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Role of oncogenic transcription factor c-Myc in cell cycle regulation, apoptosis and metabolism

Abstract

Themyc gene was initially discovered as a prototypical retrovirally transduced oncogene. Over the decades, abundant evidence has emerged to support a causal role for the activated cellular gene, c-myc, in animal and human tumors. The gene encodes an oncogenic helix-loop-helix leucine zipper transcription factor that acts as a heterodimer with its partner protein, Max, to activate genes regulating the cell cycle machinery as well as critical metabolic enzymes. The additional ability of c-Myc to repress transcription of differentiation-related genes suggest that c-Myc is a central and key molecular integrator of cell proliferation, differentiation and metabolism.

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References

  1. 1

    Adams JM, Cory S. Transgenic models of tumor development. Science 254:1161–1167;1991.

  2. 2

    Alarcon RM, Rupnow BA, Graeber TG, Knox SJ, Giaccia AJ. Modulation of c-Myc activity and apoptosis in vivo. Cancer Res 56:4315–4319;1996.

  3. 3

    Albarosa R, DiDonato S, Finocchiaro G. Redefinition of the coding sequence of the MXI1 gene and identification of a polymorphic repeat in the 3' non-coding region that allows the detection of loss of heterozygosity of chromosome 10q25 in glioblastomas. Hum Genet 95:709–711;1995.

  4. 4

    Alland L, Muhle R, Hou H Jr, Potes J, Chin L, Schreiber-Agus N, DePinho RA. Role for N-CoR and histone deacetylase in Sin 3-mediated transcriptional repression. Nature 387:49–55;1997.

  5. 5

    Amati B, Dalton S, Brooks MW, Littlewood TD, Evan GI, Land H. Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max. Nature 359:423–426;1992.

  6. 6

    Amin C, Wagner AJ, Hay N. Sequence-specific transcriptional activation by Myc and repression by Max. Mol Cell Biol 13:383–390;1993.

  7. 7

    Askew DS, Ashmun RA, Simmons BC, Cleveland JL. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene 6:1915–1922;1991.

  8. 8

    Augenlicht LH, Wadler S, Corner G, Richards C, Ryan L, Multani AS, Pathak S, Benson A, Haller D, Heerdt BG. Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: A frequent, p53-independent mutation associated with improved outcome in a randomized multi-institutional trial. Cancer Res 57:1769–1775;1997.

  9. 9

    Ayer DE, Kretzner L, Eisenman RN. Mad: A heterodimeric partner for Max that antagonizes Myc transcriptional activity. Cell 72:211–222;1993.

  10. 10

    Ayer DE, Lawrence QA, Eisenman RN. Mad-Max transcriptional expression repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell 80:767–776;1995.

  11. 11

    Bartsch D, Peiffer SL, Kaleem Z, Wells S Jr, Goodfellow PJ. Mxi1 tumor suppressor gene is not mutated in primary pancreatic adenocarcinoma. Cancer Lett 102:73–76;1996.

  12. 12

    Battey J, Moulding C, Taub R, Murphy W, Stewart T, Potter H, Lenoir G, Leder P. The human c-myc oncogene: Structural consequences of translocation into the IgH locus in Burkitt lymphoma. Cell 34:779–787;1983.

  13. 13

    Beckmann H, Su LK, Kadesch T. TFE3: A helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev 4:167–179;1990.

  14. 14

    Bello-Fernandez C, Packham G, Cleveland JL. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc Natl Acad Sci USA 90:7804–7808;1993.

  15. 15

    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 6:2513–2523;1992.

  16. 16

    Berberich SJ, Cole MD. Casein kinase II inhibits the DNA-binding activity of Max homodimers but not Myc/Max heterodimers. Genes Dev 6:166–176;1992.

  17. 17

    Bhatia K, Huppi K, Spangler G, Siwarski D, Iyer R, Magrath I. Point mutations in the c-Myc transactivation domain are common in Burkitt's lymphoma and mouse plasmacytoma. Nature Genet 5:56–61;1993.

  18. 18

    Bhatia K, Spangler G, Gaidano G, Hamdy N, Dalla-Favera R, Magrath I. Mutations in the coding region of c-myc occur frequently in acquired immunodeficiency syndrome-associated lymphomas. Blood 84:883–888;1994.

