Apoptosis pp 63-84 | Cite as

C-MYC: Oncogene and Tumour Suppressor Gene

  • Gerard Evan
  • Trevor Littlewood
  • David Hancock
  • Martin Bennett
  • Elizabeth Harrington
  • Abdallah Fanidi
Part of the Pezcoller Foundation Symposia book series (PFSO, volume 5)


Eukaryotic cell proliferation in metazoans is regulated by a variety of positive and negative signals that serve to rigidly control cell division. This underscores a major problem facing multicellular organisms: namely, how to allow the rapid proliferation of component cells and at the same time never allow those component cells to engage in competition with each other. In principle, any cell that acquires a growth advantage through mutation should out-compete its siblings and generate a hyperplastic clone from which ever more rapidly proliferating mutants are likely to arise. Such an event is, however, extremely rare as demonstrated by the fact that cancer arises in only one in three individuals during the entire course of their lives. Part of the answer to this paradox appears to reside in the multifunctional nature of the components that mediate cell proliferation. One of these, c-Myc, is the subject of this paper.


Sister Cell Early Growth Response Gene Primary Vascular Smooth Muscle Cell Eukaryotic Cell Proliferation 
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.


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  1. 1.
    C.A. Spencer and M. Groudine, Control of c-myc regulation in normal and neoplastic cells. Adv Cancer Res. 56: 1–48 (1991)PubMedCrossRefGoogle Scholar
  2. 2.
    G. Evan and T. Littlewood, The role of c-myc in cell growth. Curr. Opin. Genet. & Dev. 3:44–49(1993)CrossRefGoogle Scholar
  3. 3.
    J.M. Almendral, D. Sommer, H. MacDonald-Bravo, J. Burckhardt, J. Perera and R. Bravo, Complexity of the early genetic response to growth factors in mouse fibroblasts. Mol Cell Biol. 8: 2140–2148 (1988)PubMedGoogle Scholar
  4. 4.
    K. Kelly, B.H. Cochran, C.D. Stiles and P. Leder, Cell specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell. 35: 603–610 (1983)PubMedCrossRefGoogle Scholar
  5. 5.
    H. Persson, L. Hennighausen, R. Taub, W. DeGrado and P. Leder, Antibodies to human c-myc oncogene product: evidence of an evolutionarily conserved protein induced during cell proliferation. Science. 225: 687–693 (1984)PubMedCrossRefGoogle Scholar
  6. 6.
    G. Ramsay, G.I. Evan and J.M. Bishop, The protein encoded by the human protooncogene c-myc. Proc. Natl Acad. Sci. USA. 81: 7742–7746 (1984)PubMedCrossRefGoogle Scholar
  7. 7.
    S.R. Hann and R.N. Eisenman, Proteins encoded by the human c-myc oncogene: differential expression in neoplastic cells. Mol. Cell. Biol. 4: 2486–2497 (1984)PubMedGoogle Scholar
  8. 8.
    G.I. Evan and D.C. Hancock, Studies on the interaction of the human c-myc protein with cell nuclei: p62c-myc as a member of a discrete subset of nuclear proteins. Cell. 43: 253–261 (1985)PubMedCrossRefGoogle Scholar
  9. 9.
    E.M. Blackwood and R.N. Eisenman, Max. a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science. 251: 1211–7 (1991)PubMedCrossRefGoogle Scholar
  10. 10.
    T.K. Blackwell, L. Kretzner, E.M. Blackwood, R.N. Eisenman and H. Weintraub, Sequence-specific DNA binding by the c-Myc protein. Science. 250: 1149–51 (1990)PubMedCrossRefGoogle Scholar
  11. 11.
    G.C. Prendergast, D. Lawe and E.B. Ziff, Association of Myn, the murine homolog of max, with c-Myc stimulates methylation-sensitive DNA binding and ras cotransformation. Cell. 65: 395–407 (1991)PubMedCrossRefGoogle Scholar
  12. 12.
    G.C. Prendergast and E.B. Ziff, Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science. 251: 186–9 (1991)PubMedCrossRefGoogle Scholar
  13. 13.
    T. Littlewood, B. Amati, H. Land and G. Evan, Max and c-Myc/Max DNA binding activities in cell extracts. Oncogene. 7: 1783–1792 (1992)PubMedGoogle Scholar
  14. 14.
    E.M. Blackwood, B. Luscher and R.N. Eisenman, Myc and Max associate in vivo. Genes Dev. 6: 71–80(1992)CrossRefGoogle Scholar
  15. 15.
    B. Amati, S. Dalton, M. Brooks, T. Littlewood, G. Evan and H. Land, Transcriptional activation by c-Myc oncoprotein in yeast requires interaction with Max. Nature. 359: 423–426(1992)PubMedCrossRefGoogle Scholar
  16. 16.
    L. Kretzner, E. Blackwood and R. Eisenman, Myc and Max possess distinct transcriptional activities. Nature. 359: 426–429 (1992)PubMedCrossRefGoogle Scholar
  17. 17.
    B. Amati, M. Brooks, N. Levy, T. Littlewood, G. Evan and H. Land, Oncogenic activity of the c-Myc protein requires dimerisation with Max. Cell. 72: 233–245 (1993)PubMedCrossRefGoogle Scholar
  18. 18.
    G.J. Kato, J. Barrett, G.M. Villa and C.V. Dang, An amino-terminal c-myc domain required for neoplastic transformation activates transcription. Mol Cell Biol. 10: 5914–20 (1990)PubMedGoogle Scholar
  19. 19.
    G.J. Kato, W.M. Lee, L.L. Chen and C.V. Dang, Max. functional domains and interaction with c-Myc. Genes Dev. 6: 81–92 (1992)PubMedCrossRefGoogle Scholar
  20. 20.
    J.P. Moore, D.C. Hancock, T.D. Littlewood and G.I. Evan, A sensitive and quantitative enzyme-linked immunosorbence assay for the c-myc and N-myc oncoproteins. Oncogene Res. 2: 65–80(1987)PubMedGoogle Scholar
  21. 21.
    C.B. Thompson, P.B. Challoner, P.E. Neiman and M. Groudine, Levels of c-myc oncogene mRNA are invariant throughout the cell cycle. Nature. 314: 363–366 (1985)PubMedCrossRefGoogle Scholar
  22. 22.
    C. Waters, T. Littlewood, D. Hancock, J. Moore and G. Evan, c-myc protein expression in untransformed fibroblasts. Oncogene. 6: 101–109 (1991)Google Scholar
  23. 23.
    S.R. Hann, C.B. Thompson and R.N. Eisenman, C-myc oncogene protein synthesis is independent of the cell cycle in human and avian cells. Nature. 314: 366–369 (1985)PubMedCrossRefGoogle Scholar
  24. 24.
    M. Dean, R.A. Levine, W. Ran, M.S. Kindy, G.E. Sonenshein and J. Campisi, Regulation of c-myc transcription and mRNA abundance by serum growth factors and cell contact. J. Biol. Chem. 261: 9161–6 (1986)PubMedGoogle Scholar
  25. 25.
    A.B. Pardee, Gl events and regulation of cell proliferation. Science. 246: 603–608 (1989)PubMedCrossRefGoogle Scholar
  26. 26.
    G. Evan, A. Wyllie, C. Gilbert, T. Littlewood, H. Land, M. Brooks, C. Waters, L. Penn and D. Hancock, Induction of apoptosis in fibroblasts by c-myc protein. Cell. 63: 119–125(1992)CrossRefGoogle Scholar
  27. 27.
    M. Eilers, D. Picard, K.R. Yamamoto and M.J. Bishop, Chimaeras of Myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells. Nature. 340: 66–68(1989)PubMedCrossRefGoogle Scholar
  28. 28.
    M. Eilers, S. Schirm and J M. Bishop, The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J. 10: 133–41 (1991)PubMedGoogle Scholar
  29. 29.
    J. Stone, T. de Lange, G. Ramsay, E. Jakobvits, J.M. Bishop, H. Varmus and W. Lee, Definition of regions in human c-myc that are involved in transformation and nuclear localization. Mol. Cell Biol. 7: 1697–1709 (1987)PubMedGoogle Scholar
  30. 30.
    B. Amati, T. Littlewood, G. Evan and H. Land, The c-Myc protein induces cell cycle progression and apoptosis through dimerisation with Max. Submitted. (1993)Google Scholar
  31. 31.
    V. Quarmby, W. Beekman, E. Wilson and F. French, Androgen regulation of c-myc messenger ribonucleic acid levels in rat ventral prostate. Mol Endocrinol. 1: 865–874 (1987)PubMedCrossRefGoogle Scholar
  32. 32.
    R. Buttyan, Z. Zakeri, R. Lockshin and D. Wolgemuth, Cascade induction of c-fos, c-myc, and heat shock 70K transcripts during regression of the rat ventral prostate gland. Mol Endocrinol. 2: 650–7 (1988)PubMedCrossRefGoogle Scholar
  33. 33.
    N. Kyprianou, H.F. English, N.E. Davidson and J.T. Isaacs, Programmed cell death during regression of the MCF-7 human breast cancer following estrogen ablation. Cancer Res. 51: 162–6(1991)Google Scholar
  34. 34.
    J.S. Riegel, E.R. Richie and J.P. Allison, Nuclear events after activation of CD4+8+ thymocytes. J Immunol. 144: 3611–8 (1990)PubMedGoogle Scholar
  35. 35.
    Y. Shi, J. Glynn, L. Guilbert, T. Cotter, R. Bissonette and D. Green, Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science. 257: 212–214 (1992)PubMedCrossRefGoogle Scholar
  36. 36.
    J. Cohen, Overview: Mechanisms of apoptosis. Immunol Today. 14: 126–130 (1993)PubMedCrossRefGoogle Scholar
  37. 37.
    N. Touchette, Dying cells reveal new role for cancer genes. J. NIH Research. 4: 48–52 (1992)Google Scholar
  38. 38.
    R. Baserga, The double life of the IGF-1 receptor. Receptor. 2: 261–6 (1992)PubMedGoogle Scholar
  39. 39.
    A. Fanidi, E. Harrington and G. Evan, Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature. 359: 554–556 (1992)PubMedCrossRefGoogle Scholar
  40. 40.
    A. Strasser, A.W. Harris, ML. Bath and S. Cory, Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature. 348: 331–3 (1990)CrossRefGoogle Scholar
  41. 41.
    G. Klein, Comparative action of myc and bcl-2 in B-cell malignancy. Cancer Cells. 3: 141–3(1991)PubMedGoogle Scholar
  42. 42.
    T.J. McDonnell, N. Deane, FM. Platt, G. Nunez, U. Jaeger, J P. McKearn and S.J. Korsmeyer, bcl -2 -immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 57: 79–88 (1989)PubMedCrossRefGoogle Scholar
  43. 43.
    G. Nunez, L. London, D. Hockenbery, M. Alexander, J.P. McKearn and S.J. Korsmeyer, Deregulated bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 144: 3602–10 (1990)PubMedGoogle Scholar
  44. 44.
    D.L. Vaux, S. Cory and J.M. Adams, bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 335: 440–2 (1988)PubMedCrossRefGoogle Scholar
  45. 45.
    D. Hockenbery, G. Nunez, C. Milliman, R.D. Schreiber and S.J. Korsmeyer, Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 348: 334–336(1990)PubMedCrossRefGoogle Scholar
  46. 46.
    C.L. Sentman, J.R. Shutter, D. Hockenbery, O. Kanagawa and S.J. Korsmeyer, bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 67: 879–88(1991)PubMedCrossRefGoogle Scholar
  47. 47.
    A. Strasser, A.W. Harris and S. Cory, bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 67: 889–99 (1991)PubMedCrossRefGoogle Scholar
  48. 48.
    R. Bissonnette, F. Echeverri, A. Mahboubi and D. Green. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature. 359: 552–554 (1992)PubMedCrossRefGoogle Scholar
  49. 49.
    A.J. Wagner, M.B. Small and N. Hay, Myc-mediated apoptosis is blocked by ectopic expression of bcl-2. Mol Cell Biol 13: 2432–2440 (1993)PubMedGoogle Scholar
  50. 50.
    T. Miyashita and J.C. Reed, bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res. 52: 5407–11 (1992)PubMedGoogle Scholar
  51. 51.
    J.C. Reed, S. Haldar, C.M. Croce and M.P. Cuddy, Complementation by BCL2 and C-HA-RAS oncogenes in malignant transformation of rat embryo fibroblasts. Mol Cell Biol. 10:4370–4(1990)PubMedGoogle Scholar
  52. 52.
    M. van Lohuizen, S. Verbeek, B. Scheijen, E. Wientjens, H. van der Gulden and A. Berns, Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell. 65: 737–52 (1991)PubMedCrossRefGoogle Scholar
  53. 53.
    M. van Lohuizen, M. Frasch, E. Wientjens and A. Berns, Sequence similarity between the mammalian bmi-1 proto-oncogene and the Drosophila regulatory genes Psc and Su(z)2. Nature. 353: 353–5 (1991)PubMedCrossRefGoogle Scholar
  54. 54.
    Y. Haupt, W.S. Alexander, G. Barri, S.P. Klinken and J.M. Adams, Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell. 65: 753–63 (1991)PubMedCrossRefGoogle Scholar
  55. 55.
    S. Verbeek, M. van Lohuizen, M. van der Valk, J. Domen, G Kraal and A. Berns, Mice bearing the E mu-myc and E mu-pim- 1 transgenes develop pre-B-cell leukemia prenatally. Mol Cell Biol. 11:1176–9 (1991)PubMedGoogle Scholar
  56. 56.
    J.M. Adams and S. Cory, Transgenic models for haemopoietic malignancies. Biochim Biophys Acta. 1072: 9–31 (1991)PubMedGoogle Scholar
  57. 57.
    M.C. Raff, Social controls on cell survival and cell death. Nature. 356: 397–400 (1992)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Gerard Evan
    • 1
  • Trevor Littlewood
    • 1
  • David Hancock
    • 1
  • Martin Bennett
    • 1
  • Elizabeth Harrington
    • 1
  • Abdallah Fanidi
    • 1
  1. 1.Biochemistry of the Cell Nucleus LaboratoryImperial Cancer Research FundLondonUK

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