Melanoma pp 287-323 | Cite as

Signal Transduction Abnormalities as Therapeutic Targets

  • Ruth Halaban
  • Maria C. von Willebrand
Part of the Current Clinical Oncology book series (CCO)


The transformation of normal melanocytes to melanoma cells is associated with accumulation of genetic alterations that impact directly and/or indirectly on cell cycle regulators. As a result, melanoma cells acquire the ability to proliferate and resist apoptosis regardless of environmental cues that control normal melanocytes. Although the full scope of the mutations acquired by melanocytes in their malignant progression has not yet been elucidated, the few that have been identified are in regulatory proteins that control cell cycle progression. The transition to self-sufficiency is a step-wise process, initiated as melanocytic lesions advance from benign to dysplastic nevi, to primary superficial spreading melanomas, and further on to invasive, nodular and metastatic lesions (1,2). This aberrant self-proliferating loop is likely to play a role in fixation and propagation of oncogenic mutations (3). Any mechanism-based approach for melanoma therapy requires the detailed knowledge of the critical players in maintaining autonomous cell proliferation. For example, up-regulated activity of receptor kinases has been implicated in the progression of numerous tumors (4). Prominent in this category are receptors from the epidermal growth factor receptor (EGFR) family, such as Erb-2 (also called HER or Neu), a tyrosine kinase receptor, which is overexpressed in 20 to 30% of human breast and ovarian tumors (5–7). Erb-2 is the target for current and future therapeutic strategies (8), such as the use of neutralizing antibodies or specific kinase inhibitors (4, 9,10). Another example is bcr-abl fusion gene, a hallmark of chronic myelogenous leukemia (CML), which encodes the constitutively active abl-kinase fused to Bcr. A competitive inhibitor of the Bcr-Abl kinase, STI571(CGP57148), is currently one of the most promising treatments of CML (11–15). The discovery of the kinase inhibitor CGP57148, as an effective tumor suppressor specifically for CML, serves as an example for a successful logical mechanistic approach and provides the impetus for searching specific signal transduction targets in other cancers, including melanomas. In fact, as will be described here, investigators and pharmaceutical companies have already developed several inhibitors that target various intermediates in growth factor-mediated signaling, and some of these compounds are already in clinical trials (4,16,17).


Melanoma Cell Fibroblast Growth Factor Chronic Myelogenous Leukemia Fibroblast Growth Factor Receptor Human Melanoma 
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.
    Elder DE, Jucovy PM, Tuthill RJ, Clark WH Jr. The classification of malignant melanoma. Am J Dermatopathol 1980; 2: 315–320.PubMedCrossRefGoogle Scholar
  2. 2.
    Clark WH Jr, Elder DE, Guerry D, Epstein MN, Greene MH, Van Horn M. A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 1984; 15: 1147–1165.PubMedCrossRefGoogle Scholar
  3. 3.
    Eccles SA, Modjtahedi H, Box G, Court W, Sandle J, Dean CJ. Significance of the c-erbB family of receptor tyrosine kinases in metastatic cancer and their potential as targets for immunotherapy. Invasion Metastasis 1994; 14: 337–348.PubMedGoogle Scholar
  4. 4.
    Gibbs JB. Anticancer drug targets: growth factors and growth factor signaling. J Clin Invest 2000; 105: 9–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: 707–712.PubMedCrossRefGoogle Scholar
  6. 6.
    Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1994; 1198: 165–184.PubMedGoogle Scholar
  7. 7.
    Fan QB, Bian ML, Huang SZ, et al. Amplification of the C-erbB-2(HER-2/neu) proto-oncogene in ovarian carcinomas. Chin Med J (Engl) 1994; 107: 589–593.Google Scholar
  8. 8.
    Kirschbaum MH, Yarden Y. The ErbB/HER family of receptor tyrosine kinases: a potential target for chemoprevention of epithelial neoplasms. J Cell Biochem 2000; 77: 52–60.CrossRefGoogle Scholar
  9. 9.
    Dougall WC, Greene MI. Biological studies and potential therapeutic applications of monoclonal antibodies and small molecules reactive with the neu/c-erbB-2 protein. Cell Biophys 1994; 25: 209–218.Google Scholar
  10. 10.
    Hurwitz E, Stancovski I, Sela M, Yarden Y. Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. Proc Natl Acad Sci USA 1995; 92: 3353–3357.PubMedCrossRefGoogle Scholar
  11. 11.
    Sawyers CL, Druker B. Tyrosine kinase inhibitors in chronic myeloid leukemia. Cancer J Sci Am 1999; 5: 63–69.PubMedGoogle Scholar
  12. 12.
    Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000; 105: 3–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Stephenson J. Researchers buoyed by promise of targeted leukemia therapy. JAMA 2000; 283: 317, 21.Google Scholar
  14. 14.
    Sausville EA. A Bcr/Abl kinase antagonist for chronic myelogenous leukemia: a promising path for progress emerges. J Natl Cancer Inst 1999; 91: 102–103.PubMedCrossRefGoogle Scholar
  15. 15.
    le Coutre P, Mologni L, Cleris L, et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 1999; 91: 163–168.PubMedCrossRefGoogle Scholar
  16. 16.
    Courtneidge SA, Plowman GD. The discovery and validation of new drug targets in cancer. Curr Opin Biotechnol 1998; 9: 632–636.PubMedCrossRefGoogle Scholar
  17. 17.
    Gibbs JB. Mechanism-based target identification and drug discovery in cancer research. Science 2000; 287: 1969–1973.PubMedCrossRefGoogle Scholar
  18. 18.
    Halaban R. The regulation of normal melanocyte proliferation. Pigment Cell Res 2000; 13: 4–14.PubMedCrossRefGoogle Scholar
  19. 19.
    Böhm M, Moellmann G, Cheng E, et al. Identification of p90RSK as the probable CREB-Ser133 kinase in human melanocytes. Cell Growth Differ 1995; 6: 291–302.PubMedGoogle Scholar
  20. 20.
    Bull HA, Bunker CB, Terenghi G, et al. Endothelin-1 in human skin: immunolocalization, receptor binding, mRNA expression, and effects on cutaneous microvascular endothelial cells. J Invest Dermatol 1991; 97: 618–623.PubMedCrossRefGoogle Scholar
  21. 21.
    Hara M, Yaar M, Gilchrest BA. Endothelin-1 of keratinocyte origin is a mediator of melanocyte dendricity. J Invest Dermatol 1995; 105: 744–748.PubMedCrossRefGoogle Scholar
  22. 22.
    Halaban R, Tyrrell L, Longley J, Yarden Y, Rubin J. Pigmentation and proliferation of human melanocytes and the effects of melanocyte-stimulating hormone and ultraviolet B light. Ann NY Acad Sci 1993; 680: 290–301.PubMedCrossRefGoogle Scholar
  23. 23.
    Tada A, Suzuki I, Im S, et al. Endothelin-1 is a paracrine growth factor that modulates melanogenesis of human melanocytes and participates in their responses to ultraviolet radiation. Cell Growth Differ 1998; 9: 575–584.PubMedGoogle Scholar
  24. 24.
    Pawelek JM, Chakraborty AK, Osber MP, et al. Molecular cascades in UV-induced melanogenesis: a central role for melanotropins? Pigment Cell Res 1992; 5: 348–356.PubMedCrossRefGoogle Scholar
  25. 25.
    Bhardwaj RS, Luger TA. Proopiomelanocortin production by epidermal cells: evidence for an immune neuroendocrine network in the epidermis. Arch Dermatol Res 1994; 287: 85–90.PubMedCrossRefGoogle Scholar
  26. 26.
    Luger TA, Scholzen T, Brzoska T, Becher E, Slominski A, Paus R. Cutaneous immunomodulation and coordination of skin stress responses by alpha-melanocyte-stimulating hormone. Ann NYAcad Sci 1998; 840: 381–394.CrossRefGoogle Scholar
  27. 27.
    Luger TA. Immunomodulation by UV light: role of neuropeptides. EurJDermatol 1998; 8: 198–199.Google Scholar
  28. 28.
    Costa JJ, Demetri GD, Harrist TJ, et al. Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. J Exp Med 1996; 183: 2681–2686.PubMedCrossRefGoogle Scholar
  29. 29.
    Grichnik JM, Burch JA, Burchette J, Shea CR. The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol 1998; 111: 233–238.PubMedCrossRefGoogle Scholar
  30. 30.
