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From Melanocytes to Melanoma pp 119–147Cite as

Altered Signal Transduction in Melanoma

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Abstract

Our understanding of signal transduction pathways involved in the regulation of melanoma development and resistance to treatment has advanced significantly in recent years. Here we focus on the current understanding of major cascades—from the receptors (including HGF, TNFR-associated factors, and Wnt), to kinases (including phosphatidylinositol phosphate 3’-phosphate and mitogen-activated protein kinase), to the affected corresponding transcription factors (including activating transcription factor 2 [ATF2], nuclear factor-κB, β-catenin, and Stat)—that contribute to the course of melanoma development.

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References

  1. Yang-Snyder J, Miller JR, Brown JD, Lai CJ, Moon RT. A frizzled homolog functions in a vertebrate Wnt signaling pathway. Curr Biol 1996;6:1302–1306.

    Article  PubMed  CAS  Google Scholar 

  2. Barker N, Clevers H. Catenins, Wnt signaling and cancer. Bioessays 2000;22:961–965.

    Article  PubMed  CAS  Google Scholar 

  3. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000;103:311–320.

    Article  PubMed  CAS  Google Scholar 

  4. Seidensticker MJ, Behrens J. Biochemical interactions in the Wnt pathway. Biochim Biophys Acta 2000;1495:168–182.

    Article  PubMed  CAS  Google Scholar 

  5. Margottin F, Bour SP, Durand H, et al. A novel human WD protein, hbeta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol Cell 1998;1:565–574.

    Article  PubMed  CAS  Google Scholar 

  6. Hart M, Concordet JP, Lassot I, et al. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr Biol 1999;9:207–210.

    Article  PubMed  CAS  Google Scholar 

  7. Latres E, Chiaur DS, Pagano M. The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene 1999;18:849–854.

    Article  PubMed  CAS  Google Scholar 

  8. Polakis P. More than one way to skin a catenin. Cell 2001;105:563–566.

    Article  PubMed  CAS  Google Scholar 

  9. Fuchs SY, Spiegelman VS, Kumar KG. The many faces of beta-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer. Oncogene 2004;23:2028–2036.

    Article  PubMed  CAS  Google Scholar 

  10. Cook D, Fry MJ, Hughes K, Sumathipala R, Woodgett JR, Dale TC. Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C. EMBO J 1996;15:4526–4536.

    PubMed  CAS  Google Scholar 

  11. Funayama N, Fagotto F, McCrea P, Gumbiner BM. Embryonic axis induction by the armadillo repeat domain of beta-catenin: evidence for intracellular signaling. J Cell Biol 1995;128:959–968.

    Article  PubMed  CAS  Google Scholar 

  12. He TC, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science 1998;281:1509–1512.

    Article  PubMed  CAS  Google Scholar 

  13. Lin SY, Xia W, Wang JC, et al. Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci U S A 2000;97:4262–4266.

    Article  PubMed  CAS  Google Scholar 

  14. Tago K, Nakamura T, Nishita M, et al. Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev 2000;14:1741–1749.

    PubMed  CAS  Google Scholar 

  15. Pollock PM, Trent JM. The genetics of cutaneous melanoma. Clin Lab Med 2000;20:667–690.

    PubMed  CAS  Google Scholar 

  16. Saida T. Recent advances in melanoma research. J Dermatol Sci 2001;26:1–13.

    Article  PubMed  CAS  Google Scholar 

  17. Castellano M, Parmiani G. Genes involved in melanoma: an overview of INK4a and other loci. Melanoma Res 1999;9:421–432.

    Article  PubMed  CAS  Google Scholar 

  18. Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 1999;59:269–273.

    PubMed  CAS  Google Scholar 

  19. Koch A, Waha A, Tonn JC, et al. Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 2001;93:445–449.

    Article  PubMed  CAS  Google Scholar 

  20. Rimm DL, Caca K, Hu G, Harrison FB, Fearon ER. Frequent nuclear/cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma. Am J Pathol 1999;154:325–329.

    PubMed  CAS  Google Scholar 

  21. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997;275:1790–1792.

    Article  PubMed  CAS  Google Scholar 

  22. Worm J, Christensen C, Gronbaek K, Tulchinsky E, Guldberg P. Genetic and epigenetic alterations of the APC gene in malignant melanoma. Oncogene 2004;23:5215–5226.

    Article  PubMed  CAS  Google Scholar 

  23. Omholt K, Platz A, Ringborg U, Hansson J. Cytoplasmic and nuclear accumulation of beta-catenin is rarely caused by CTNNB1 exon 3 mutations in cutaneous malignant melanoma. Int J Cancer 2001;92:839–842.

    Article  PubMed  CAS  Google Scholar 

  24. Reifenberger J, Knobbe CB, Wolter M, et al. Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. Int J Cancer. 2002;100:549–556.

    Article  PubMed  CAS  Google Scholar 

  25. Murakami T, Toda S, Fujimoto M, et al. Constitutive activation of Wnt/beta-catenin signaling pathway in migration-active melanoma cells: role of LEF-1 in melanoma with increased metastatic potential. Biochem Biophys Res Commun 2001;288:8–15.

    Article  PubMed  CAS  Google Scholar 

  26. Kielhorn E, Provost E, Olsen D, et al. Tissue microarray-based analysis shows phospho-beta-catenin expression in malignant melanoma is associated with poor outcome. Int J Cancer 2003;103:652–656.

    Article  PubMed  CAS  Google Scholar 

  27. Goodall J, Martinozzi S, Dexter TJ, et al. Brn-2 expression controls melanoma proliferation and is directly regulated by beta-catenin. Mol Cell Biol 2004;27:2915–2922.

    Article  CAS  Google Scholar 

  28. Goodall J, Wellbrock C, Dexter TJ, Roberts K, Marais R, Goding CR. The Brn-2 transcription factor activated BRAF to melanoma proliferation. Mol Cell Biol 2004;24:2924–2932.

    Google Scholar 

  29. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954.

    Article  PubMed  CAS  Google Scholar 

  30. Thomson JA, Murphy K, Baker E, Sutherland GR, Parsons PG, Sturm RA. The brn-2 gene regulates the melanocytic phenotype and tumorigenic potential of human melanoma cells. Oncogene 1995;11:690–700.

    Google Scholar 

  31. Dorsky RI, Raible DW, Moon RT. Direct regulation of nacre, a zebrafish MITF homolog required for pigment cell formation, by the Wnt pathway. Genes Dev 2000;14:158–162.

    PubMed  CAS  Google Scholar 

  32. Takeda K, Yasumoto K, Takada R, et al. Induction of melanocyte-specific microphthalmia-associated transcription factor by Wnt-3a. J Biol Chem 2000;275:14,013–14,016.

    Article  PubMed  CAS  Google Scholar 

  33. Hodgkinson CA, Moore KJ, Nakayama A, et al. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 1993;74:395–404.

    Article  PubMed  CAS  Google Scholar 

  34. Hughes MJ, Lingrel JB, Krakowsky JM, Anderson KP. A helix-loop-helix transcription factor-like gene is located at the mi locus. J Biol Chem 1993;268:20,687–20,690.

    PubMed  CAS  Google Scholar 

  35. Goding CR. Mitf from neural crest to melanoma: signal transduction and transcription in the melanocyte lineage. Genes Dev 2000;14:1712–1728.

    PubMed  CAS  Google Scholar 

  36. Widlund HR, Horstmann MA, Price ER, et al. Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor. J Cell Biol 2002;158:1079–1087.

    Article  PubMed  CAS  Google Scholar 

  37. Crnogorac-Jurcevic T, Efthimiou E, Capelli P, et al. Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene 2001;20:7437–7446.

    Article  PubMed  CAS  Google Scholar 

  38. Iozzo RV, Eichstetter I, Danielson KG. Aberrant expression of the growth factor Wnt-5A in human malignancy. Cancer Res. 1995;55:3495–3499.

    CAS  Google Scholar 

  39. Lejeune S, Huguet EL, Hamby A, Poulsom R, Harris AL. Wnt5a cloning, expression, and up-regulation in human primary breast cancers. Clin Cancer Res 1995;1:215–222.

    PubMed  CAS  Google Scholar 

  40. Bittner M, Meltzer P, Chen Y, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 2000;406:536–540.

    Article  PubMed  CAS  Google Scholar 

  41. Carr KM, Bittner M, Trent JM. Gene-expression profiling in human cutaneous melanoma. Oncogene 2003;22:3076–3080.

    Article  PubMed  CAS  Google Scholar 

  42. Weeraratna AT, Jiang Y, Hostetter G, et al. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 2002;1:279–288.

    Article  PubMed  CAS  Google Scholar 

  43. Weeraratna AT, Becker D, Carr KM, et al. Generation and analysis of melanoma SAGE libraries: SAGE advice on the melanoma transcriptome. Oncogene 2004;23:2264–2274.

    Article  PubMed  CAS  Google Scholar 

  44. Kuhl M, Sheldahl LC, Park M, Miller JR, Moon RT. The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet 2000;16:279–283.

    Article  PubMed  CAS  Google Scholar 

  45. Lahn MM, Sundell KL. The role of protein kinase C-alpha (PKC-alpha) in melanoma. Melanoma Res. 2004;14:85–89.

    Article  PubMed  CAS  Google Scholar 

  46. Powell MB, Rosenberg RK, Graham MJ, et al. Protein kinase C beta expression correlates with biological responses to 12-0-tetradecanoylphorbol 13-acetate. J Cancer Res Clin Oncol 1993;119:199–206.

    Article  PubMed  CAS  Google Scholar 

  47. Jonsson M, Smith K, Harris AL. Regulation of Wnt5a expression in human mammary cells by protein kinase C activity and the cytoskeleton. Br J Cancer 1998;78:430–438.

    PubMed  CAS  Google Scholar 

  48. Fults D, Pedone C. Deletion mapping of the long arm of chromosome 10 in glioblastoma multiforme. Genes Chromosomes Cancer 1993;7:173–177.

    Article  PubMed  CAS  Google Scholar 

  49. Isshiki K, Elder DE, Guerry D, Linnenbach AJ. Chromosome 10 allelic loss in malignant melanoma. Genes Chromosomes Cancer 1993;8:178–184.

    Article  PubMed  CAS  Google Scholar 

  50. Herbst RA, Weiss J, Ehnis A, Cavenee WK, Arden KC. Loss of heterozygosity for 10q22-10qter in malignant melanoma progression. Cancer Res 1994;54:3111–3114.

    PubMed  CAS  Google Scholar 

  51. Healy E, Rehman I, Angus B, Rees JL. Loss of heterozygosity in sporadic primary cutaneous melanoma. Genes Chromosomes Cancer 1995;12:152–156.

    Article  PubMed  CAS  Google Scholar 

  52. Ittmann M. Allelic loss on chromosome 10 in prostate adenocarcinoma. Cancer Res 1996;56:2143–2147.

    PubMed  CAS  Google Scholar 

  53. Parmiter AH, Balaban G, Clark WH Jr, Nowell PC. Possible involvement of the chromosome region 10q24–q26 in early stages of melanocytic neoplasia. Cancer Genet Cytogenet 1988;30:313–317.

    Article  PubMed  CAS  Google Scholar 

  54. Dahia PL, Marsh DJ, Zheng Z, et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res 1997;57:4710–4713.

    PubMed  CAS  Google Scholar 

  55. 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.

    PubMed  CAS  Google Scholar 

  56. Tashiro H, Blazes MS, Wu R, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 1997;57:3935–3940.

    PubMed  CAS  Google Scholar 

  57. Poetsch M, Lorenz G, Kleist B. Detection of new PTEN/MMAC1 mutations in head and neck squamous cell carcinomas with loss of chromosome 10. Cancer Genet Cytogenet 2002;132:20–24.

    Article  PubMed  CAS  Google Scholar 

  58. Simpson L, Parsons R. PTEN: life as a tumor suppressor. Exp Cell Res 2001;264:29–41.

    Article  PubMed  CAS  Google Scholar 

  59. Dudek H, Datta SR, Franke TF, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997;275:661–665.

    Article  PubMed  CAS  Google Scholar 

  60. Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, et al. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 1997;385:544–548.

    Article  PubMed  CAS  Google Scholar 

  61. Kennedy SG, Wagner AJ, Conzen SD, et al. The PI 3-kinase/Akt signaling pathway delivers an antiapoptotic signal. Genes Dev 1997;11:701–713.

    Article  PubMed  CAS  Google Scholar 

  62. Kulik G, Klippel A, Weber MJ. Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol 1997;17:1595–1606.

    PubMed  CAS  Google Scholar 

  63. Songyang Z, Baltimore D, Cantley LC, Kaplan DR, Franke TF. Interleukin 3-dependent survival by the Akt protein kinase. Proc Natl Acad Sci U S A 1997;94:11,345–11,350.

    Article  PubMed  CAS  Google Scholar 

  64. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cellintrinsic death machinery. Cell 1997;91:231–241.

    Article  PubMed  CAS  Google Scholar 

  65. Cheney IW, Johnson DE, Vaillancourt MT, et al. Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res 1998;58:2331–2334.

    PubMed  CAS  Google Scholar 

  66. Teng DH, Hu R, Lin H, et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 1997;57:5221–5225.

    PubMed  CAS  Google Scholar 

  67. 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.

    Article  PubMed  CAS  Google Scholar 

  68. Birck A, Ahrenkiel V, Zeuthen J, Hou-Jensen K, Guldberg P. Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J Invest Dermatol 2000;114:277–280.

    Article  PubMed  CAS  Google Scholar 

  69. Reifenberger J, Wolter M, Boström J, Schulte K, Ruzicka T, Reifenberger G. Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas. Virchows Arch 2000;436:487–493.

    Article  PubMed  CAS  Google Scholar 

  70. Celebi JT, Shendrik I, Silvers DN, Peacocke MJ. Identification of PTEN mutations in metastatic melanoma specimens. J Med Genet 2000;37:653–657.

    Article  PubMed  CAS  Google Scholar 

  71. Boni R, Vortmeyer AO, Burg G, Hofbauer G, Zhuang Z. The PTEN tumour suppressor gene and malignant melanoma. Melanoma Res 1998;8:300–302.

    Article  PubMed  CAS  Google Scholar 

  72. Poetsch M, Dittberner T, Woenckhaus C. PTEN/MMAC1 in malignant melanoma and its importance for tumor progression. Cancer Genet Cytogenet 2001;125:21–26.

    Article  PubMed  CAS  Google Scholar 

  73. Cairns P, Polascik TJ, Eby Y, et al. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat Genet 1995;11:210–212.

    Article  PubMed  CAS  Google Scholar 

  74. Zhou XP, Gimm O, Hampel H, Niemann T, Walker MJ, Eng C. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am J Pathol 2000;157:1123–1128.

    PubMed  CAS  Google Scholar 

  75. Whang YE, Wu X, Suzuki H, et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 1998;95:5246–5250.

    Article  PubMed  CAS  Google Scholar 

  76. Salvesen HB, MacDonald N, Ryan A, et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int J Cancer 2001;91:22–26.

    Article  PubMed  CAS  Google Scholar 

  77. Whiteman DC, Zhou XP, Cummings MC, Pavey S, Hayward NK, Eng C. Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma. Int J Cancer 2002;99:63–67.

    Article  PubMed  CAS  Google Scholar 

  78. Robertson GP, Herbst RA, Nagane M, Huang HJ, Cavenee WK. The chromosome 10 monosomy common in human melanomas results from loss of two separate tumor suppressor loci. Cancer Res 1999;59:3596–3601.

    PubMed  CAS  Google Scholar 

  79. 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.

    Article  PubMed  CAS  Google Scholar 

  80. Hwang PH, Yi HK, Kim DS, Nam SY, Kim JS, Lee DY. Suppression of tumorigenicity and metastasis in B16F10 cells by PTEN/MMAC1/TEP1 gene. Cancer Lett 2001;172:83–91.

    Article  PubMed  CAS  Google Scholar 

  81. Harlan JE, Yoon HS, Hajduk PJ, Fesik SW. Structural characterization of the interaction between a pleckstrin homology domain and phosphatidylinositol 4,5-bisphosphate. Biochemistry 1995;34:9859–9864.

    Article  PubMed  CAS  Google Scholar 

  82. Karin M, Lin A. NF-B at the crossroads of life and death. Nat Immunol 2002;3:221–227.

    Article  PubMed  CAS  Google Scholar 

  83. Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998;282:1318–1321.

    Article  PubMed  CAS  Google Scholar 

  84. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857–868.

    Article  PubMed  CAS  Google Scholar 

  85. Romashkova JA, Makarov SS. NF-B is a target of AKT in anti-apoptotic PDGF signalling. Nature 1999;401:86–90.

    Article  PubMed  CAS  Google Scholar 

  86. Aoki M, Batista O, Bellacosa A, Tsichlis P, Vogt PK. The akt kinase: molecular determinants of oncogenicity. Proc Natl Acad Sci USA 1998;95:14,950–14,955.

    Article  PubMed  CAS  Google Scholar 

  87. Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 2002;14:381–395.

    Article  PubMed  CAS  Google Scholar 

  88. Waldmann V, Wacker J, Deichmann M. Absence of mutations in the pleckstrin homology (PH) domain of protein kinase B (PKB/Akt) in malignant melanoma. Melanoma Res 2002;12:45–50.

    Article  PubMed  CAS  Google Scholar 

  89. Waldmann V, Wacker J, Deichmann M. Mutations of the activation-associated phosphorylation sites at codons 308 and 473 of protein kinase B are absent in human melanoma. Arch Dermatol Res 2001;293:368–372.

    Article  PubMed  CAS  Google Scholar 

  90. Dhawan P, Singh AB, Ellis DL, Richmond A. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res 2002;62:7335–7342.

    PubMed  CAS  Google Scholar 

  91. Andjelkovic M, Alessi DR, Meier R, et al. Role of translocation in the activation and function of protein kinase B. J Biol Chem 1997;272:31,515–31,524.

    Article  PubMed  CAS  Google Scholar 

  92. Li G, Kalabis J, Xu X, et al. Reciprocal regulation of MelCAM and AKT in human melanoma. Oncogene 2003;22:6891–6899.

    Article  PubMed  CAS  Google Scholar 

  93. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489–501.

    Article  PubMed  CAS  Google Scholar 

  94. Jiang K, Sun J, Cheng J, Djeu JY, Wei S, Sebti S. Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Cancer Res 2003;63:2881–2890.

    Google Scholar 

  95. Stewart AL, Mhashilkar AM, Yang XH, et al. PI3 kinase blockade by Ad-PTEN inhibits invasion and induces apoptosis in RGP and metastatic melanoma cells. Mol Med 2002;8:451–461.

    PubMed  CAS  Google Scholar 

  96. Krasilnikov M, Ivanov VN, Dong J, Ronai Z. ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis. Oncogene 2003;22:4092–4101.

    Article  PubMed  CAS  Google Scholar 

  97. Stahl JM, Cheung M, Sharma A, Trivedi NR, Shanmugam S, Robertson GP. Loss of PTEN promotes tumor development in malignant melanoma. Cancer Res 2003;63:2881–2890.

    PubMed  CAS  Google Scholar 

  98. Larribere L, Khaled M, Tartare-Deckert S. PI3K mediates protection against TRAIL-induced apoptosis in primary human melanocytes. Cell Death Differ 2004;1038:4401–4475.

    Google Scholar 

  99. Hess AR, Seftor EA, Seftor RE, Hendrix MJ. Phosphoinositide 3-kinase regulates membrane Type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry. Cancer Res 2003;63:4757–4762.

    PubMed  CAS  Google Scholar 

  100. Johnson JP. Cell adhesion molecules in the development and progression of malignant melanoma. Cancer Metastasis Rev 1999;18:345–357.

    Article  PubMed  CAS  Google Scholar 

  101. Chen Z, Sun J, Pradines A, Favre G, Adnane J, Sebti SM. Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. J Biol Chem 2000;275:17,974–17,978.

    Article  PubMed  CAS  Google Scholar 

  102. Kim D, Kim S, Koh H, et al. Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J 2001;15:1953–1962.

    Article  PubMed  CAS  Google Scholar 

  103. Park BK, Zeng X, Glazer RI. Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. Cancer Res 2001;61:7647–7653.

    PubMed  CAS  Google Scholar 

  104. Fritz G, Kaina B. Ras-related GTPase Rhob represses NF-kappaB signaling. J Biol Chem 2001;276:3115–3122.

    Article  PubMed  CAS  Google Scholar 

  105. van Elsas A, Zerp S, van der Flier S, et al. Analysis of N-Ras mutations in human cutaneous melanoma: tumour heterogeneity detected by polymerase chain reaction/single-stranded conformation polymerism analysis. Rec Results Cancer Res 1995;139:57–67.

    Google Scholar 

  106. Carr J, MacKie RM. Point mutations in the N-Ras oncogene in malignant melanoma and congenital naevi. Br J Dermatol 1994;131:72–77.

    Article  PubMed  CAS  Google Scholar 

  107. Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet 2003;33:19–20.

    Article  PubMed  CAS  Google Scholar 

  108. Gorden A, Osman I, Gai W, et al. Analysis of BRAF and N-Ras mutations in metastatic melanoma tissues. Cancer Res. 2003;63:3955–3957.

    PubMed  CAS  Google Scholar 

  109. Kumar R, Angelini S, Czene K, et al. BRAF mutations in metastatic melanoma: a possible association with clinical outcome. Clin Cancer Res 2003;9:3362–3368.

    PubMed  CAS  Google Scholar 

  110. Houben R, Becker JC, Kappel A, et al. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog 2004;3:6.

    Article  PubMed  Google Scholar 

  111. Ball NJ, Yohn JJ, Morelli JG, Norris DA, Golitz LE, Hoeffler JP. Ras mutations in human melanoma: a marker of malignant progression. J Investig Dermatol 1994;102:285–290.

    Article  PubMed  CAS  Google Scholar 

  112. Satyamoorthy K, Li G, Gerrero MR, et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res. 2003;63:756–759.

    PubMed  CAS  Google Scholar 

  113. Bohm 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.

    PubMed  CAS  Google Scholar 

  114. Imokawa G, Kobayasi T, Miyagishi M. Intracellular signaling mechanisms leading to synergistic effects of endothelin-1 and stem cell factor on proliferation of cultured human melanocytes. Crosstalk via trans-activation of the tyrosine kinase c-kit receptor. J Biol Chem 2000;275:33,321–33,328.

    Article  PubMed  CAS  Google Scholar 

  115. Wellbrock C, Weisser C, Geissinger E, Troppmair J, Schartl M. Activation of p59(Fyn) leads to melanocyte dedifferentiation by influencing MKP-1-regulated mitogen-activated protein kinase signaling. J Biol Chem 2002;277:6443–6454.

    Article  PubMed  CAS  Google Scholar 

  116. Wilson RE, Dooley TP, Hart IR. Induction of tumorigenicity and lack of in vitro growth requirement for 12-O-tetradecanoylphorbol-13-acetate by transfection of murine melanocytes with v-Ha-Ras. Cancer Res 1989;49:711–716.

    PubMed  CAS  Google Scholar 

  117. Albino AP, Sozzi G, Nanus DM, Jhanwar SC, Houghton AN. Malignant transformation of human melanocytes: induction of a complete melanoma phenotype and genotype. Oncogene 1992;7:2315–2321.

    PubMed  CAS  Google Scholar 

  118. Wellbrock C, Ogilvie L, Hedley D, et al. V599EB-RAF is an oncogene in melanocytes. Cancer Res 2004;64:2338–2342.

    Article  PubMed  CAS  Google Scholar 

  119. Takayama T, Ohi M, Hayashi T, et al. Analysis of K-Ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis. Gastroenterology 2001;121:599–611.

    Article  PubMed  CAS  Google Scholar 

  120. Yamashita N, Minamoto T, Ochiai A, Onda M, Esumi H. Frequent and characteristic K-Ras activation and absence of p53 protein accumulation in aberrant crypt foci of the colon. Gastroenterology 1995;108:434–440.

    Article  PubMed  CAS  Google Scholar 

  121. Dong J, Phelps RG, Qiao R, et al. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res 2003;63:3883–3885.

    PubMed  CAS  Google Scholar 

  122. Saldanha G, Purnell D, Fletcher A, Potter L, Gillies A, Pringle JH. High BRAF mutation frequency does not characterize all melanocytic tumor types. Int J Cancer 2004;111:705–710.

    Article  PubMed  CAS  Google Scholar 

  123. Rivers JK. Is there more than one road to melanoma? Lancet 2004;363:728–730.

    Article  PubMed  Google Scholar 

  124. Tomicic J, Wanebo HJ. Mucosal melanomas. Surg Clin N Am 2003;83:237–252.

    Article  PubMed  Google Scholar 

  125. Cohen Y, Goldenberg-Cohen N, Parrella P, et al. Lack of BRAF mutation in primary uveal melanoma. Invest Ophthalmol Vis Sci 2003;44:2876–2878.

    Article  PubMed  Google Scholar 

  126. Edmunds SC, Cree IA, Di Nicolantonio F, Hungerford JL, Hurren JS, Kelsell DP. Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas. Br J Cancer 2003;88:1403–1405.

    Article  PubMed  CAS  Google Scholar 

  127. Edwards RH, Ward MR, Wu H, et al. Absence of BRAF mutations in UV-protected mucosal melanomas. J Med Genet 2004;41:270–272.

    Article  PubMed  CAS  Google Scholar 

  128. Klc E, Bruggenwirth HT, Verbiest MM, et al The Ras-BRAF kinase pathway is not involved in uveal melanoma. Melanoma Res 2004;14:203–205.

    Article  CAS  Google Scholar 

  129. Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 2003;95:1878–1890.

    PubMed  CAS  Google Scholar 

  130. Cohen Y, Rosenbaum E, Begum S, et al. Clin exon 15 BRAF mutations are uncommon in melanomas arising in nonsun-exposed sites. Cancer Res 2004;10:3444–3447.

    Article  CAS  Google Scholar 

  131. Daniotti M, Oggionni M, Ranzani T, et al. BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene 2004;23:5968–5977.

    Article  PubMed  CAS  Google Scholar 

  132. Tsao H, Zhang X, Fowlkes K, Haluska FG. Relative reciprocity of NRas and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res 2000;60:1800–1804.

    PubMed  CAS  Google Scholar 

  133. Weber A, Hengge UR, Urbanik D, et al. Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Lab Invest 2003;83:1771–1776.

    Article  PubMed  CAS  Google Scholar 

  134. Kortylewski M, Heinrich PC, Kauffmann ME, Bohm M, MacKiewicz A, Behrmann I. Mitogenactivated protein kinases control p27/Kip1 expression and growth of human melanoma cells. Biochem J 2001;357:297–303.

    Article  PubMed  CAS  Google Scholar 

  135. Lefebre G, Calipel A, Mouriaux F, Hecquet C, Malecaze F, Mascarelli F. Opposite long-term regulation of c-Myc and p27Kip1 through overactivation of Raf-1 and the MEK/ERK module in proliferating human choroidal melanoma cells. Oncogene 2003;22:8813–8822.

    Article  CAS  Google Scholar 

  136. Wu M, Hemesath TJ, Takemoto CM, et al. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev 2000;14:301–312.

    PubMed  CAS  Google Scholar 

  137. Kim DS, Hwang ES, Lee JE, Kim SY, Kwon SB, Park KC. Sphingosine-1-phosphate decreases melanin synthesis via sustained ERK activation and subsequent MITF degradation. J Cell Sci 2003;116:1699–706.

    Article  PubMed  CAS  Google Scholar 

  138. Eisenmann KM, VanBrocklin MW, Staffend NA, Kitchen SM, Koo HM. Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Cancer Res. 2003;63:8330–8337.

    PubMed  CAS  Google Scholar 

  139. Aguirre Ghiso JA, Kovalski K, Ossowski L. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 1999;147:89–104.

    Article  PubMed  CAS  Google Scholar 

  140. Santibanez JF, Iglesias M, Frontelo P, Martinez J, Quintanilla M. Involvement of the Ras/MAPK signaling pathway in the modulation of urokinase production and cellular invasiveness by transforming growth factor-beta (1) in transformed keratinocytes. Biochem Biophys Res Commun 2000;273:521–527.

    Article  PubMed  CAS  Google Scholar 

  141. Genersch E, Hayess K, Neuenfeld Y, Haller H. Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras-dependent and-independent pathways. J Cell Sci 2000;113:4319–4330.

    PubMed  CAS  Google Scholar 

  142. Tower GB, Coon CC, Benbow U, Vincenti MP, Brinckerhoff CE. Erk 1/2 differentially regulates the expression from the 1G/2G single nucleotide polymorphism in the MMP-1 promoter in melanoma cells. Biochim Biophys Acta 2002;1586:265–274.

    PubMed  CAS  Google Scholar 

  143. Ishii Y, Ogura T, Tatemichi M, Fujisawa H, Otsuka F, Esumi H. Induction of matrix metalloproteinase gene transcription by nitric oxide and mechanisms of MMP-1 gene induction in human melanoma cell lines. Int J Cancer 2003;103:161–168.

    Article  PubMed  CAS  Google Scholar 

  144. Ramos MC, Steinbrenner H, Stuhlmann D, Sies H, Brenneisen P. Induction of MMP-10 and MMP-1 in a squamous cell carcinoma cell line by ultraviolet radiation. Biol Chem 2004;385:75–86.

    Article  PubMed  CAS  Google Scholar 

  145. Huntington JT, Shields JM, Der CJ, et al. Overexpression of collagenase 1 (MMP-1) is mediated by the ERK pathway in invasive melanoma cells: role of BRAF mutation and FGF signaling. J Biol Chem 2004;279:33,168–33,176.

    Article  PubMed  CAS  Google Scholar 

  146. Woods D, Cherwinski H, Venetsanakos E, et al. Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase signaling pathway. Mol Cell Biol 2001;21:3192–3205.

    Article  PubMed  CAS  Google Scholar 

  147. Halaban R. Growth factors and tyrosine protein kinases in normal and malignant melanocytes. Cancer Metastasis Rev 1991;10:129–140.

    Article  PubMed  CAS  Google Scholar 

  148. Halaban R. Growth factors and melanomas. Semin Oncol 1996;23:673–681.

    PubMed  CAS  Google Scholar 

  149. Easty DJ, Bennett DC. Protein tyrosine kinases in malignant melanoma. Melanoma Res 2000;10:401–411.

    Article  PubMed  CAS  Google Scholar 

  150. Miglarese MR, Halaban R, Gibson NW. Regulation of fibroblast growth factor 2 expression in melanoma cells by the c-MYB proto-oncoprotein. Cell Growth Differ 1997;8:1199–1210.

    PubMed  CAS  Google Scholar 

  151. Richmond A, Lawson DH, Nixon DW, Stevens JS, Chawla RK. In vitro growth promotion in human malignant melanoma cells by fibroblast growth factor. Cancer Res 1982;42:3175–3180.

    PubMed  CAS  Google Scholar 

  152. Nesbit M, Nesbit HK, Bennett J, et al. Basic fibroblast growth factor induces a transformed phenotype in normal human melanocytes. Oncogene 1999;18:6469–6476.

    Article  PubMed  CAS  Google Scholar 

  153. Meier F, Caroli U, Satyamoorthy K, et al. Fibroblast growth factor-2 but not Mel-CAM and/or beta3 integrin promotes progression of melanocytes to melanoma. Exp Dermatol 2003;12:296–306.

    Article  PubMed  CAS  Google Scholar 

  154. Ozen M, Medrano EE, Ittmann M. Inhibition of proliferation and survival of melanoma cells by adenoviral-mediated expression of dominant negative fibroblast growth factor receptor. Melanoma Res 2004;14:13–21.

    Article  PubMed  CAS  Google Scholar 

  155. Furge KA, Kiewlich D, Le P, et al. Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase. Proc Natl Acad Sci USA 2001;98:10,722–10,727.

    Article  PubMed  CAS  Google Scholar 

  156. Cruz J, Reis-Filho JS, Silva P, Lopes JM. Expression of c-met tyrosine kinase receptor is biologically and prognostically relevant for primary cutaneous malignant melanomas. Oncology 2003;65:72–82.

    Article  PubMed  CAS  Google Scholar 

  157. Hendrix MJ, Seftor EA, Seftor RE, et al. Regulation of uveal melanoma interconverted phenotype by hepatocyte growth factor/scatter factor (HGF/SF). AM J Pathol 1998;152:855–863.

    PubMed  CAS  Google Scholar 

  158. 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.

    PubMed  CAS  Google Scholar 

  159. Elia G, Ren Y, Lorenzoni P, et al. Mechanisms regulating c-met overexpression in liver-metastatic B16-LS9 melanoma cells. J Cell Biochem 2001;81:477–487.

    Article  PubMed  CAS  Google Scholar 

  160. Tomida M, Satio T. The human hepatocyte growth factor (HGF) gene is transcriptionally activated by leukemia inhibitory factor through the Stat binding element. Oncogene 2004;23:679–686.

    Article  PubMed  CAS  Google Scholar 

  161. Recio JA, Merlino G. Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1. Oncogene 2002;21:1000–1008.

    Article  PubMed  CAS  Google Scholar 

  162. Noonan FP, Recio JA, Takayama H, et al. Neonatal sunburn and melanoma in mice. Nature 2001;413:271–272.

    Article  PubMed  CAS  Google Scholar 

  163. Scholl FA, Kamarashev J, Murmann OV, Geertsen R, Dummer R, Schafer BW. PAX3 is expressed in human melanomas and contributes to tumor cell survival. Cancer Res 2001;61:823–826.

    PubMed  CAS  Google Scholar 

  164. Galibert MD, Yavuzer U, Dexter TJ, Goding CR. Pax3 and regulation of the melanocyte-specific tyrosinase-related protein-1 promoter. J Biol Chem 1999;274:26,894–26,900.

    Article  PubMed  CAS  Google Scholar 

  165. Dahl E, Koseki H, Balling R. Pax genes and organogenesis. BioEssays 1997;19:755–765.

    Article  PubMed  CAS  Google Scholar 

  166. Bober E, Franz T, Arnold HH, Gruss P, Tremblay P. PAX3 is required for the development of limb muscles: a possible role for the migration of dermomyotomal muscle progenitor cells. Development 1994;120:603–612.

    PubMed  CAS  Google Scholar 

  167. Tassabehji M, Read AP, Newton VE, et al. Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2. Nat Genet 1993;3:26–30.

    Article  PubMed  CAS  Google Scholar 

  168. Barr FG, Galili N, Holick J, Biegel JA, Rovera G, Emanuel BS. Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nat Genet 1993;3:113–117.

    Article  PubMed  CAS  Google Scholar 

  169. Epstein DJ, Vekemans M, Gros P. Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell 1991;67:767–774.

    Article  PubMed  CAS  Google Scholar 

  170. Epstein JA, Shapiro DN, Cheng J, Lam PY, Maas RL. Pax3 modulates expression of the c-Met receptor during limb muscle development. Proc Natl Acad Sci USA 1996;93:4213–4218.

    Article  PubMed  CAS  Google Scholar 

  171. Wang W, Kumar P, Wang W, et al. Insulin-like growth factor II and PAX3-FKHR cooperate in the oncogenesis of rhabdomyosarcoma. Cancer Res 1998;58:4426–4433.

    PubMed  CAS  Google Scholar 

  172. Margue CM, Bernasconi M, Barr FG, Schafer BW. Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR. Oncogene 2000;19:2921–2929.

    Article  PubMed  CAS  Google Scholar 

  173. Ihle JN, Kerr IM. Jaks and stats in signaling by the cytokine receptor superfamily. Trends Genet 1995;11:69–74.

    Article  PubMed  CAS  Google Scholar 

  174. Darnell JE Jr. STATs and gene regulation. Science 1997;277:1630–1635.

    Article  PubMed  CAS  Google Scholar 

  175. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994;264:1415–1421.

    Article  PubMed  CAS  Google Scholar 

  176. Turkson J, Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 2000;19:6613–6626.

    Article  PubMed  CAS  Google Scholar 

  177. Garcia R, Jove R. Activation of STAT transcription factors in oncogenic tyrosine kinase signaling. J Biomed Sci 1998;5:79–85.

    Article  PubMed  CAS  Google Scholar 

  178. Catlett-Falcone R, Dalton WS, Jove R. STAT proteins as novel targets for cancer therapy. Signal transducer and activator of transcription. Curr Opin Oncol 1999;11:490–496.

    Article  PubMed  CAS  Google Scholar 

  179. Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene 2000;19:2474–2488.

    Article  PubMed  CAS  Google Scholar 

  180. Song JI, Grandis JR. STAT signaling in head and neck cancer. Oncogene 2000;19:2489–2495.

    Article  PubMed  CAS  Google Scholar 

  181. Coffer PJ, Koenderman L, de Groot RP. The role of STATs in myeloid differentiation and leukemia. Oncogene 2000;19:2511–2522.

    Article  PubMed  CAS  Google Scholar 

  182. Wang T, Niu G, Kortylewski M, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 2004;10:48–54.

    Article  PubMed  CAS  Google Scholar 

  183. Bromberg JF, Horvath CM, Wen Z, Schreiber RD, Darnell JE Jr. Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon γ and interferon γ. Proc Natl Acad Sci USA 1996;93:7673–7678.

    Article  PubMed  CAS  Google Scholar 

  184. Kovarik J, Boudny V, Kocak I, Lauerova L, Fait V, Vagundova M. Malignant melanoma associates with deficient IFN-induced STAT1 phosphorylation. Int J Mol Med 2003;12:335–340.

    PubMed  CAS  Google Scholar 

  185. Wong LH, Krauer KG, Hatzinisiriou I, et al. Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2, and p48-ISGF3gamma. J Biol Chem 1997;272:28,779–28,785.

    Article  PubMed  CAS  Google Scholar 

  186. Ivanov VN, Bhoumik A, Krasilnikov M, et al. Cooperation between STAT3 and c-jun suppresses Fas transcription. Mol Cell 2001;7:517–528.

    Article  PubMed  CAS  Google Scholar 

  187. Niu G, Bowman T, Huang M, et al. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 2002;21:7001–7010.

    Article  PubMed  CAS  Google Scholar 

  188. Ivanov VN, Krasilnikov M, Ronai Z. Regulation of Fas expression by STAT3 and c-Jun is mediated by phosphatidylinositol 3-kinase-AKT signaling. J Biol Chem 2002;277:4932–4944.

    Article  PubMed  CAS  Google Scholar 

  189. Krasilnikov M, Ivanov VN, Dong J, Ronai Z. ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis. Oncogene 203;22:4092–4101.

    Google Scholar 

  190. Turkson J, Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 2000;19:6613–6626.

    Article  PubMed  CAS  Google Scholar 

  191. Arch RH, Gedrich RW, Thompson CB. Translocation of TRAF proteins regulates apoptotic threshold of cells. Biochem Biophys Res Commun 2000;272:936–945.

    Article  PubMed  CAS  Google Scholar 

  192. Hsu H, Shu HB, Pan MG, Goeddel DV. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 1996;84:299–308.

    Article  PubMed  CAS  Google Scholar 

  193. Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev 1999;13:1297–1308.

    PubMed  CAS  Google Scholar 

  194. Duckett CS, Thompson CB. CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival. Genes Dev 1997;11:2810–2821.

    PubMed  CAS  Google Scholar 

  195. Galibert L, Tometsko ME, Anderson DM, Cosman D, Dougall WC. The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. J Biol Chem 1998;273:34,120–34,127.

    Article  PubMed  CAS  Google Scholar 

  196. Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitors of apoptosis proteins. Cell 1995;83:1243–1252.

    Article  PubMed  CAS  Google Scholar 

  197. