 7: 2399–405.PubMedGoogle Scholar
  27. 27.
    Askew DS, Ashmun RA, Simmons BC, Cleveland JL. Constitutive cmyc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene 1991; 6: 1915–22.PubMedGoogle Scholar
  28. 28.
    Auvinen M, Paasinen A, Andersson LC, Holtta E. Ornithine de-carboxylase activity is critical for cell transformation. Nature 1992; 360: 355–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Bello-Fernandez C, Packham G, Cleveland JL. The ornithine de-carboxylase gene is a transcriptional target of c-Myc. Proc Natal Acad Sci USA 1993; 90: 7804–8.CrossRefGoogle Scholar
  30. 30.
    Pena A, Reddy CD, Wu S, et al. Regulation of human ornithine decarboxylase expression by the c-Myc.Max protein complex. J Biol Chem 1993; 268: 27277–85.PubMedGoogle Scholar
  31. 31.
    Wagner AJ, Meyers C, Laimins LA, Hay N. c-Myc induces the expression and activity of ornithine decarboxylase. Cell Growth Differ 1993; 4: 879–83.Google Scholar
  32. 32.
    Pena A, Wu S, Hickok NJ, Soprano DR, Soprano KJ. Regulation of human ornithine decarboxylase expression following prolonged quiescence: role for the c-Myc/Max protein complex. J Cell Physiol 1995; 162: 234–45.PubMedCrossRefGoogle Scholar
  33. 33.
    Packham G, Bellofernandez C, Cleveland JL. Position and orientation independent transactivation by c-Myc. Cell Molec Biol Res 1994; 40: 699–706, 1994.Google Scholar
  34. 34.
    Gregor PD, Sawadogo M, Roeder RG. The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. Genes Dev 1990; 4: 1730–40.PubMedCrossRefGoogle Scholar
  35. 35.
    Beckmann H, Kadesch T. The leucine zipper of TFE3 dictates helix-loop-helix dimerization specificity. Genes Dev 1991; 5: 1057–66.PubMedCrossRefGoogle Scholar
  36. 36.
    Fisher DE, Carr CS, Parent LA, Sharp PA. TFEB has DNA-binding and oligomerization properties of a unique helix-loop-helix/leucine-zipper family. Genes Dev 1991; 5: 2342–52.PubMedCrossRefGoogle Scholar
  37. 37.
    Mai S, Jalava A. C-myc binds to 5’ flanking sequence motifs of the dihydrofolate reductase gene in cellular extracts–role in proliferation. Nucleic Acids Res 1994; 22: 2264–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Miltenberger RJ, Sukow KA, Farnham PJ. An E-box-mediated increase in cad transcription at the G1/S-phase boundary is suppressed by inhibitory c-Myc mutants. Mol Cell Biol 1995; 15: 2527–35.PubMedGoogle Scholar
  39. 39.
    Karn J, Watson J, Lowe A, Green S, Vedeckis W. Regulation of cell cycle duration by c-myc levels. Oncogene 1989; 4: 773–87.PubMedGoogle Scholar
  40. 40.
    Prouty SM, Hanson KD, Boyle AL, et al. A cell culture model system for genetic analyses of the cell cycle by targeted homologous recombination. Oncogene 1993; 8: 899–907.PubMedGoogle Scholar
  41. 41.
    Shichiri M, Hanson KD, Sedivy JM. Effects of c-myc expression on proliferation, quiescence, and the GO to G1 transition in nontransformed cells. Cell Growth Differ 1993; 4: 93–104.PubMedGoogle Scholar
  42. 42.
    Hanson KD, Shichiri M, Follansbee MR, Sedivy JM. Effects of cmyc expression on cell cycle progression. Mol Cell Biol 1994; 14: 5748–55.PubMedCrossRefGoogle Scholar
  43. 43.