    Lerner AB, McGuire J. Effect of a-and b-melanocyte-stimulating hormones on the skin colour of man. Nature 1961; 189: 176–179.PubMedCrossRefGoogle Scholar
  31. 31.
    Hadley ME, Sharma SD, Hruby VJ, Levine N, Dorr RT. Melanotropic peptides for therapeutic and cosmetic tanning of the skin. Ann NYAcad Sci 1993; 680: 424–439.CrossRefGoogle Scholar
  32. 32.
    Hadley ME, Hruby VJ, Blanchard J, et al. Discovery and development of novel melanogenic drugs. Melanotan-I and -II. Pharm Biotechnol 1998; 11: 575–595.PubMedCrossRefGoogle Scholar
  33. 33.
    Stocker KM, Sherman L, Rees S, Ciment G. Basic FGF and TGF-bl influence commitment to melanogenesis in neural crest-derived cells of avian embryos. Development 1991; 111: 635–641.PubMedGoogle Scholar
  34. 34.
    Sherman L, Stocker KM, Morrison R, Ciment G. Basic fibroblast growth factor (bFGF) acts intracellularly to cause the transdifferentiation of avian neural crest-derived Schwann cell precursors into melanocytes. Development 1993; 118: 1313–1326.PubMedGoogle Scholar
  35. 35.
    Reid K, Nishikawa S, Bartlett PF, Murphy M. Steel factor directs melanocyte development in vitro through selective regulation of the number of c-kit+ progenitors. Dev Biol 1995; 169: 568–579.PubMedCrossRefGoogle Scholar
  36. 36.
    Guo CS, Wehrle-Haller B, Rossi J, Ciment G. Autocrine regulation of neural crest cell development by steel factor. Dev Biol 1997; 184: 61–69.PubMedCrossRefGoogle Scholar
  37. 37.
    Lahav R, Dupin E, Lecoin L, et al. Endothelin 3 selectively promotes survival and proliferation of neural crest-derived glial and melanocytic precursors in vitro. Proc Natl Acad Sci USA 1998; 95: 14214–14219.PubMedCrossRefGoogle Scholar
  38. 38.
    Lahav R, Ziller C, Dupin E, LeDouarin NM. Endothelin 3 promotes neural crest cell proliferation and mediates a vast increase in melanocyte number in culture. Proc Natl Acad Sci USA 1996; 93: 3892–3897.PubMedCrossRefGoogle Scholar
  39. 39.
    Kos L, Aronzon A, Takayama H, et al. Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development. Pigment Cell Res 1999; 12: 13–21.PubMedCrossRefGoogle Scholar
  40. 40.
    Ito M, Kawa Y, Ono H, et al. Removal of stem cell factor or addition of monoclonal antic-KIT antibody induces apoptosis in murine melanocyte precursors. J Invest Dermatol 1999; 112: 796–801.PubMedCrossRefGoogle Scholar
  41. 41.
    Halaban R, Moellmann G. White mutants in mice shedding light on humans. J Invest Dermatol 1993; 100 (Suppl): 176s - 85s.PubMedGoogle Scholar
  42. 42.
    Spritz RA. Molecular basis of human piebaldism. J Invest Dermatol 1994; 103: 137S - 140S.CrossRefGoogle Scholar
  43. 43.
    Fleischman RA. From white spots to stem cells: the role of the Kit receptor in mammalian development. Trends Genet 1993; 9: 285–290.PubMedCrossRefGoogle Scholar
  44. 44.
    Puffenberger EG, Hosoda K, Washington SS, et al. A missense mutation of the endothelinB receptor gene in multigenic Hirschsprung’s disease. Cell 1994; 79: 1257–1266.PubMedCrossRefGoogle Scholar
  45. 45.
    Attie T, Till M, Pelet A, et al. Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet 1995; 4: 2407–2409.PubMedCrossRefGoogle Scholar
  46. 46.
    Edery P, Attie T, Amiel J, et al. Mutation of the endothelin-3 gene in the WaardenburgHirschsprung disease (Shah-Waardenburg syndrome). Nat Genet 1996; 12: 442–444.PubMedCrossRefGoogle Scholar
  47. 47.
    Amiel J, Attie T, Jan D, et al. Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet 1996; 5: 355–357.PubMedCrossRefGoogle Scholar
  48. 48.
    Seri M, Yin L, Barone V, et al. Frequency of RET mutations in long-and short-segment Hirschsprung disease. Hum Mutat 1997; 9: 243–249.PubMedCrossRefGoogle Scholar
  49. 49.
    Hofstra RM, Osinga J, Tan-Sindhunata G, et al. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nat Genet 1996; 12: 445–447.PubMedCrossRefGoogle Scholar
  50. 50.
    Edery P, Eng C, Munnich A, Lyonnet S. RET in human development and oncogenesis. Bioessays 1997; 19: 389–395.PubMedCrossRefGoogle Scholar
  51. 51.
    Baynash AG, Hosoda K, Giaid A, et al. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 1994; 79: 1277–1285.PubMedCrossRefGoogle Scholar
  52. 52.
    Hosoda K, Hammer RE, Richardson JA, et al. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 1994; 79: 1267–1276.PubMedCrossRefGoogle Scholar
  53. 53.
    Hubbard SR, Mohammadi M, Schles singer J. Autoregulatory mechanisms in protein-tyrosine kinases. J Biol Chem 1998; 273: 11987–11990.PubMedCrossRefGoogle Scholar
  54. 54.
    Lemmon MA, Schlessinger J. Transmembrane signaling by receptor oligomerization. Methods Mol Biol 1998; 84: 49–71.PubMedGoogle Scholar
  55. 55.
    Weiss A, Schlessinger J. Switching signals on or off by receptor dimerization. Cell 1998; 94: 277–280.PubMedCrossRefGoogle Scholar
  56. 56.
    Stoffel RH 3rd, Pitcher JA, Lefkowitz RI. Targeting G protein-coupled receptor kinases to their receptor substrates. J Membr Biol 1997; 157: 1–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Halaban R, Kwon BS, Ghosh S, Delli Bovi P, Baird A. bFGF as an autocrine growth factor for human melanomas. Oncogene Res 1988; 3: 177–186.PubMedGoogle Scholar
  58. 58.
    Rodeck U, Menssen HD, Herlyn M. Growth factors in the pathogenesis of malignant diseases. Dtsch Med Wochenschr 1988; 113: 904–906.PubMedCrossRefGoogle Scholar
  59. 59.
    Albino AP, Shea CR, McNutt NS. Oncogenes in melanomas. J Dermatol 1992; 19: 853–867.PubMedGoogle Scholar
  60. 60.
    Meier F, Nesbit M, Hsu MY, et al. Human melanoma progression in skin reconstructs: biological significance of bFGF. Am J Pathol 2000; 156: 193–200.PubMedCrossRefGoogle Scholar
  61. 61.
    Aviezer D, Hecht D, Safran M, Eisinger M, David G, Yayon A. Perlecan, basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis, and angiogenesis. Cell 1995; 79: 1005–1013.CrossRefGoogle Scholar
  62. 62.
    Safran M, Eisenstein M, Aviezer D, Yayon A. Oligomerization reduces heparin affinity but enhances receptor binding of fibroblast growth factor 2. Biochem J 2000; 1: 107–113.CrossRefGoogle Scholar
  63. 63.
    DiGabriele AD, Lax I, Chen DI, et al. Structure of a heparin-linked biologically active dimer of fibroblast growth factor. Nature 1998; 393: 812–817.PubMedCrossRefGoogle Scholar
  64. 64.
    Plotnikov AN, Schlessinger J, Hubbard SR, Mohammadi M. Structural basis for FGF receptor dimerization and activation. Cell 1999; 98: 641–650.PubMedCrossRefGoogle Scholar
  65. 65.
    Klint P, Claesson-Welsh L. Signal transduction by fibroblast growth factor receptors. Front Biosci 1999; 15: D165 - D177.CrossRefGoogle Scholar
  66. 66.
    Hadari YR, Kouhara H, Lax I, Schlessinger J. Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC 12 cell differentiation. Mol Cell Biol 1998; 18: 3966–3973.PubMedGoogle Scholar
  67. 67.
    Ong SH, Guy GR, Hadari YR, et al. FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Mol Cell Biol 2000; 20: 979–989.PubMedCrossRefGoogle Scholar
  68. 68.
    Landgren E, Blumejensen P, Courtneidge SA, Claessonwelsh L. Fibroblast growth factor receptor-1 regulation of Src family kinases. Oncogene 1995; 10: 2027–2035.PubMedGoogle Scholar
  69. 69.
    Larsson H, Klint P, Landgren E, Claesson-Welsh L. Fibroblast growth factor receptor-1- mediated endothelial cell proliferation is dependent on the Src homology (SH) 2/SH3 domain-containing adaptor protein Crk. J Biol Chem 1999; 274: 25726–25734.PubMedCrossRefGoogle Scholar
  70. 70.
    Klint P, Kanda S, Kloog Y, Claesson-Welsh L. Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation. Oncogene 1999; 18: 3354–3364.PubMedCrossRefGoogle Scholar
  71. 71.
    Malumbres M, Pellicer A. RAS pathways to cell cycle control and cell transformation. Front Biosci 1998; 6: d887 - d912.Google Scholar
  72. 72.
    Vojtek AB, Der CJ. Increasing complexity of the Ras signaling pathway. J Biol Chem 1998; 273: 19925–19928.CrossRefGoogle Scholar
  73. 73.
    Cobb MH. MAP kinase pathways. Prog Biophys Mol Biol 1999; 71: 479–500.PubMedCrossRefGoogle Scholar
  74. 74.
    Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res 1998; 74: 49–139.PubMedCrossRefGoogle Scholar
  75. 75.
    Imokawa G, Yada Y, Kimura M. Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in human melanocytes. Biochem J 1996; 314: 305–312.PubMedGoogle Scholar
  76. 76.
    Medrano EE, Yang F, Boissy R, et al. Terminal differentiation and senescence in the human melanocyte: repression of tyrosine-phosphorylation of the extracellular signal-regulated kinase 2 selectively defines the two phenotypes. Mol Biol Cell 1994; 5: 497–509.PubMedGoogle Scholar
  77. 77.
    Montminy M. Transcriptional regulation by cyclic AMP. Annu Rev Biochem 1997; 66: 807–822.PubMedCrossRefGoogle Scholar
  78. 78.
    Eckner R. p300 and CBP as transcriptional regulators and targets of oncogenic events. Biol Chem 1996; 377: 685–688.PubMedGoogle Scholar
  79. 79.
    Goldman PS, Tran VK, Goodman RH. The multifunctional role of the co-activator CBP in transcriptional regulation. Recent Prog Horm Res 1997; 52: 103–119.PubMedGoogle Scholar
  80. 80.
    De Cesare D, Fimia GM, Sassone-Corsi P. Signaling routes to CREM and CREB: plasticity in transcriptional activation. Trends Biochem Sci 1999; 24: 281–285.PubMedCrossRefGoogle Scholar
  81. 81.
    Bertolotto C, Abbe P, Hemesath TJ, et al. Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes. J Cell Biol 1998; 142: 827–835.PubMedCrossRefGoogle Scholar
  82. 82.
    Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE. MAPK links the transcription factor Microphthalmia to c-Kit signaling in melanocytes. Nature 1998; 391: 298–301.PubMedCrossRefGoogle Scholar
  83. 83.
    Sato S, Roberts K, Gambino G, Cook A, Kouzarides T, Goding CR. CBP/p300 as a co-factor for the Microphthalmia transcription factor. Oncogene 1997; 14: 3083–3092.PubMedCrossRefGoogle Scholar
  84. 84.
    Goding CR, Fisher DE. Regulation of melanocyte differentiation and growth. Cell Growth Differ 1997; 8: 935–940.PubMedGoogle Scholar
  85. 85.
    Adams PD, Kaelin WG Jr. Transcriptional control by E2F. Semin Cancer Biol 1995; 6: 99–108.PubMedCrossRefGoogle Scholar
  86. 86.
    Adams PD, Kaelin WG Jr. The cellular effects of E2F overexpression. Curr Top Microbiol Immunol 1996; 208: 79–93.PubMedCrossRefGoogle Scholar
  87. 87.
    Sherr CJ. Growth factor-regulated G 1 cyclins. Stem Cells 1994; 1: 47–55.Google Scholar
  88. 88.
    Sherr CJ. G1 phase progression: cycling on cue. Cell 1994; 79: 551–555.PubMedCrossRefGoogle Scholar
  89. 89.
    Halaban R, Miglarese MR, Smicun Y, Puig S. Melanomas, from the cell cycle point of view. Int J Mol Med 1998; 1: 419–425.PubMedGoogle Scholar
  90. 90.
    Halaban R, Cheng C, Smicun Y, Germino J. Deregulated E2F transcriptional activity in autonomously growing melanoma cells. J Exp Med 2000; 191: 1005–1016.PubMedCrossRefGoogle Scholar
  91. 91.
    Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323–330.PubMedCrossRefGoogle Scholar
  92. 92.
    Kaelin WG Jr. Recent insights into the functions of the retinoblastoma susceptibility gene product. Cancer Invest 1997; 15: 243–254.PubMedCrossRefGoogle Scholar
  93. 93.
    Sherr CJ. Cancer cell cycles. Science 1996; 274: 1672–1677.PubMedCrossRefGoogle Scholar
  94. 94.
    Zarkowska T, Mittnacht S. Differential phosphorylation of the retinoblastoma protein by GI/S cyclin-dependent kinases. JBiol Chem 1997; 272: 12738–12746.CrossRefGoogle Scholar
  95. 95.
    Weinberg RA. The molecular basis of carcinogenesis-understanding the cell cycle clock. Cytokines Mol Ther 1996; 2: 105–110.PubMedGoogle Scholar
  96. 96.
    Taya Y. Rb kinases and Rb-binding proteins: new points of view. Trends Biochem Sci1997; 22: 14–17.PubMedCrossRefGoogle Scholar
  97. 97.
    Pardee A. G1 events and regulation of cell proliferation. Science 1989; 246: 603–608.PubMedCrossRefGoogle Scholar
  98. 98.
    Bartek J, Bartkova J, Lukas J. The retinoblastoma protein pathway and the restriction point. Curr Opin Cell Biol 1996; 8: 805–814.PubMedCrossRefGoogle Scholar
  99. 99.
    Planas-Silva MD, Weinberg RA. The restriction point and control of cell proliferation. Curr Opin Cell Biol 1997; 9: 768–772.PubMedCrossRefGoogle Scholar
  100. 100.
    Nevins JR. Toward an understanding of the functional complexity of the E2F and retinoblastoma families. Cell Growth Differ 1998; 9: 585–593.PubMedGoogle Scholar
  101. 101.
    Lai A, Lee JM, Yang WM, et al. RBP1 recruits both histone deacetylase-dependent and -independent repression activities to retinoblastoma family proteins. Mol Cell Biol 1999; 19: 6632–6641.PubMedGoogle Scholar
  102. 102.
    Magnaghi-Jaulin L, Groisman R, Naguibneva I, et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 1998; 391: 601–605.PubMedCrossRefGoogle Scholar
  103. 103.
    Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D. The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase. Proc Natl Acad Sci USA 1998; 95: 10493–10498.PubMedCrossRefGoogle Scholar
  104. 104.
    Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 1998; 391: 597–601.PubMedCrossRefGoogle Scholar
  105. 105.
    Jacks T, Weinberg RA. Cell-cycle control and its watchman. Nature 1996; 381: 643–644.PubMedCrossRefGoogle Scholar
  106. 106.
    Weinberg RA. How cancer arises. Sci Am 1996; 275: 62–70.PubMedCrossRefGoogle Scholar
  107. 107.
    Grana X, Garriga J, Mayol X. Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth. Oncogene 1998; 17: 3365–3383.PubMedCrossRefGoogle Scholar
  108. 108.
    Johnson DG, Schneider-Broussard R. Role of E2F in cell cycle control and cancer. Front Biosci 1998; 27: d447 - d448.Google Scholar
  109. 109.
    Hiyama H, Iavarone A, Reeves SA. Regulation of the CDK inhibitor p21 gene during cell cycle progression is under the control of the transcription factor E2F. Oncogene 1998; 16: 1513–1523.PubMedCrossRefGoogle Scholar
  110. 110.
    Rodeck U, Herlyn M, Menssen HD, Furlanetto RW, Koprowsk H. Metastatic but not primary melanoma cell lines grow in vitro independently of exogenous growth factors. Int J Cancer 1987; 40: 687–690.PubMedCrossRefGoogle Scholar
  111. 111.
    Furlanetto RW, Harwell SE, Baggs RB. Effects of insulin-like growth factor receptor inhibition on human melanomas in culture and in athymic mice. Cancer Res 1993; 53: 2522 2526.Google Scholar
  112. 112.
    Halaban R. Receptor tyrosine protein kinases in normal and malignant melanocytes. In: Okhawara A, McGuire J, eds. The Biology of the Epidermis. Elsevier, New York, 1992, pp. 133–140.Google Scholar
  113. 113.
    Easty DJ, Ganz SE, Farr CJ, Lai C, Herlyn M, Bennett DC. Novel and known protein tyrosine kinases and their abnormal expression in human melanomas. J invest Dermatol 1993; 101: 679–684.PubMedCrossRefGoogle Scholar
  114. 114.
    Scott G, Stoler M, Sarkar S, Halaban R. Localization of basic fibroblast growth factor mRNA in melanocytic lesions by in situ hybridization. J Invest Dermatol 1991; 96: 318–322.PubMedCrossRefGoogle Scholar
  115. 115.
    Ueda M, Funasaka Y, Ichihashi M, Mishima Y. Stable and strong expression of basic fibroblast growth factor in naevus cell naevus contrasts with aberrant expression in melanoma. Br J Dermatol 1994; 130: 320–324.PubMedCrossRefGoogle Scholar
  116. 116.
    al-Alousi S, Carlson JA, Blessing K, Cook M, Karaoli T, Barnhill RL. Expression of basic fibroblast growth factor in desmoplastic melanoma. J Cutan. Pathol 1996; 23: 118–125.PubMedCrossRefGoogle Scholar
  117. 117.
    Reed JA, McNutt NS, Albino AP. Differential expression of basic fibroblast growth factor (bFGF) in melanocytic lesions demonstrated by in situ hybridization. Implications for tumor progression. Am J Pathol 1994; 144: 329–336.PubMedGoogle Scholar
  118. 118.
    Halaban R. Growth factors and melanomas. Semin Oncol 1996; 23: 673–681.PubMedGoogle Scholar
  119. 119.
    Rodeck R, Melber K, Kath R, et al. Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes. J Invest Dermatol 1991; 97: 20–26.PubMedCrossRefGoogle Scholar
  120. 120.
    Rodeck U, Becker D, Herlyn M. Basic fibroblast growth factor in human melanoma. Cancer Cells 1991; 3: 308–311.PubMedGoogle Scholar
  121. 121.
    Albino AP. The role of oncogenes and growth factors in progressive melanoma-genesis. Pigment Cell Res 1992; 2: 199–218.PubMedGoogle Scholar
  122. 122.
    Kanter-Lewensohn L, Dricu A, Girnita L, Wejde J, Larsson O. Expression of insulin-like growth factor-1 receptor (IGF-1R) and p27Kip1 in melanocytic tumors: a potential regulatory role of IGF-1 pathway in distribution of p27Kipl between different cyclins. Growth Factors 2000; 17: 193–202.PubMedCrossRefGoogle Scholar
  123. 123.
    Dotto GP, Moellmann G, Ghosh S, Edwards M, Halaban R. Transformation of murine melanocytes by basic fibroblast growth factor cDNA and oncogenes and selective suppression of the transformed phenotype in a reconstituted cutaneous environment. J Cell Biol 1989; 109: 3115–3128.PubMedCrossRefGoogle Scholar
  124. 124.
    Balentien E, Mufson BE, Shattuck RL, Derynck R, Richmond A. Effects of MGSA/GRO alpha on melanocyte transformation. Oncogene 1991; 6: 1115–1124.PubMedGoogle Scholar
  125. 125.
    Richmond A. The pathogenic role of growth factors in melanoma. Semin Dermatol 1991; 10: 246–255.PubMedGoogle Scholar
  126. 126.
    Tettelbach W, Nanney L, Ellis D, King L, Richmond A. Localization of MGSA/GRO protein in cutaneous lesions. J Cutan Pathol 1993; 20: 259–266.PubMedCrossRefGoogle Scholar
  127. 127.
    Rodeck U, Herlyn M. Growth factors in melanoma. Cancer Metastasis Rev 1991; 10: 89–101.PubMedCrossRefGoogle Scholar
  128. 128.
    Easty DJ, Herlyn M, Bennett DC. Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. Int J Cancer 1995; 60: 129–136.PubMedCrossRefGoogle Scholar
  129. 129.
    Ellis DL, Kafka SP, Chow JC, et al. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trelat, and multiple acrocordons: a possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. N Engl J Med 1987; 317: 1582–1587.PubMedCrossRefGoogle Scholar
  130. 130.
    Forsberg K, Valyi-Nagy I, Heldin C-H, Herlyn M, Westermark B. Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. Proc Natl Acad Sci USA 1993; 90: 393–397.PubMedCrossRefGoogle Scholar
  131. 13.
    I. Danielsen T, Rofstad EK. The constitutive level of vascular endothelial growth factor (VEGF) is more important than hypoxia-induced VEGF up-regulation in the angiogenesis of human melanoma xenografts. Br J Cancer 2000; 82: 1528–1534.PubMedCrossRefGoogle Scholar
  132. 132.
    Weber F, Sepp N, Fritsch P. Vascular endothelial growth factor and basic fibroblast growth factor in melanoma. Br J Dermatol 2000; 142: 392–393.PubMedCrossRefGoogle Scholar
  133. 133.
    Herold-Mende C, Steiner HH, Andl T, et al. Expression and functional significance of vascular endothelial growth factor receptors in human tumor cells. Lab Invest 1999; 79: 1573–1582.PubMedGoogle Scholar
  134. 134.
    Birck A, Kirkin AF, Zeuthen J, Hou-Jensen K. Expression of basic fibroblast growth factor and vascular endothelial growth factor in primary and metastatic melanoma from the same patients. Melanoma Res 1999; 9: 375–381.PubMedCrossRefGoogle Scholar
  135. 135.
    Bayer-Garner IB, Hough Ai Jr, Smoller BR. Vascular endothelial growth factor expression in malignant melanoma: prognostic versus diagnostic usefulness. Mod Pathol 1999; 12: 770–774.PubMedGoogle Scholar
  136. 136.
    Rofstad EK, Danielsen T. Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer 1999; 80: 1697–1707.PubMedCrossRefGoogle Scholar
  137. 137.
    Graeven U, Fiedler W, Karpinski S, et al. Melanoma-associated expression of vascular endothelial growth factor and its receptors FLT-1 and KDR. J Cancer Res Clin Oncol 1999; 125: 621–629.PubMedCrossRefGoogle Scholar
  138. 138.
    Iwamoto T, Takahashi M, Ito M, et al. Aberrant melanogenesis and melanocytic tumour development in transgenic mice that carry a metallothionein/ret fusion gene. EMBO J 1991; 10: 3167–3175.PubMedGoogle Scholar
  139. 139.
    Kato M, Takahashi M, Akhand AA, et al. Transgenic mouse model for skin malignant melanoma. Oncogene 1998; 17: 1885–1888.PubMedCrossRefGoogle Scholar
  140. 140.
    Kato M, Liu W, Akhand AA, et al. Linkage between melanocytic tumor development and early burst of Ret protein expression for tolerance induction in metallothionein-I/ret transgenic mouse lines. Oncogene 1999; 18: 837–842.PubMedCrossRefGoogle Scholar
  141. 141.
    Takayama H, LaRochelle WJ, Sharp R, et al. Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc NatlAcad Sci USA 1997; 94: 701–706.CrossRefGoogle Scholar
  142. 142.
    Otsuka T, Takayama H, Sharp R, et al. c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype. Cancer Res 1998; 58: 5157–5167.PubMedGoogle Scholar
  143. 143.
    Halaban R, Rubin JS, Funasaka Y, et al. Met and hepatocyte growth factor/scatter factor signal transduction in normal melanocytes and melanoma cells. Oncogene 1992; 7: 2195 2206.Google Scholar
  144. 144.
    Halaban R. Molecular correlates in the progression of normal melanocytes to melanomas. Sem Cancer Biol 1993; 4: 171–181.Google Scholar
  145. 145.
    Halaban R, Rubin W, White W. Met and HGF/SF in normal melanocytes and melanoma cells. In: Goldberg ID, ed. Hepatocyte Growth Factor-Scatter Factor and the C-Met Receptor. Birkhäuser Verlag, Basel, Switzerland, 1993, pp. 329–339.Google Scholar
  146. 146.
    Natali PG, Nicotra MR, Sures I, Santoro E, Bigotti A, Ullrich A. Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res 1992; 52: 6139–6143.PubMedGoogle Scholar
  147. 147.
    Zakut R, Perlis R, Eliyahu S, et al. KIT ligand (mast cell growth factor) inhibits the growth of KIT-expressing melanoma cells. Oncogene 1993; 8: 2221–2229.PubMedGoogle Scholar
  148. 148.
    Lassam N, Bickford S. Loss of c-kit expression in cultured melanoma cells. Oncogene 1992; 7: 51–56.PubMedGoogle Scholar
  149. 149.
    Huang SY, Luca M, Gutman M, et al. Enforced C-Kit expression renders highly metastatic human melanoma cells susceptible to stem cell factor-induced apoptosis and inhibits their tumorigenic and metastatic potential. Oncogene 1996; 13: 2339–2347.PubMedGoogle Scholar
  150. 150.
    Segev O, Chumakov I, Nevo Z, et al. Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice. Hum Mol Genet 2000; 9: 249–258.PubMedCrossRefGoogle Scholar
  151. 151.
    Monsonego-Ornan E, Adar R, Feferman T, Segev O, Yayon A. The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Mol Cell Biol 2000; 20: 516–522.PubMedCrossRefGoogle Scholar
  152. 152.
    Garofalo S, Kliger-Spatz M, Cooke JL, et al. Skeletal dysplasia and defective chondrocyte differentiation by targeted overexpression of fibroblast growth factor 9 in transgenic mice. J Bone Miner Res 1999; 14: 1909–1915.PubMedCrossRefGoogle Scholar
  153. 153.
    Vlodaysky I, Miao HQ, Medalion B, Danagher P, Ron D. Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor. Cancer Metastasis Rev 1996; 15: 177–186.CrossRefGoogle Scholar
  154. 154.
    Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 1991; 64: 841–848.PubMedCrossRefGoogle Scholar
  155. 155.
    Ornitz DM, Yayon A, Flanagan JG, Svahn CM, Levi E, Leder P. Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells. Mol Cell Biol 1992; 12: 240–247.PubMedGoogle Scholar
  156. 156.
    Kan M, Wang F, Xu J, Crabb JW, Hou J, McKeehan WL. An essential heparin-binding domain in the fibroblast growth factor receptor kinase. Science 1993; 259: 1918–1921.PubMedCrossRefGoogle Scholar
  157. 157.
    Li LY, Safran M, Aviezer D, Bohlen P, Seddon AP, Yayon A. Diminished heparin binding of a basic fibroblast growth factor mutant is associated with reduced receptor binding, mitogenesis, plasminogen activator induction, and in vitro angiogenesis. Biochemistry 1994; 33: 10999–11007.PubMedCrossRefGoogle Scholar
  158. 158.
    Aviezer D, Iozzo RV, Noonan DM, Yayon A. Suppression of autocrine and paracrine functions of basic fibroblast growth factor by stable expression of perlecan anti sense cDNA. Mol Cell Biol 1997; 17: 1938–1946.PubMedGoogle Scholar
  159. 159.
    Miao HQ, Ornitz DM, Aingorn E, Ben-Sasson SA, Vlodaysky I. Modulation of fibroblast growth factor-2 receptor binding, dimerization, signaling, and angiogenic activity by a synthetic heparin-mimicking polyanionic compound. J Clin Invest 1997; 99: 1565–1575.PubMedCrossRefGoogle Scholar
  160. 160.
    Liekens S, Leali D, Neyts J, et al. Modulation of fibroblast growth factor-2 receptor binding, signaling, and mitogenic activity by heparin-mimicking polysulfonated compounds. Mol Pharmacol 1999; 56: 204–213.PubMedGoogle Scholar
  161. 161.
    Werner S, Weinberg W, Liao X, et al. Targeted expression of a dominant-negative FGF receptor mutant in the epidermis of transgenic mice reveals a role of FGF in keratinocyte organization and differentiation. EMBO J 1993; 12: 2635–2643.PubMedGoogle Scholar
  162. 162.
    Peters K, Werner S, Liao X, Wert S, Whitsett J, Williams L. Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. EMBO J 1994; 13: 3296–3301.PubMedGoogle Scholar
  163. 163.
    Celli G, LaRochelle WJ, Mackem S, Sharp R, Merlino G. Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning. EMBO J 1998; 17: 1642–1655.PubMedCrossRefGoogle Scholar
  164. 164.
    Yayon A, Ma YS, Safran M, Klagsbrun M, Halaban R. Suppression of autocrine cell proliferation and tumorigenesis of human melanoma cells and fibroblast growth factor transformed fibroblasts by a kinase-deficient FGF receptor 1: evidence for the involvement of Src-family kinases. Oncogene 1997; 14: 2999–3009.PubMedCrossRefGoogle Scholar
  165. 165.
    Becker D, Meier CB, Becker. Proliferation of human malignant melanomas is inhibited by antisense oligodeoxynucleotides targeted against basic fibroblast growth factor. EMBO J 1989; 8: 3685–3691.PubMedGoogle Scholar
  166. 166.
    Becker D, Lee PL, Rodeck U, Herlyn M. Inhibition of the fibroblast growth factor receptor 1 (FGFR-1) gene in human melanocytes and malignant melanomas leads to inhibition of proliferation and signs indicative of differentiation. Oncogene 1992; 7: 2303–2313.PubMedGoogle Scholar
  167. 167.
    Kato J, Wanebo H, Calabresi P, Clark JW. Basic fibroblast growth factor production and growth factor receptors as potential targets for melanoma therapy. Melanoma Res 1992; 2: 13–23.PubMedCrossRefGoogle Scholar
  168. 168.
    Wang Y, Becker D. Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nature Med 1997; 3: 887–893.PubMedCrossRefGoogle Scholar
  169. 169.
    Traxler P, Furet P. Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol Ther 1999; 82: 195–206.PubMedCrossRefGoogle Scholar
  170. 170.
    al-Obeidi FA, Wu JJ, Lam KS. Protein tyrosine kinases: structure, substrate specificity, and drug discovery. Biopolymers 1998; 47: 197–223.PubMedCrossRefGoogle Scholar
  171. 171.
    Fry DW. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy: progression from reversible to irreversible inhibitors. Pharmacol Ther 1999; 82: 207–218.PubMedCrossRefGoogle Scholar
  172. 172.
    Klapper LN, Kirschbaum MH, Sela M, Yarden Y. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000; 77: 25–79.PubMedCrossRefGoogle Scholar
  173. 173.
    Klohs WD, Fry DW, Kraker AJ. Inhibitors of tyrosine kinase. Curr Opin Oncol 1997; 9: 562–568.PubMedCrossRefGoogle Scholar
  174. 174.
    Hamby JM, Connolly CJ, Schroeder MC, et al. Structure-activity relationships for a novel series of pyrido[2,3- d]pyrimidine tyrosine kinase inhibitors. J Med Chem 1997; 40: 2296 2303.Google Scholar
  175. 175.
    Showalter HD, Kraker AJ. Small molecule inhibitors of the platelet-derived growth factor receptor, the fibroblast growth factor receptor, and Src family tyrosine kinases. Pharmacol Ther 1997; 76: 55–71.PubMedCrossRefGoogle Scholar
  176. 176.
    Mohammadi M, McMahon G, Sun L, et al. Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 1997; 276: 955–960.PubMedCrossRefGoogle Scholar
  177. 177.
    Mohammadi M, Froum S, Hamby JM, et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J 1998; 17: 5896–5904.PubMedCrossRefGoogle Scholar
  178. 178.
    Dimitroff CJ, Klohs W, Sharma A, et al. Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: implications for combination treatment with photodynamic therapy. Invest New Drugs 1999; 17: 121–135.PubMedCrossRefGoogle Scholar
  179. 179.
    Lappi DA, Ying W, Barthelemy I, et al. Expression and activities of a recombinant basic fibroblast growth factor-saporin fusion protein. J Biol Chem 1994; 269: 12552–12558.PubMedGoogle Scholar
  180. 180.
    Beitz JG, Davol P, Clark JW, et al. Antitumor activity of basic fibroblast growth factorsaporin mitotoxin in vitro and in vivo. Cancer Res 1992; 52: 227–230.PubMedGoogle Scholar
  181. 181.
    Ying WB, Martineau D, Beitz J, Lappi DA, Baird A. Anti-B16–B10 melanoma activity of a basic fibroblast growth factor-saporin mitotoxin. Cancer 1994; 74: 848–853.PubMedCrossRefGoogle Scholar
  182. 182.
    Lappi DA. Tumor targeting through fibroblast growth factor receptors. Semin Cancer Biol 1995; 6: 279–288.PubMedCrossRefGoogle Scholar
  183. 183.
    Michael SI, Curiel DT. Strategies to achieve targeted gene delivery via the receptor-mediated endocytosis pathway. Gene Ther 1994; 1: 223–232.PubMedGoogle Scholar
  184. 184.
    Wickham TJ, Roelvink PW, Brough DE, Kovesdi I. Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types. Nat Biotechnol 1996; 14: 1570–1573.PubMedCrossRefGoogle Scholar
  185. 185.
    Kochanek S. High-capacity adenoviral vectors for gene transfer and somatic gene therapy. Hum Gene Ther 1999; 10: 2451–2459.PubMedCrossRefGoogle Scholar
  186. 186.
    Rodeck U, Herlyn M. Characteristics of cultured human melanocytes from different stages of tumor progression. Cancer Treat Res 1988; 43: 3–16.PubMedCrossRefGoogle Scholar
  187. 187.
    Baserga R. The IGF-I receptor in cancer research. Exp Cell Res 1999; 253: 1–6.PubMedCrossRefGoogle Scholar
  188. 188.
    Herlyn M, Balaban G, Bennicelli J, et al. Primary melanoma cells of the vertical growth phase: similarities to metastatic cells. J Natl Cancer Inst 1985; 74: 283–289.PubMedGoogle Scholar
  189. 189.
    Baserga R. The insulin-like growth factor I receptor: a key to tumor growth? Cancer Res 1995; 55: 249–252.PubMedGoogle Scholar
  190. 190.
    Resnicoff M, Coppola D, Sell C, Rubin R, Ferrone S, Baserga R. Growth inhibition of human melanoma cells in nude mice by antisense strategies to the type 1 insulin-like growth factor receptor. Cancer Res 1994; 54: 4848–4850.PubMedGoogle Scholar
  191. 191.
    Parrizas M, Gazit A, Levitzki A, Wertheimer E, LeRoith D. Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins. Endocrinology 1997; 138: 1427–1433.PubMedCrossRefGoogle Scholar
  192. 192.
    Khosravifar R, White MA, Westwick JK, et al. Oncogenic ras activation of raf/mitogenactivated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol 1996; 16: 3923–3933.Google Scholar
  193. 193.
    Albino AP, Nanus DM, Mentle IR, et al. Analysis of ras oncogenes in malignant melanoma and precursor lesions: correlation of point mutations with differentiation phenotype. Oncogene 1989; 4: 1363–1374.PubMedGoogle Scholar
  194. 194.
    Albino AP, Nanus DM, Davis ML, McNutt NS. Lack of evidence of Ki-ras codon 12 mutations in melanocytic lesions. J Cutan Pathol 1991; 18: 273–278.PubMedCrossRefGoogle Scholar
  195. 195.
    O’Mara SM, Todd AV, Russell PJ. Analysis of expressed N-ras mutations in human melanoma short-term cell lines with allele specific restriction analysis induced by the polymerase chain reaction. Eur J Cancer 1992; 28: 9–11.PubMedCrossRefGoogle Scholar
  196. 196.
    Jiveskog S, Ragnarsson-Olding B, Platz A, Ringborg U. N-ras mutations are common in melanomas from sun-exposed skin of humans but rare in mucosal membranes or unexposed skin. J Invest Dermatol 1998; 111: 757–761.PubMedCrossRefGoogle Scholar
  197. 197.
    Carr J, Mackie RM. Point mutations in the N-ras oncogene in malignant melanoma and congenital naevi. Br J Dermatol 1994; 131: 72–77.PubMedCrossRefGoogle Scholar
  198. 198.
    van Elsas A, Zerp SF, van der Flier S, et al. Relevance of ultraviolet-induced N-ras oncogene point mutations in development of primary human cutaneous melanoma. Am J Pathol 1996; 149: 883–893.PubMedGoogle Scholar
  199. 199.
    Platz A, Ringborg U, Grafstrom E, Hoog A, Lagerlof B. Immunohistochemical analysis of the N-ras p21 and the p53 proteins in naevi, primary tumours and metastases of human cutaneous malignant melanoma-increased immunopositivity in hereditary melanoma. Melanoma Res 1995; 5: 101–106.PubMedCrossRefGoogle Scholar
  200. 200.
    Powell MB, Hyman P, Bell OD, et al. Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 Ha-ras gene regulated by a mouse tyrosinase promoter. Mol Carcinog 1995; 12: 82–90.PubMedCrossRefGoogle Scholar
  201. 201.
    Powell MB, Gause PR, Hyman P, et al. Induction of melanoma in TPras transgenic mice. Carcinogenesis 1999; 20: 1747–1753.CrossRefGoogle Scholar
  202. 202.
    Chin L, Tam A, Pomerantz J, et al. Essential role for oncogenic Ras in tumour maintenance. Nature 1999; 400: 468–472.PubMedCrossRefGoogle Scholar
  203. 203.
    Chin L, Pomerantz J, Polsky D, et al. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dey 1997; 11: 2822–2834.CrossRefGoogle Scholar
  204. 204.
    Chin L, Merlino G, DePinho RA. Malignant melanoma: modern black plague and genetic black box. Genes Dey 1998; 12: 3467–3481.CrossRefGoogle Scholar
  205. 205.
    Ohta Y, Tone T, Shitara T, et al. H-ras ribozyme-mediated alteration of the human melanoma phenotype. Ann NY Acad Sci 1994; 716: 242–253.PubMedCrossRefGoogle Scholar
  206. 206.
    Kashani-Sabet M, Funato T, Florenes VA, Fodstad O, Scanlon KJ. Suppression of the neo-plastic phenotype in vivo by an anti-ras ribozyme. Cancer Res 1994; 54: 900–902.PubMedGoogle Scholar
  207. 207.
    Ohta Y, Kijima H, Ohkawa T, Kashani-sabet M, Scanlon KJ. Tissue-specific expression of an anti-ras ribozyme inhibits proliferation of human malignant melanoma cells. Nucleic Acids Res 1996; 24: 938–942.PubMedCrossRefGoogle Scholar
  208. 208.
    Prendergast GC. Farnesyltransferase inhibitors: antineoplastic mechanism and clinical prospects. Curr Opin Cell Biol 2000; 12: 166–173.PubMedCrossRefGoogle Scholar
  209. 209.
    Jansen B, Schlagbauer-Wadl H, Kahr H, et al. Novel Ras antagonist blocks human melanoma growth. Proc Nall Acad Sci USA 1999; 96: 14019–14024.CrossRefGoogle Scholar
  210. 210.
    Gibbs BS, Zahn TJ, Mu Y, Sebolt-Leopold JS, Gibbs RA. Novel farnesol and geranylgeraniol analogues: a potential new class of anticancer agents directed against protein prenylation. J Med Chem 1999; 42: 3800–3808.PubMedCrossRefGoogle Scholar
  211. 211.
    Gelb MH, Scholten JD, Sebolt-Leopold JS. Protein prenylation: from discovery to prospects for cancer treatment. Curr Opin Chem Biol 1998; 2: 40–48.PubMedCrossRefGoogle Scholar
  212. 212.
    Vogt A, Qian Y, McGuire TF, Hamilton AD, Sebti SM. Protein geranylgeranylation, not farnesylation, is required for the G1 to S phase transition in mouse fibroblasts. Oncogene 1996; 13: 1991–1999.PubMedGoogle Scholar
  213. 213.
    Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM. The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in GO/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J Biol Chem 1997; 272: 27224–27229.PubMedCrossRefGoogle Scholar
  214. 214.
    Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD, Sebti SM. Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 1997; 15: 1283–1288.PubMedCrossRefGoogle Scholar
  215. 215.
    Miguel K, Pradines A, Sun J, et al. GGTI-298 induces GO-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res 1997; 57: 1846–1850.Google Scholar
  216. 216.
    Sun J, Qian Y, Chen Z, Marfurt J, Hamilton AD, Sebti SM. The geranylgeranyltransferase I inhibitor GGTI-298 induces hypophosphorylation of retinoblastoma and partner switching of cyclin-dependent kinase inhibitors. A potential mechanism for GGTI-298 antitumor activity. J Biol Chem 1999; 274: 6930–6934.PubMedCrossRefGoogle Scholar
  217. 217.
    Pollack IF, Bredel M, Erff M, Hamilton AD, Sebti SM. Inhibition of Ras and related guanosine triphosphate-dependent proteins as a therapeutic strategy for blocking malignant glioma growth: II-preclinical studies in a nude mouse model. Neurosurgery 1999; 45: 1208–1214.PubMedCrossRefGoogle Scholar
  218. 218.
    Liu X, Brodeur SR, Gish G, et al. Regulation of c-Src tyrosine kinase activity by the Src SH2 domain. Oncogene 1993; 8: 1119–1126.PubMedGoogle Scholar
  219. 219.
    Pawson T, Schlessinger J. SH2 and SH3 domains. Curr Biol 1993; 3: 434–442.PubMedCrossRefGoogle Scholar
  220. 220.
    Schlessinger J. New roles for Src kinases in control of cell survival and angiogenesis. Cell 2000; 100: 293–296.PubMedCrossRefGoogle Scholar
  221. 221.
    Pawson T. Protein modules and signalling networks. Nature 1995; 373: 573–580.PubMedCrossRefGoogle Scholar
  222. 222.
    Pawson T, Hunter T. Signal transduction and growth control in normal and cancer cells. Curr Opin Genet Dey 1994; 4: 1–4.CrossRefGoogle Scholar
  223. 223.
    Lawrence DS, Niu J. Protein kinase inhibitors: the tyrosine-specific protein kinases. Pharmacol Ther 1998; 77: 81–114.PubMedCrossRefGoogle Scholar
  224. 224.
    Moasser MM, Srethapakdi M, Sachar KS, Kraker AJ, Rosen N. Inhibition of Src kinases by a selective tyrosine kinase inhibitor causes mitotic arrest. Cancer Res 1999; 59: 61456152.Google Scholar
  225. 225.
    Roginskaya V, Zuo S, Caudell E, Nambudiri G, Kraker AJ, Corey Si. Therapeutic targeting of Src-kinase Lyn in myeloid leukemic cell growth. Leukemia 1999; 13: 855–861.PubMedCrossRefGoogle Scholar
  226. 226.
    le Coutre P, Tassi E, Varella-Garcia M, et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 2000; 95: 1758–1766.PubMedGoogle Scholar
  227. 227.
    Carlo-Stella C, Regazzi E, Sammarelli G, et al. Effects of the tyrosine kinase inhibitor AG957 and an Anti-Fas receptor antibody on CD34(+) chronic myelogenous leukemia progenitor cells. Blood 1999; 93: 3973–3982.PubMedGoogle Scholar
  228. 228.
    O’Dwyer PJ, Stevenson JP, Gallagher M, et al. c-raf-1 depletion and tumor responses in patients treated with the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A). Clin Cancer Res 1999; 5: 3977–3982.Google Scholar
  229. 229.
    Cunningham CC, Holmlund JT, Schiller JH, et al. A phase I trial of c-Raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res 2000; 6: 1626–1631.PubMedGoogle Scholar
  230. 230.
    Sebolt-Leopold JS, Dudley DT, Herrera R, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 1999; 5: 810–816.PubMedCrossRefGoogle Scholar
  231. 231.
    Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 1997; 57: 3660–3663.PubMedGoogle Scholar
  232. 232.
    Robertson GP, Furnari FB, Miele ME, et al. In vitro loss of heterozygosity targets the PTEN/ MMAC1 gene in melanoma. Proc Natl Acad Sci USA 1998; 95: 9418–9423.PubMedCrossRefGoogle Scholar
  233. 233.
    Tsao H, Zhang X, Benoit E, Haluska FG. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene 1998; 16: 3397–3402.PubMedCrossRefGoogle Scholar
  234. 234.
    Du W, Liu A, Prendergast GC. Activation of the PI3’ K-AKT pathway masks the proapoptotic effects of farnesyltransferase inhibitors. Cancer Res 1999; 59: 4208–4212.PubMedGoogle Scholar
  235. 235.
    Horowitz JM, Park S-H, Bogenman E, et al. Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci USA 1990; 87: 2772–2779.CrossRefGoogle Scholar
  236. 236.
    Bartkova J, Lukas J, Guldberg P, et al. The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res 1996; 56: 5475–5483.PubMedGoogle Scholar
  237. 237.
    Bataille V, Hiles R, Bishop JA. Retinoblastoma, melanoma and the atypical mole syndrome. Br J Dermatol 1995; 132: 134–138.PubMedCrossRefGoogle Scholar
  238. 238.
    Moll AC, Imhof SM, Bouter LM, Tan KE. Second primary tumors in patients with retino-blastoma. A review of the literature. Ophthalmic Genet 1997; 18: 27–34.PubMedCrossRefGoogle Scholar
  239. 239.
    Vogt T, Kroiss M, McClelland M, et al. Deficiency of a novel retinoblastoma binding protein 2-homolog is a consistent feature of sporadic human melanoma skin cancer. Lab Invest 1999; 79: 1615–1627.PubMedGoogle Scholar
  240. 240.
    Sherr CJ. Mammalian G1 cyclins and cell cycle progression. Proc Assoc Am Physicians 1995; 107: 181–186.PubMedGoogle Scholar
  241. 241.
    Halaban R, Funasaka Y, Lee P, Rubin J, Ron D, Birnbaum D. Fibroblast growth factors in normal and malignant melanocytes. Ann NY Acad Sci 1991; 638: 232–243.PubMedCrossRefGoogle Scholar
  242. 242.
    Gaudray P, Szepetowski P, Escot C, Birnbaum D, Theillet C. DNA amplification at l 1q13 in human cancer: from complexity to perplexity. Mutat Res 1992; 276: 317–328.PubMedCrossRefGoogle Scholar
  243. 243.
    Halaban R. Melanoma cell autonomous growth: the Rb/E2F pathway. Cancer Metastasis Rev 1999; 8: 333–343.CrossRefGoogle Scholar
  244. 244.
    Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclindependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994; 368: 753–756.PubMedCrossRefGoogle Scholar
  245. 245.
    Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994; 264: 436–440.PubMedCrossRefGoogle Scholar
  246. 246.
    Kamb A, Shattuck-Eidens D, Eeles R, et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 1994; 8: 23–26.PubMedCrossRefGoogle Scholar
  247. 247.
    Wolfel T, Hauer M, Schneider J, et al. A p16LNx4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995; 269: 1281–1284.PubMedCrossRefGoogle Scholar
  248. 248.
    Senderowicz AM, Sausville EA. Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 2000; 92: 376–387.PubMedCrossRefGoogle Scholar
  249. 249.
    Gray N, Detivaud L, Doerig C, Meijer L. ATP-site directed inhibitors of cyclin-dependent kinases. Curr Med Chem 1999; 6: 859–875.PubMedGoogle Scholar
  250. 250.
    Hajduch M, Havlieek L, Vesely J, Novotny R, Mihal V, Strnad M. Synthetic cyclin dependent kinase inhibitors. New generation of potent anti-cancer drugs. Adv Exp Med Biol 1999; 457: 341–353.PubMedCrossRefGoogle Scholar
  251. 251.
    Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res 1996; 56: 2973–2978.PubMedGoogle Scholar
  252. 252.
    Patel V, Senderowicz AM, Pinto D Jr, et al. Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J Clin Invest 1998; 102: 1674–1681.PubMedCrossRefGoogle Scholar
  253. 253.
    Schrump DS, Matthews W, Chen GA, Mixon A, Altorki NK. Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. Clin Cancer Res 1998; 4: 2885–2890.PubMedGoogle Scholar
  254. 254.
    Senderowicz AM. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs 1999; 17: 313–320.PubMedCrossRefGoogle Scholar
  255. 255.
    Li Y, Bhuiyan M, Alhasan S, Senderowicz AM, Sarkar FH. Induction of apoptosis and inhibition of c-erbB-2 in breast cancer cells by flavopiridol. Clin Cancer Res 2000; 6: 223–229.PubMedGoogle Scholar
  256. 256.
