Advertisement

c-Myc Dependent Initiation of Genomic Instability During Neoplastic Transformation

  • C. Taylor
  • A. Jalava
  • S. Mai
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 224)

Abstract

The dihydrofolate reductase (DHFR) gene is a target of c-Myc in genomic instability. The induced overexpression of c-Myc in cell lines is followed by the amplification and rearrangement of the DHFR gene. Furthermore, the constitutive upregulation of c-Myc protein coincides with genomic instability of the DHFR gene in lymphoid, non-lymphoid and in tumor lines. The amplification of the DHFR gene is locus-specific and independent of species origins. We have now addressed the question whether inducible deregulation of c-Myc is followed by DHFR gene amplification in vivo. We show that the DHFR gene is a target of c-Myc-dependent neoplasia in vivo and propose a role for genomic instability during the initiation of neoplastic transformation.

Keywords

Gene Amplification Genomic Instability Dihydrofolate Reductase DHFR Gene Normal Diploid Cell 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Santelli, R.V., Machado-Santelli, G.M., Pueyo, M.T., Navarro-Cattapan, L.D., and Lara, F.J.S. (1991). Replication and transcription in the course of DNA amplification of the C3 and C8 puffs of Rhynchosciara americana. Mech. Dev. 36: 59–66, 1991.Google Scholar
  2. 2.
    Delikadis, C. and Kafatos, F.C. (1989). Amplification enhancers and replication origins in the autosomal chorion cluster of Drosophila. The EMBO J. 8: 891–901.Google Scholar
  3. 3.
    Stark, G.R. and Wahl, G.M. (1984). Gene amplification. Ann. Rev. Biochem., 53, 447–491.PubMedCrossRefGoogle Scholar
  4. 4.
    Yokota, Y., Tsunetsugu-Yokota, Y., Battifora, C.L., and Cline, M.J. (1986). Alterations in myc, myb, ras Ha proto-oncogenes in cancers are frequent and show clinical correlation. Science 231:261–265.PubMedCrossRefGoogle Scholar
  5. 5.
    Mai, S., Hanley-Hyde, J., Fluri, M. (1996). c-Myc overexpression associated DHFR gene amplification in hamster, rat, mouse and human cell Unes. Oncogene 12: 277–288.PubMedGoogle Scholar
  6. 6.
    Mai, S., Fluri, M., Siwarski, D., Huppi, K. (1996). Genomic instability in MycER activated Rat1A-MycER cells. Chromosome Research 4: 365–372.PubMedCrossRefGoogle Scholar
  7. 7.
    Mai, S., Hanley-Hyde, J., Coleman, A., Siwarski, D., Huppi, K. (1995). Amplified extrachromosomal elements containing c-Myc and Pvt 1 in a mouse plasmacytoma. Genome 38: 780–85.PubMedCrossRefGoogle Scholar
  8. 8.
    Van Der Bliek, A. M., Van Der Velde-Koerts, T., Ling, V., Borst, P. (1986). Overexpression and amplification of five genes in a multidrug-resistant Chinese hamster ovary line. Mol. Cell. Biol. 6: 1671–1678.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Corvi, R., Amler, L. C, Savelyeva, L., Gehring, M., Schwab, M. (1994). MycN is retained in single copy at chromosome 2 band p23–23 during amplification in human neuroblastoma. Proc. Natl. Acad. Sci. (USA) 91: 5523–5527.CrossRefGoogle Scholar
  10. 10.
    Stark, G.R. (1993). Regulation and mechanisms of mammalian gene amplification. Adv. Cancer Res. 61: 87–113.CrossRefGoogle Scholar
  11. 11.
    Schimke, R.T., Kaufman, R.J., Alt, F.W., and Kellems, R.F. (1978). Gene amplification and drug resistance in cultured murine cells. Science 202: 1051–1055.PubMedCrossRefGoogle Scholar
  12. 12.