  19. 19

    Bishop JM. Retroviruses and cancer genes. Adv Cancer Res 37:1–32;1982.

  20. 20

    Bissonette R, Echeverri F, Mahboubi A, Green D. Apoptotic cell death induced by c-myc is inhibited bybcl-2. Nature 359:552–554;1992.

  21. 21

    Bister K, Jansen HW. Oncogenes in retroviruses and cells: Biochemistry and molecular genetics. Adv Cancer Res 47:99–188;1986.

  22. 22

    Blackwell TK, Huang J, Ma A, Kretzner L, Alt FW, Eisenman RN, Weintraub H. Binding of myc proteins to canonical and noncanonical DNA sequences. Mol Cell Biol 13:5216–5224;1993.

  23. 23

    Blackwell TK, Kretzner L, Blackwood EM, Eisenman RN, Weintraub H. Sequence-specific DNA binding by the c-Myc protein. Science 250:1149–1151;1990.

  24. 24

    Blackwood EM, Eisenman RN. Max: A helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 251:1211–1217;1991.

  25. 25

    Blackwood EM, Kretzner L, Eisenman RN. Myc and Max function as a nucleoprotein complex. Curr Opin Genet Dev 2:227–235;1992.

  26. 26

    Born TL, Frost JA, Schonthal A, Prendergast GC, Feramisco JR. C-myc cooperates with activated ras to induce the cdc2 promoter. Mol Cell Biol 14:5710–5718;1994.

  27. 27

    Chou TY, Dang CV, Hart GW. Glycosylation of the c-Myc transactivation domain. Proc Natl Acad Sci USA 92:4417–4421;1995.

  28. 28

    Chou TY, Hart GW, Dang CV. c-Myc is glycosylated at threonine-58, a known phosphorylation site and a mutational hot spot in lymphomas. J Biol Chem 270:18961–18965;1995.

  29. 29

    Clark HM, Yano T, Otsuki T, Jaffe ES, Shibata D, Raffeld M. Mutations in the coding region of c-myc in AIDS-associated and other aggressive lymphomas. Cancer Res 54:3383–3386;1994.

  30. 30

    Cole MD. The myc oncogene: Its role in transformation and differentiation. Ann Rev Genet 20:361–384;1986.

  31. 31

    Daksis JI, Lu RY, Facchini LM, Marhin WW, Penn LJ. Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene 9:3635–3645;1994.

  32. 32

    Dalla-Favera R, Gelmann EP, Martinotti S, Franchini G, Papas TS, Gallo RC, Wong-Staal F. Cloning and characterization of different human sequences related to the one gene (v-myc) of avian myelocytomatosis virus (MC29). Proc Natl Acad Sci USA 79:6497–6501;1982.

  33. 33

    Dang CV, Dolde C, Gillison ML, Kato GJ. Discrimination between related DNA sites by a single amino acid residue of Myc-related basic-helix-loop-helix proteins. Proc Natl Acad Sci USA 89:599–602;1992.

  34. 34

    Dang CV, Lee LA. c-Myc function in neoplasia. Austin, Landes, 1995.

  35. 35

    Davis AC, Wims M, Spotts GD, Hann SR, Bradley A. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev 7:671–682;1993.

  36. 36

    Dong QP, Blatter EE, Ebright YW, Bister K, Ebright RH. Identification of amino acid-base contacts in the Myc-DNA complex by site-specific bromouracil mediated photocrosslinking. EMBO J 13:200–204;1994.

  37. 37

    Eagle LR, Yin X, Brothman AR, Williams BJ, Atkin NB, Prochownik EV. Mutation of the MXI1 gene in prostate cancer. Nat Genet 9:249–255;1995.

  38. 38

    Edelhoff S, Ayer DE, Zervos AS, Steingrimsson E, Jenkins NA, Copeland NG, Eisenman RN, Brent R, Disteche CM. 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 9:665–668;1994.

  39. 39

    Eilers M, Schirm S, Bishop JM. The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J 10:133–141;1991.