    Carlson B, Lahusen T, Singh S, et al. Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res 1999; 59: 4634–4641.PubMedGoogle Scholar
  257. 257.
    Morishita R, Gibbons GH, Horiuchi M, et al. A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo. Proc Natl Acad Sci USA 1995; 92: 5855–5859.PubMedCrossRefGoogle Scholar
  258. 258.
    Maeshima Y, Kashihara N, Yasuda T, et al. Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo. J Clin Invest 1998; 101: 2589–2597.PubMedCrossRefGoogle Scholar
  259. 259.
    Mann MJ, Whittemore AD, Donaldson MC, et al. Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial. Lancet 1999; 354: 1493–1498.PubMedCrossRefGoogle Scholar
  260. 260.
    Parr MJ, Manome Y, Tanaka T, et al. Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector. Nat Med 1997; 3: 1145–1149.PubMedCrossRefGoogle Scholar
  261. 261.
    Park BJ, Brown CK, Hu Y, et al. Augmentation of melanoma-specific gene expression using a tandem melanocyte-specific enhancer results in increased cytotoxicity of the purine nucleoside phosphorylase gene in melanoma. Hum Gene Ther 1999; 10: 889–898.PubMedCrossRefGoogle Scholar
  262. 262.
    Siders WM, Halloran PJ, Fenton RG. Melanoma-specific cytotoxicity induced by a tyrosinase promoter-enhancer/herpes simplex virus thymidine kinase adenovirus. Cancer Gene Ther 1998; 5: 281–291.PubMedGoogle Scholar
  263. 263.
    Eberle J, Garbe C, Wang NP, Orfanos CE. Incomplete expression of the tyrosinase gene family (tyrosinase, TRP-1, and TRP-2) in human malignant melanoma cells in vitro. Pigment Cell Res 1995; 8: 307–313.PubMedCrossRefGoogle Scholar
  264. 264.
    Dong YB, Yang HL, Jane M, et al. Adenovirus-mediated E2F-1 gene transfer efficiently induces apoptosis in melanoma cells. Cancer 1999; 86: 2021–2033.PubMedCrossRefGoogle Scholar
  265. 265.
    Kowalik TF, DeGregori J, Schwarz JK, Nevins JR. E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J Virol 1995; 69: 2491–2500.PubMedGoogle Scholar
  266. 266.
    Phillips AC, Bates S, Ryan KM, Helin K, Vousden KH. Induction of DNA synthesis and apoptosis are separable functions of E2F-1. Genes Dev 1997; 11: 1853–1863.PubMedCrossRefGoogle Scholar
  267. 267.
    Holmberg C, Helin K, Sehested M, Karlstrom O. E2F-1-induced p53-independent apoptosis in transgenic mice. Oncogene 1998; 17: 143–155.PubMedCrossRefGoogle Scholar
  268. 268.
    DeGregori J, Leone G, Miron A, Jakoi L, Nevins JR. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci USA 1997; 94: 7245–7250.PubMedCrossRefGoogle Scholar
  269. 269.
    Shan B, Farmer AA, Lee WH. The molecular basis of E2F-1/DP-1-induced S-phase entry and apoptosis. Cell Growth Differ 1996; 7: 689–697.PubMedGoogle Scholar
  270. 270.
    Trimarchi JM, Fairchild B, Verona R, Moberg K, Andon N, Lees JA. E2F-6, a member of the E2F family that can behave as a transcriptional repressor. Proc Natl Acad Sci USA 1998; 95: 2850–2855.PubMedCrossRefGoogle Scholar
  271. 271.
    Cartwright P, Muller H, Wagener C, Holm K, Helin K. E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription. Oncogene 1998; 17: 611–623.PubMedCrossRefGoogle Scholar
  272. 272.
    Gaubatz S, Wood JG, Livingston DM. Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6. Proc Natl Acad Sci USA 1998; 95: 9190–9195.CrossRefGoogle Scholar
  273. 273.
    Kanitakis J, Montazeri A, Ghohestani R, Faure M, Claudy A. Bc1–2 oncoprotein expression in benign nevi and malignant melanomas of the skin. Eur J Dermatol 1995; 5: 501–507.Google Scholar
  274. 274.
    Rutberg SE, Goldstein IM, Yang YM, Stackpole CW, Ronai Z. Expression and transcriptional activity of AP-1, CRE, and URE binding proteins in B16 mouse melanoma subclones. Mol Carcinog 1994; 10: 82–87.PubMedCrossRefGoogle Scholar
  275. 275.
    Saenz-Santamaria MC, Reed JA, McNutt NS, Shea CR. Immunohistochemical expression of BCL-2 in melanomas and intradermal nevi. J Cutan Pathol 1994; 21: 393–397.PubMedCrossRefGoogle Scholar
  276. 276.
    Borner C, Schlagbauer Wadl H, Fellay I, Selzer E, Polterauer P, Jansen B. Mutated N-ras upregulates Bc1–2 in human melanoma in vitro and in SCID mice. Melanoma Res 1999; 9: 347–350.PubMedCrossRefGoogle Scholar
  277. 277.
    Grossman D, McNiff JM, Li F, Altieri DC. Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol 1999; 113: 1076–1081.PubMedCrossRefGoogle Scholar
  278. 278.
    Madireddi MT, Dent P, Fisher PB. Regulation of mda-7 gene expression during human melanoma differentiation. Oncogene 2000; 19: 1362–1368.PubMedCrossRefGoogle Scholar
  279. 279.
    Bar-Eli M. Role of AP-2 in tumor growth and metastasis of human melanoma. Cancer Metastasis Rev 1999; 18: 377–385.PubMedCrossRefGoogle Scholar
  280. 280.
    Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M. Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis. EMBO J 1998; 17: 4358–4369.PubMedCrossRefGoogle Scholar
  281. 281.
    Fournel M, Sapieha P, Beaulieu N, Besterman JM, MacLeod AR. Down-regulation of human DNA-(cytosine-5) methyltransferase induces cell cycle regulators p16(ink4A) and p21(WAF/Cipl) by distinct mechanisms. J Biol Chem 1999; 274: 24250–24256.PubMedCrossRefGoogle Scholar
  282. 282.
    Milutinovic S, Knox JD, Szyf M. DNA methyltransferase inhibition induces the transcription of the tumor suppressor p21(WAF1/CIP1/sdil). J Biol Chem 2000; 275: 6353–6359.PubMedCrossRefGoogle Scholar
  283. 283.
    Ramchandani S, MacLeod AR, Pinard M, von Hofe E, Szyf M. Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligodeoxynucleotide. Proc Natl Acad Sci USA 1997; 94: 684–689.PubMedCrossRefGoogle Scholar
  284. 284.
    Slack A, Cervoni N, Pinard M, Szyf M. DNA methyltransferase is a downstream effector of cellular transformation triggered by simian virus 40 large T antigen. J Biol Chem 1999; 274: 10105–10112.PubMedCrossRefGoogle Scholar
  285. 285.
    Halaban R, Ghosh S, Duray P, Kirkwood JM, Lerner AB. Human melanocytes cultured from nevi and melanomas. J Invest Dermatol 1986; 87: 95–101.PubMedCrossRefGoogle Scholar
  286. 286.
    De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R. Socs 1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation. EMBO J 1999; 18: 904–915.PubMedCrossRefGoogle Scholar
  287. 287.
    Martin KJ, Kritzman BM, Price LM, et al. Linking gene expression patterns to therapeutic groups in breast cancer. Cancer Res 2000; 60: 2232–2238.PubMedGoogle Scholar
  288. 288.
    Perou CM, Jeffrey SS, van de Rijn M, et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci USA 1999; 96: 9212–9217.PubMedCrossRefGoogle Scholar
  289. 289.
    Nacht M, Ferguson AT, Zhang W, et al. Combining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancer. Cancer Res 1999; 59: 5464–5470.PubMedGoogle Scholar
  290. 290.
    Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.PubMedCrossRefGoogle Scholar
  291. 291.
    Lai A, Marcellus RC, Corbeil HB, Branton PE. RBP1 induces growth arrest by repression of E2F-dependent transcription. Oncogene 1999; 18: 2091–2100.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc.,Totowa, NJ 2002

Authors and Affiliations

  • Ruth Halaban
  • Maria C. von Willebrand

There are no affiliations available

Personalised recommendations