    Shah, D.M., Horsch, R.B., Klee, H.J., Kishore, G.M., Winter, J.A., Turner, N.E., Hironaka, C.M., Sanders, P.R., Gasser, C.S., Aykent, S., Siegel, N.R., Rogers, S.G., and Fraley, R.T. (1986). Engeneering herbicide tolerance in transgenic plants. Science 233: 478–481.PubMedCrossRefGoogle Scholar
  13. 13.
    Huang, A. and Wright, J.A. (1994). Fibroblast growth factor mediated alterations in drug resistance, and evidence of gene amplification. Oncogene 9: 491–499.PubMedGoogle Scholar
  14. 14.
    Huang, A., Jin, H., and Wright, J.A. (1994). Aberrant expression of basic fibroblast growth factor in NIH-3T3 cells alters drug resistance and gene amplification potential. Exp. Cell Res. 213: 335–339.PubMedCrossRefGoogle Scholar
  15. 15.
    Huang, A., Jin, H., and Wright, J.A. (1995). Drug resistance and gene amplification potential regulated by transforming growth factor-ß 1 gene expression. Cancer Res. 55: 1758–1762.PubMedGoogle Scholar
  16. 16.
    Lavi, S. (1981). Carcinogen-mediated amplification of viral DNA sequences in simian virus 40-transformed Chinese hamster embryo cells. Proc. Natl. Acad. Sci. (USA) 78: 6144–6148.CrossRefGoogle Scholar
  17. 17.
    Tlsty, T.D., Brown, P.E., and Schimke, R.T. (1984). UV radiation facilitates methotrexate resistance and amplification of the dihydrofolate reductase gene in cultured mouse cells. Mol. Cell.Biol. 4: 1050–1056.Google Scholar
  18. 18.
    Lücke-Huhle, C, Pech, M., and Herrlich, P. (1990). SV40 DNA amplification and reintegration in surviving hamster cells after 60 Co gamma-irradiation. Int. J. Radiat. Biol. 58: 577–588.PubMedCrossRefGoogle Scholar
  19. 19.
    Yalkinoglu, A.Ö., Zentgraf, H., and Hübscher, U. (1991). The origin of adeno-associated virus DNA replication is a target for carcinogen-induced DNA amplification. J. Virol. 65: 3175–3184.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Lücke-Huhle, C. (1989). Review: gene amplification — a cellular response to genotoxic stress. Mol. Toxicol. 2: 237–253.Google Scholar
  21. 21.
    Mai, S. (1994). Overexpression of c-myc precedes amplification of the gene encoding dihydrofolate reductase. Gene 148: 253–260.PubMedCrossRefGoogle Scholar
  22. 22.
    Denis, N., Kitzis, A., Kruh, J., Dautry, F., and Crocos, D. (1991). Stimulation of methotrexate resistance and dihydrofolate reductase gene amplification by c-myc. Oncogene 6: 1453–1457.PubMedGoogle Scholar
  23. 23.
    Johnston, R.N., Beverley, S.M., and Schimke, R.T. (1983). Rapid spontaneous dihydrofolate reductase gene amplification shown by fluorescence-activated cell sorting. Proc. Natl. Acad. Sci. (USA) 80: 3711–3715.CrossRefGoogle Scholar
  24. 24.
    Prody, CA., Dreyfus, P., Zamir, R., Zakut, H., and Soreq, H. (1989). De novo amplification within a “silent” human Cholinesterase gene in a family subjected to prolonged exposure to organophosphorus insecticides. Proc. Natl. Acad. Sci. (USA) 86: 690–694.CrossRefGoogle Scholar
  25. 25.
    Wright, J.A., Smith, H.S., Watt, F.M., Hancock, M.C., Hudson, D.L., and Stark, G.R. (1990). DNA amplification is rare in normal human cells. Proc. Natl. Acad. Sci. (USA) 87: 1791–1795.CrossRefGoogle Scholar
  26. 26.
    Tlsty, T.D. (1990). Normal diploid cells lack a detectable frquency of gene amplification. Proc. Natl. Acad. Sci. (USA) 87: 3132–3136, 1990.CrossRefGoogle Scholar
  27. 27.
    Yin, Y., Tainsky, M. A., Bischoff, F.Z., Strong, L. C, and Wahl, G. M. (1992). Wildtype p53 restores cell cycle control and inhibits gene amplifictaion in cells with mutant p53 alleles. Cell 70: 937–948.PubMedCrossRefGoogle Scholar