    Jansen-Durr P, Meichle A, Steiner P, et al. Differential modulation of cyclin gene expression by MYC. Proc Natl Acad Sci USA 1993; 90: 3685–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Philipp A, Schneider A, Vasrik I, et al. Repression of cyclin D1–a novel function of myc. Mol Cell Biol 1994; 14: 4032–43.PubMedGoogle Scholar
  45. 45.
    Daksis JI, Lu RY, Facchini LM, Marhin WW, Penn U. Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene 1994; 9: 3635–45.PubMedGoogle Scholar
  46. 46.
    Rosenwald IB Lazariskaratzas A, Sonenberg N, Schmidt EV. Elevated levels of cyclin DI protein in response to increased expression of eukaryotic initiation factor 4E. Mol Cell Biol 1993; 13:7358–63.Google Scholar
  47. 47.
    Hoang AT, Cohen KJ, Barrett JF, Bergstrom DA, Dang CV. Participation of cyclin A in Myc-induced apoptosis. Proc Natl Acad Sci USA 1994; 91: 6875–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Henglein B, Chenivesse X, Wang J, Eick D, Brechot C. Structure and cell cycle-regulated transcription of the human cyclin A gene. Proc Natl Acad Sci USA 1994; 91: 5490–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Yamamoto M, Yoshida M, Ono K, et al. Effect of tumor suppressors on cell cycle-regulatory genes: RB suppresses p34cdc2 expression and normal p53 suppresses cyclin A expression. Exp Cell Res 1994; 210: 94–101.PubMedCrossRefGoogle Scholar
  50. 50.
    Yoshizumi M, Hsieh CM, Zhou F, et al. The ATF site mediates downregulation of the cyclin A gene during contact inhibition in vascular endothelial cells. Mol Cell Biol 1995; 6: 3266–72.Google Scholar
  51. 51.
    Desdouets C, Matesic G, Molina CA, et al. Cell cycle regulation of cyclin A gene expression by the cyclic AMP-responsive transcription factors CREB and CREM. Mol Cell Biol 1995; 6: 3301–9.Google Scholar
  52. 52.
    Nakamura T, Okuyama S, Okamoto S, Nakajima T, Sekiya S, Oda K. Down-regulation of the cyclin A promoter in differentiating human embryonal carcinoma cells is mediated by depletion of ATF1 and ATF-2 in the complex at the ATF/CRE site. Exp Cell Res 1995; 216: 422–30.PubMedCrossRefGoogle Scholar
  53. 53.
    Guadagno TM, Ohtsubo M, Roberts JM, Assoian RK. A link between cyclin A expression and adhesion-dependent cell cycle progression [published erratum appears in Science 1994 Jan 28; 263(5146):455]. Science 1993; 262: 1572–5.Google Scholar
  54. 54.
    Guadagno TM, Assoian RK. G1/S control of anchorage-independent growth in the fibroblast cell cycle. J Cell Biol 1991; 115: 1419–25.PubMedCrossRefGoogle Scholar
  55. 55.
    Han EK, Guadagno TM, Dalton SL, Assoian RK. A cell cycle and mutational analysis of anchorage-independent growth: cell adhesion and TGF-beta 1 control G1/S transit specifically. J Cell Biol 1993; 122: 461–71.PubMedCrossRefGoogle Scholar
  56. 56.
    Barrett JF, Lewis BC, Hoang AT, Alvarez JRJ, Dang CV. Cyclin A links c-Myc to adhesion-independent cell proliferation. J Biol Chem 1995; 270: 15923–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Born TL, Frost JA, Schonthal A, Prendergast GC, Feramisco JR. C-myc cooperates with activated ras to induce the cdc2 promoter. Mol Cell Biol 1994; 14: 5710–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Kim YH, Buchholz MA, Chrest FJ, Nordin AA. Up-regulation of c-myc induces the gene expression of the murine homologues of p34(cdc2) and cyclin-dependent kinase-2 in T lymphocytes. J Immun 1994; 152: 4328–35.PubMedGoogle Scholar
  59. 59.