  40. 40

    Erisman MD, Rothberg PG, Diehl RE, Morse CC, Spandorfer JM, Astrin SM. Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol Cell Biol 5:1969–1976;1985.

  41. 41

    Escot C, Theillet C, Lidereau R, Spyratos F, Champeme MH, Gest J, Callahan R. Genetic alteration of the c-myc protooncogene (MYC) in human primary breast carcinomas. Proc Natl Acad Sci USA 83:4834–4838;1986.

  42. 42

    Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC. Induction of apoptosis in fibroblasts by c-myc protein. Cell 69:119–128;1992.

  43. 43

    Fanidi A, Harrington EA, Evan GI. Cooperative interaction between c-myc and bcl-2 protooncogenes. Nature 359:554–556;1992.

  44. 44

    Ferre-D'Amare AR, Pognonec P, Roeder RG, Burley SK. Structure and function of the b/HLH/Z domain of USF. EMBO J 13:180–189;1994.

  45. 45

    Ferre-D'Amare AR, Prendergast GC, Ziff EB, Burley SK. Recognition by Max of its cognate DNA through a dimeric b/HLH/Z domain. Nature 363:38–45;1993.

  46. 46

    Firth JD, Ebert BL, Ratcliffe PJ. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem 270:21021–21027.

  47. 47

    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 5:2342–2352;1991.

  48. 48

    Fisher F, Jayaraman PS, Goding CR. C-myc and the yeast transcription factor PHO4 share a common CACGTG-binding motif. Oncogene 6:1099–1104;1991.

  49. 49

    Galaktionov K, Chen X, Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 382:511–517;1996.

  50. 50

    Grandori C, Mac J, Siebelt F, Ayer DE, Eisenman RN. Myc-Max heterodimers activate a DEAD box gene and interact with multiple E box-related sites in vivo. EMBO J 15:4344–4357;1996.

  51. 51

    Gray IC, Phillips SM, Lee SJ, Neoptolemos JP, Weissenbach J, Spurr NK. Loss of the chromosomal region 10q23-25 in prostate cancer. Cancer Res 55:4800–4803;1995.

  52. 52

    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 4:1730–1740;1990.

  53. 53

    Gu WK, Bhatia K, Magrath IT, Dang CV, Dalla-Favera R. Binding and suppression of the Myc transcriptional activation domain by p107. Science 264:251–254;1994.

  54. 54

    Gu W, Cechova K, Tassi V, Dalla-Favera R. Opposite regulation of gene transcription and cell proliferation by c-Myc and Max. Proc Natl Acad Sci USA 90:2935–2939;1993.

  55. 55

    Hann SR, Dixit M, Sears RC, Sealy L. The alternatively initiated c-Myc proteins differentially regulate transcription through a noncanonical DNA-binding site. Genes Dev 8:2441–2452;1994.

  56. 56

    Hann SR, Sloan-Brown K, Spotts GD. Translational activation of the non-AUG-initiated c-myc 1 protein at high cell densities due to methionine deprivation. Genes Dev 6:1229–1240;1992.

  57. 57

    Hanson KD, Shichiri M, Follansbee MR, Sedivy JM. Effects of c-myc expression on cell cycle progression. Mol Cell Biol 14:5748–5755;1994.

  58. 58

    Harper SE, Qiu Y, Sharp PA. Sin3 corepressor function in Myc-induced transcription and transformation. Proc Natl Acad Sci USA 93:8536–8540;1996.

  59. 59

    Hayward WS, Neel BG, Astrin SM. Activation of a cellular one gene by promoter insertion in ALV-induced lymphoid leukosis. Nature 290:475–480;1981.

  60. 60

    Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387:43–48;1997.

  61. 61

    Hermeking H, Eick D. Mediation of c-myc-induced apoptosis by p53. Science 265:2091–2093;1994.

  62. 62

    Hoang AT, Cohen KJ, Barrett JF, Bergstrom DA, Dang CV. Participation of cyclin A in Myc-induced apoptosis. Proc Natl Acad Sci USA 91:6875–6879;1994.

  63. 63

    Hoang AT, Lutterbach B, Lewis BC, Yano T, Chou TY, Barrett JF, Raffeld M, Hann SR, Dang CV. A link between increased transforming activity of lymphoma-derived MYC mutant alleles, their defective regulation by p107, and altered phosphorylation of the c-Myc transactivation domain. Mol Cell Biol 15:4031–4042;1995.

  64. 64

    Hurlin PJ, Foley KP, Ayer DE, Eisenman RN, Hanahan D, Arbeit JM. Regulation of Myc and Mad during epidermal differentiation and HPV-associated tumorigenesis. Oncogene 11:2487–2501;1995.

  65. 65

    Hurlin PJ, Queva C, Eisenman RN. Mnt, a novel Max-interacting protein is coexpressed with Myc in proliferating cells and mediates repression at Myc binding sites. Genes Dev 11:44–58;1997.

  66. 66

    Hurlin PJ, Queva C, Koskinen PJ, Steingrimsson E, Ayer DE, Copeland NG, Jenkins NA, Eisenman RN. Mad3 and Md4: Novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation. EMBO J 14:5646–5659;1995.

  67. 67

    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 250:682–686;1990.

  68. 68

    Jansen-Durr P, Meichle A, Steiner P, Pagano M, Finke D, Botz J, Wessbecher J, Draetta G, Eilers M. Differential modulation of cyclin gene expression by MYC. Proc Natl Acad Sci USA 90:3685–3689;1993.

  69. 69

    Jones RM, Branda J, Johnston KA, Polymenis M, Gadd M, Rustgi A, Callanan L, Schmidt EV. An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc. Mol Cell Biol 16:4754–4764;1996.

  70. 70

    Kato GJ, Barrett J, Villa-Garcia M, Dang CV. An amino-terminal c-myc domain required for neoplastic transformation activates transcription. Mol Cell Biol 10:5914–5920;1990.

  71. 71

    Kato GJ, Lee WM, Chen LL, Dang CV. Max: Functional domains and interaction with c-Myc. Genes Dev 6:81–92;1992.

  72. 72

    Kawamata N, Park D, Wilczynski S, Yokota J, Koeffler HP. Point mutations of the Mxil gene are rare in prostate cancers. Prostate 29:191–193;1996.

  73. 73

    Koskinen PJ, Vastrik I, Makela TP, Eisenman RN, Alitalo K. Max activity is affected by phosphorylation at two NH2-terminal sites. Cell Growth Differ 5:313–320;1994.

  74. 74

    Kretzner L, Blackwood EM, Eisenman RN. Myc and Max proteins possess distinct transcriptional activities. Nature 359:426–429;1992.

  75. 75

    Lee LA, Dolde C, Barrett J, Wu CS, Dang CV. A link between c-Myc-mediated transcriptional repression and neoplastic transformation. J Clin Invest 97:1687–1695;1996.

  76. 76

    Lee LA, Resar LM, Dang CV. Cell density and paradoxical transcriptional properties of c-Myc and Max in cultured mouse fibroblasts. J Clin Invest 95:900–904;1995.

  77. 77

    Leone G, DeGregori J, Sears R, Jakoi L, Nevins JR. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature 387:422–426;1997.

  78. 78

    Lewis BC, Shim H, Li Q, Wu CS, Lee LA, Maity A, Dang CV. Identification of putative c-Myc-responsive genes: Characterization of rel, a novel growth-related gene. Mol Cell Biol 17:4967–4978;1997.

  79. 79

    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella C, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947;1997.

  80. 80

    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 13:4070–4079;1994.

  81. 81

    Little CD, Nau MM, Carney DN, Gazdar AF, Minna JD. Amplication and expression of the c-myc oncogene in human lung cancer cell lines. Nature 306:194–196;1983.

  82. 82

    Littlewood TD, Amati B, Land H, Evan GI. Max and c-Myc/Max DNA-binding activities in cell extracts. Oncogene 7:1783–1792;1992.

  83. 83

    Liu Z, Thompson KS, Towle HC. Carbohydrate regulation of the rat L-type pyruvate kinase gene requires two nuclear factors: LF-A1 and a member of the c-myc family. J Biol Chem 268:12787–12795;1993.

  84. 84

    Luscher B, Eisenman RN. Mitosis-specific phosphorylation of the nuclear oncoproteins Myc and Myb. J Cell Biol 118:775–784;1992.

  85. 85

    Luscher B, Kuenzel EA, Krebs EG, Eisenman RN. Myc oncoproteins are phosphorylated by casein kinase II. EMBO J 8:1111–1119;1989.

  86. 86

    Lutterbach B, Hann SR. Hierarchical phosphorylation at n-terminal transformation-sensitive sites in c-myc protein is regulated by mitogens and in mitosis. Mol Cell Biol 14:5510–5522;1994.

  87. 87

    Mai S, Fluri M, Siwarski D, Huppi K. Genomic instability in MycER-activated Rat1A-MycER cells. Chromosome Res 4:365–371;1996.

  88. 88

    Mai S, Hanley-Hyde J, Fluri M. c-Myc overex-pression associated DHFR gene amplification in hamster, rat, mouse and human cell lines. Oncogene 12:277–288;1996.

  89. 89

    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 22:2264–2273;1994.

  90. 90

    Mai S, Martensson IL. The c-myc protein represses the lambda 5 and TdT initiators. Nucleic Acids Res 23:1–9;1995.

  91. 91

    Marcu K, Bossone S, Patel A. Myc function and regulation. Annu Rev Biochem 61:809–860;1992.

  92. 92

    Marhin WW, Chen S, Facchini LM, Fornace J, Penn AJ, Penn LZ. Myc represses the growth arrest gene gadd45. Oncogene 14:2825–2834;1997.

  93. 93

    Mariani-Costantini R, Escot C, Theillet C, Gentile A, Merlo G, Lidereau R, Callahan R. In situ c-myc expression and genomic status of the c-myc locus in infiltrating ductal carcinomas of the breast. Cancer Res 48:199–205;1988.

  94. 94

    Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells. Isolation, sequence, and activity of the promoter for type II hexokinase. J Biol Chem 270:16918–16925;1995.

  95. 95

    Miltenberger RJ, Sukow KA, Farnham PJ. An E-box-mediated increase incad transcription at the G1/S-phase boundary is suppressed by inhibitory c-Myc mutants. Mol Cell Biol 15:2527–2535;1995.

  96. 96

    Munzel P, Marx D, Kochel H, Schauer A, Bock KW. Genomic alterations of the c-myc protooncogene in relation to the overexpression of c-erbB2 and Ki-67 in human breast and cervix carcinomas. J Cancer Res Clin Oncol 117:603–607;1991.

  97. 97

    Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, Evans RM. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89:373–380;1997.

  98. 98

    Neel BG, Hayward WS, Robinson HL, Fang J, Astrin SM. Avian leukosis virus-induced tumors have common proviral integration sites and synthesize discrete new RNAs: Oncogenesis by promoter insertion. Cell 23:323–334;1981.

  99. 99

    Nozaki N, Naoe T, Okazaki T. Immunoaffinity purification and characterization of CACGTG sequence-binding proteins from cultured mammalian cells using an anti c-Myc monoclonal antibody recognizing the DNA-binding domain. J Biochem 121:550–559;1997.

  100. 100

    Packham G, Bellofernandez C, Cleveland JL. Position and orientation independent transactivation by c-Myc. Cell Mol Biol Res 40:699–706;1994.

  101. 101

    Packham G, Cleveland JL. Ornithine decarboxylase is a mediator of c-myc-induced apoptosis. Mol Cell Biol 14:5741–5747;1994.

  102. 102

    Pedersen PL. Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res 22:190–274;1978.

  103. 103

    Pena A, Reddy CD, Wu S, Hickok NJ, Reddy EP, Yumet G, Soprano DR, Soprano KJ. Regulation of human ornithine decarboxylase expression by the c-Myc. Max protein complex. J Biol Chem 268:27277–27285;1993.

  104. 104

    Perez-Roger I, Solomon DLC, Sewing A, Land H. Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27Kip1 binding to newly formed complexes. Oncogene 14:2373–2381;1997.

  105. 105

    Philipp A, Schneider A, Vasrik I, Finke K, Xiong Y, Beach D, Alitalo K, Eilers M. Repression of cyclin d1 — a novel function of myc. Mol Cell Biol 14:4032–4043;1994.

  106. 106

    Potter M, Wiener F. Plasmacytomagenesis in mice: Model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis 13:1681–1697;1992.

  107. 107

    Prendergast GC, Diamond LE, Dahl D, Cole MD. The c-myc-regulated gene mrl encodes plasminogen activator inhibitor 1. Mol Cell Biol 10:1265–1269;1990.

  108. 108

    Prendergast GC, Lawe D, Ziff EB. Association of Myn, the murine homolog of max, with c-Myc stimulates methylation-sensitive DNA binding and ras cotransformation. Cell 65:395–407;1991.

  109. 109

    Prendergast GC, Ziff EB. DNA-binding motif. Nature 341:392;1989.

  110. 110

    Prendergast GC, Ziff EB. Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science 251:186–189;1991.

  111. 111

    Ptashne M, Gann AF. Nature 346:329–331;1990.

  112. 112

    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 4:57–65;1993.

  113. 113

    Rempel A, Mathupala SP, Griffin CA, Hawkins AL, Pedersen PL. Glucose catabolism in cancer cells: Amplification of the gene encoding type II hexokinase. Cancer Res 56:2468–2471;1996.

  114. 114

    Rosenwald IB, Lazariskaratzas A, Sonenberg N, Schmidt EV. Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol Cell Biol 13:7358–7363;1993.

  115. 115

    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 90:6175–6178;1993.

  116. 116

    Roy AL, Carruthers C, Gutjahr T, Roeder RG. Direct role for Myc in transcription initiation mediated by interactions with TFII-I. Nature 365:359–361;1993.

  117. 117

    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 14:7805–7815;1994.

  118. 118

    Rudolph B, Saffrich R, Zwicker J, Henglein B, Muller R, Ansorge W, Eilers M. Activation of cyclin-dependent kinases by Myc mediates induction of cyclin A, but not apoptosis. EMBO J 15:3065–3076;1996.

  119. 119

    Schoenenberger CA, Andres AC, Groner B, van der Valk M, LeMeur M, Gerlinger P. Targeted c-myc gene expression in mammary glands of transgenic mice induces mammary tumours with constitutive milk protein gene transcription. EMBO J 7:169–175;1988.

  120. 120

    Schreiber-Agus N, Chin L, Chen K, Torres R, Rao G, Guida P, Skoultchi AI, DePinho RA. An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell 80:777–786;1995.

  121. 121

    Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:32529–2537;1996.

  122. 122

    Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269:23757–23763;1994.

  123. 123

    Shapiro DN, Valentine V, Eagle L, Yin X, Morris SW, Prochownik EV. Assignment of the human MAD and MXI1 genes to chromosomes 2p12-p13 and 10q24-q25. Genomics 23:282–285;1994.

  124. 124

    Sheiness D, Fanshier L, Bishop JM. Identification of nucleotide sequences which may encode the oncogenic capacity of avian retrovirus MC29. J Virol 28:600–610;1978.

  125. 125

    Shih HM, Liu Z, Towle HC. Two CACGTG motifs with proper spacing dictate the carbohydrate regulation of hepatic gene transcription. J Biol Chem 270:21991–21997;1995.

  126. 126

    Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, Dalla-Favera R, Dang CV. c-Myc transactivation of LDH-A: Implications for tumor metabolism and growth. Proc Natl Acad Sci USA 94:6658–6663;1997.

  127. 127

    Shimizu E, Shirasawa H, Kodama K, Sato T, Simizu B. Expression, regulation and polymorphism of the mxil genes. Gene 176:45–48;1996.

  128. 128

    Skoda RC, Tsai SF, Orkin SH, Leder P. Expression of c-MYC under the control of GATA-1 regulatory sequences causes erythroleukemia in transgenic mice. J Exp Med 181:1603–1613;1995.

  129. 129

    Smale ST, Baltimore D. The ‘initiator’ as a transcription control element. Cell 57:103–113;1989.

  130. 130

    Smith-Sorensen B, Hijmans EM, Beijersbergen RL, Bernards R. Functional analysis of Burkitt's lymphoma mutant c-Myc proteins. J Biol Chem 271:5513–5518;1996.

  131. 131

    Spotts GD, Patel SV, Xiao Q, Hann SR. Identification of downstream-initiated c-Myc proteins which are dominant-negative inhibitors of transactivation by full-length c-Myc proteins. Mol Cell Biol 17:1459–1468;1997.

  132. 132

    Tavtigian SV, Zabludoff SD, Wold BJ. Cloning of mid-G1 serum response genes and identification of a subset regulated by conditioned myc expression. Mol Biol Cell 5:375–388;1994.

  133. 133

    Tikhonenko AT, Black DJ, Linial ML. Viral Myc oncoproteins in infected fibroblasts down-modulate thrombospondin-1, a possible tumor suppressor gene. J Biol Chem 271:30741–30747;1996.

  134. 134

    Tsuneoka M, Nakano F, Ohgusu H, Mekada E. c-myc activates RCC1 gene expression through E-box elements. Oncogene 14:2301–2311;1997.

  135. 135

    Valera A, Pujol A, Gregori X, Riu E, Visa J, Bosch F. Evidence from transgenic mice that myc regulates hepatic glycolysis. FASEB J 9:1067–1078;1995.

  136. 136

    Van Antwerp ME, Chen DG, Chang C, Prochownik EV. A point mutation in the MyoD basic domain imparts c-Myc-like properties. Proc Natl Acad Sci USA 89:9010–9014;1992.

  137. 137

    Versteeg R, Noordermeer I, Kruse-Wolters M, Ruiter D, Schrier P. c-myc down-regulates class I HLA expression in human melanomas. EMBO J 7:1023–1029;1988.

  138. 138

    Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B. Growth arrest by the cyclin-dependent kinase inhibitor p27Kipl is abrogated by c-Myc. EMBO J 15:6595–6604;1996.

  139. 139

    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 p21 waf1/cip1. Genes Dev 8:2817–2830;1994.

  140. 140

    Wagner AJ, Meyers C, Laimins LA, Hay N. c-Myc induces the expression and activity of ornithine decarboxylase. Cell Growth Differ 4:879–883;1993.

  141. 141

    Wagner AJ, Small MB, Hay N. Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2. Mol Cell Biol 13:2432–2440;1993.

  142. 142

    Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514;1995.

  143. 143

    Warburg O. The Metabolism of Tumours. London, Constable, 1930.

  144. 144

    Warburg O. On the origin of cancer cells. Science 123:309–314;1956.

  145. 145

    Wechsler DS, Hawkins AL, Li X, Jabs EW, Griffin CA, Dang CV. Localization of the human Mxi1 transcription factor gene (MXI1) to chromosome 10q24-q25. Genomics 21:669–672;1994.

  146. 146

    Wechsler DS, Shelly CA, Dang CV. Genomic organization of human MXI1, a putative tumor suppressor gene. Genomics 32:466–470;1996.

  147. 147

    Wu S, Pena A, Korcz A, Soprano DR, Soprano KJ. Overexpression of Mxi1 inhibits the induction of human ornithine decarboxylase gene by the Myc/Max protein complex. Oncogene 12:621–629;1996.

  148. 148

    Yang BS, Geddes TJ, Pogulis RJ, de Crombrugghe B, Freytag SO. Transcriptional suppression of cellular gene expression by c-Myc. Mol Cell Biol 11:2291–2295;1991.

  149. 149

    Yang BS, Gilbert JD, Freytag SO. Overexpression of Myc suppresses CCAAT transcription factor/nuclear factor 1-dependent promoters in vivo. Mol Cell Biol 13:3093–3102;1993.

  150. 150

    Yano T, Sander C, Clark H, Dolezal M, Jaffe E, Raffeld M. Clustered mutations in the second exon of the MYC gene in sporadic Burkitt's lymphoma. Oncogene 8:2741–2748;1993.

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Dang, C.V., Lewis, B.C. Role of oncogenic transcription factor c-Myc in cell cycle regulation, apoptosis and metabolism. J Biomed Sci 4, 269–278 (1997). https://doi.org/10.1007/BF02258350

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Key Words

  • c-Myc
  • Oncogene
  • Transcription
  • Cancer
  • Metabolism
  • Apoptosis