  28. 28.
    Livingstone, L. R., White, A., Sprouse, J., Livanos, E., Jacks, T., and Tlsty, T. D. (1992). Altered cell cycle arrest and gene amplification potential accompany loss of wildtype p53. Cell 70: 923–935.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhou, P., Jiang, W., Wegorst, C. M., and Weinstein, I. B. (1996). Overexpression of cyclin D1 enhances gene amplification. Cancer Research 56:36–39.PubMedGoogle Scholar
  30. 30.
    Marcu, K.B., Bossone, S.A., and Patel, A.J. (1992). Myc function and regulation. Ann. Rev. Biochem. 61: 809–860.PubMedCrossRefGoogle Scholar
  31. 31.
    Cole, M.D. (1986). The myc oncogene: its role in transformation and differentiation. Ann. Rev. Genet. 20: 361–384.PubMedCrossRefGoogle Scholar
  32. 32.
    Benevisty, N., Leder, A., Kuo, A., and Leder, P. (1992). An embryonically expressed gene is a target for c-Myc regulation via the c-Myc binding sequence. Genes Dev. 6: 2513–2523.CrossRefGoogle Scholar
  33. 33.
    Bello-Fernandez, C, Packham, G., and Cleveland, J.L. (1993). The ornithine decarboxylase is a transcriptional target of c-Myc. Proc. Natl. Acad. Sci. (USA) 90: 7804–7808.PubMedCentralCrossRefGoogle Scholar
  34. 34.
    Gaubatz, S., Meichle, A., and Eilers, M. (1994). An E-box element localized in the first intron mediates regulation of the prothymosin a gene by c-myc. Mol. Cell. Biol. 14: 3853–3862.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Jansen-Dürr, P., Meichle, A., Steiner, P., Pagano, M., Finke, K., Botz, J., Wessbecher, J., Draetta, G., and Eilers, M. (1993). Differential modulation of cyclin expression by MYC. Proc. Natl. Acad. Sci. (USA) 90: 3685–3689.CrossRefGoogle Scholar
  36. 36.
    Daksis, J.L, Lu, R.Y., Facchini, L.M., Marhin, W.W., and Penn, L.J.Z. (1994). Myc induces cyclin Dl expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene 9: 3635–3645, 1994.Google Scholar
  37. 37.
    Philipp, A., Schneider, A., Västrik, I., Finke, K., Xiong, Y., Beach, D., Alitalo, K., and Eilers, M. (1994). Repression fo cyclin D1: a novel function of MYC. Mol. Cell. Biol. 14: 4032–4043.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Galaktionov, K., Chen, X., and Beach, D. (1996). Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 382: 511–517.PubMedCrossRefGoogle Scholar
  39. 39.
    Roy, A.L., Carruthers, C., Gutjahr, T., and Roeder, R.G. (1993). Direct role for Myc in transcription initiation mediated by interactions with TFII-I. Nature 365: 359–361.PubMedCrossRefGoogle Scholar
  40. 40.
    Li, L.-h., Nerlov, C, Prendergast, G., MacGregor, D., and Ziff, E.B. (1994). c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II. The EMBO J. 13: 4070–4079.Google Scholar
  41. 41.
    Mai, S. and Mårtensson, I.-L. (1995). The c-myc protein represses λ5 and TdT initiators. Nucl. Ac. Res. 23: 1–9.CrossRefGoogle Scholar
  42. 42.
    Heikkila, R, Schwab, G., Wickstrom, E., Loke, S.L., Pluznik, D.H., Watt, R., and Neckers, L.M. (1987). A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from Go to G1. Nature 328: 445–449.PubMedCrossRefGoogle Scholar
  43. 42.
    Karn, J., Watson, J.V., Lowe, A.D., Green, S.M., and Vedeckis, W. (1989). Regulation of cell cycle duration by c-myc levels. Oncogene 4: 773–787.PubMedGoogle Scholar
  44. 43.