    Reisman D, Elkind N, Roy B, Beamon J, Rotter V. c-Myc trans-activate the p53 promoter through a required downstream CACGTG motif. Cell Growth Differ 1993; 4: 57–65.PubMedGoogle Scholar
  60. 60.
    Roy B, Beamon J, Balint E, Reisman D. Transactivation of the human p53 tumor suppressor gene by c-Myc/Max contributes to elevated mutant p53 expression in some tumors. Mol Cell Biol 1994; 14: 7805–15.PubMedGoogle Scholar
  61. 61.
    Rosenwald IB, Rhoads DB, Callanan LD, Isselbacher KJ, Schmidt EV. Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2 alpha in response to growth induction by c-myc. Proc Natl Acad Sci USA 1993; 90: 6175–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Blackwell TK, Huang J, Ma A, et al. Binding of myc proteins to canonical and noncanonical DNA sequences. Mol Cell Biol 1993; 13: 5216–24.PubMedGoogle Scholar
  63. 63.
    Chau CM, Evans MJ, Scarpulla RC. Nuclear respiratory factor 1 activation sites in genes encoding the gamma-subunit of ATP synthase, eukaryotic initiation factor 2 alpha, and tyrosine aminotransferase. Specific interaction of purified NRF-1 with multiple target genes. J Biol Chem 1992; 267: 6999–7006.PubMedGoogle Scholar
  64. 64.
    Virbasius CA, Virbasius JV, Scarpulla RC. NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators. Genes Dev 1993; 7: 2431–45.PubMedCrossRefGoogle Scholar
  65. 65.
    Virbasius JV, Scarpulla RC. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci USA 1994; 91: 1309–13.PubMedCrossRefGoogle Scholar
  66. 66.
    Takada S, Obinata M. Overexpression of c-Myc inhibits the appearance of a specific DNase I hypersensitive site in the beta-globin chromatin in murine erythroleukemia cells. Jpn J Cancer Res 1991; 82: 376–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Takada S, Yamamoto T, Ohmori Y, Matsui Y, Obinata M. c-Myc interferes with the commitment to differentiation of murine erythroleukemia cells at a reversible point. Jpn J Cancer Res 1992; 83: 61–5.PubMedCrossRefGoogle Scholar
  68. 68.
    Shoji W, Ohmori Y, Obinata M. c-Myc selectively regulates the latent period and erythroid-specific genes in murine erythroleukemia cell differentiation. Jpn J Cancer Res 1993; 84: 885–92.PubMedCrossRefGoogle Scholar
  69. 69.
    Bernards R, Dessain S, Weinberg R. N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma. Cell 1986; 47: 667–74.PubMedCrossRefGoogle Scholar
  70. 70.
    Lenardo M, Rustgi A, Schievella A, Bernards R. Suppression of MHC Class 1 gene expression by N-myc through enhancer inactivation. EMBO J 1989; 8: 3351–5.PubMedGoogle Scholar
  71. 71.
    van’t Veer LJ, Beijersbergen RL, Bernards R. N-myc suppresses major histocompatibility complex class I gene expression through down-regulation of the p50 subunit of NF-kappa B. EMBO J 1993; 12: 195–200.Google Scholar
  72. 72.
    Suen T-C, Hung M-C. c-myc reverses neu-induced transformation morphology by transcriptional repression. Mol Cell Biol 1991; 11: 354–62.PubMedGoogle Scholar
  73. 73.
    Inghirami G, Grignani F, Sternas L, Lombardi L, Knowles DM, Dalla-Favera R. Down-regulation of LFA-1 adhesion receptors by C-myc oncogene in human B lymphoblastoid cells. Science 1990; 250: 682–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Penn LJ, Brooks MW, Laufer EM, Land H. Negative autoregulation of c-myc transcription. EMBO J 1990; 9: 1113–21.PubMedGoogle Scholar
  75. 75.
    Penn LJ, Brooks MW, Laufer EM et al. Domains of human c-myc protein required for autosuppression and cooperation with ras oncogenes are overlapping. Mol Cell Biol 1990; 10: 4961–6.PubMedGoogle Scholar
  76. 76.
    Roy AL, Carruthers C, Gutjahr T, Roeder RG. Direct role for Myc in transcription initiation mediated by interactions with TFII-I. Nature 1993; 365: 359–61.PubMedCrossRefGoogle Scholar
  77. 77.
    Smale ST, Baltimore D. The “initiator” as a transcription control element. Cell 1989; 57: 103–13.PubMedCrossRefGoogle Scholar
  78. 78.
    Li LH, Nerlov C, Prendergast G, MacGregor D, Ziff EB. c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II. EMBO J 1994; 13: 4070–9.PubMedGoogle Scholar
  79. 79.
    Mai S, Martensson IL. The c-myc protein represses the lambda 5 and TdT initiators. Nucleic Acids Res 1995; 23: 1–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Evan GI, Wyllie AH, Gilbert CS, et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992; 69: 119–28.PubMedCrossRefGoogle Scholar
  81. 81.
    Fanidi A, Harrington EA, Evan GI. Cooperative interaction between c-myc and bd-2 proto-oncogenes. Nature 1992; 359: 554–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Wagner AJ, Small MB, Hay N. Myc-mediated apoptosis is blocked by ectopic expression of Bd-2. Mol Cell Biol 1993; 13: 2432–40.PubMedGoogle Scholar
  83. 83.
    Bissonette R, Echeverri F, Mahboubi A, Green D. Apoptotic cell death induced by c-myc is inhibited by bc1–2. Nature 1992; 359: 552–4.CrossRefGoogle Scholar
  84. 84.
    Harrington EA, Bennett MR, Fanidi A, Evan GI. C-myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J 1994; 13: 3286–95.PubMedGoogle Scholar
  85. 85.
    Klefstrom J, Vastrik I, Saksela E, Valle J, Eilers M, Alitalo K. c-Myc induces cellular susceptibility to the cytotoxic action of TNF-alpha. EMBO J 1994; 13: 5442–50.PubMedGoogle Scholar
  86. 86.
    Janicke RU, Lee FH, Porter AG. Nuclear c-Myc plays an important role in the cytotoxicity of tumor necrosis factor alpha in tumor cells. Mol Cell Biol 1994; 14: 5661–70.PubMedCrossRefGoogle Scholar
  87. 87.
    Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science 1992; 257: 212–4.PubMedCrossRefGoogle Scholar
  88. 88.
    Bissonnette RP, McGahon A, Mahboubi A, Green DR. Functional Myc-Max heterodimer is required for activation-induced apoptosis in T cell hybridomas. J Exp Med 1994; 180: 2413–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Shi L, Nishioka WK, Th’ng J, Bradbury EM, Litchfield DW, Greenberg AH. Premature p34cdc2 activation required for apoptosis. Science 1994; 263: 1143–5.PubMedCrossRefGoogle Scholar
  90. 90.
    Wagner AJ, Kokontis JM, Hay N. Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21wafl/cipl. Genes Dev 1994; 8: 2817–30.PubMedCrossRefGoogle Scholar
  91. 91.
    Hermeking H, Eick D. Mediation of c-myc-induced apoptosis by p53. Science 1994; 265: 2091–3.PubMedCrossRefGoogle Scholar
  92. 92.
    Packham G, Cleveland JL. Ornithine decarboxylase is a mediator of c-myc-induced apoptosis. Mol Cell Biol 1994; 14: 5741–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • Chi V. Dang
    • 1
  • Linda A. Lee
    • 1
  1. 1.School of MedicineThe Johns Hopkins UniversityBaltimoreUSA

Personalised recommendations