    Hanson, K.D., Shichiri, M., Follansbee, M.R., and Sedivy, J.M. (1994). Effects of c-myc expression on cell cycle progression. Mol. Cell. Biol. 14: 5748–5755.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 44.
    Stanton, L. W., Watt, R., Marcu, K. B. (1983). Translocation, breakage, and truncated transcripts of c-myc oncogene in murine plasmacytomas. Nature 303: 401–406.PubMedCrossRefGoogle Scholar
  46. 45.
    Potter, M. and Wiener, F. (1992). Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocation. Carcinogenesis 13: 1681–1697.PubMedCrossRefGoogle Scholar
  47. 46.
    Feo, S., Liegro, C.D., Jones, T., Read, M, and Fried, M. (1994). The DNA region around the c-myc gene and its amplification in human tumour cell lines. Oncogene 9: 955–961.PubMedGoogle Scholar
  48. 47.
    Alitalo, K. (1985). Amplification of cellular oncogenes in cancer cells. TIBS 10: 194–197.Google Scholar
  49. 48.
    Classon, M., Henriksson, M., Klein, G., and Hammaskjold, M.-L. (1987). Elevated c-myc expression facilitates the replication of SV40 in human lymphoid cells. Nature 330: 272–274.PubMedCrossRefGoogle Scholar
  50. 49.
    Classon, M., Henriksson, M., Klein, G., and Hammerskjold, M.-L. (1990). The effect of c-myc protein on SV40 replication in human lymphoid cells. Oncogene 5: 1371–1376.PubMedGoogle Scholar
  51. 50.
    Classon, M., Wennborg, M., Klein, G., and Sümegi, J. (1993). Analysis of c-Myc domains involved in stimulating SV40 replication. Gene 133: 153–161.PubMedCrossRefGoogle Scholar
  52. 51.
    Luecke-Huhle, C, Mai, S., Herrlich, P. (1989). UV-inducible early-domain binding factor as the limiting component of Simian Virus 40 DNA amplification in rodent cells. Mol. Cell. Biol. 9: 4812–4818.Google Scholar
  53. 52.
    Mai, S., Lücke-Huhle, C., Kaina, B., Rahmsdorf, H.J., Stein, B., Ponta, H., and Herrlich, P. (1990). Ionizing radiation induced formation of a replication origin binding complex involving the product of the cellular oncogene c-Myc. In: Ionizing Radiation Damage of DNA. Molecular Aspects. Wiley-Liss., New York, NY, 319–331.Google Scholar
  54. 53.
    Mai, S. and Jalava, A. (1994). c-Myc binds to 5’ flanking sequence motifs of the dihydrofolate reductase gene in cellular extracts: role in proliferation. Nucl. Acids Res. 22: 2264–2273.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 54.
    Wells, J., Held, P., Illenye, S., and Heintz, N.H. (1996). Protein-DNA interactions at the major and minor promoters of the divergently transcribed dhfr and rep 3 genes during the Chinese hamster ovary cell cycle. Mol. Cell. Biol. 16: 634–647.PubMedCentralPubMedGoogle Scholar
  56. 55.
    Luecke-Huhle, C, Mai, S., Moll, J. (1996). Correlation of gene expression and gene amplification. Proc. of the ICRR. pp. 560–564.Google Scholar
  57. 56.
    Kunz, B. A., Kohalmi, S. E., Kunkel, T. A., Mathews, C. K., Mcintosh, E. M., Reidy, J. A. (1994). Deoxyribonucleoside triphosphate levels: a critical factor in the maintenance of genetic stability. Mut. Res. 318: 1–64.CrossRefGoogle Scholar
  58. 57.
    Luecke-Huhle, C. (1994). Permissivity for methotrexate-induced DHFR gene amplification correlates with the metastatic potential of rat adenocarcinoma cells. Carcinogenesis 15: 695–700.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • C. Taylor
    • 1
  • A. Jalava
    • 1
  • S. Mai
    • 1
  1. 1.Manitoba Institute of Cell Biology and the University of ManitobaWinnipegCanada

Personalised recommendations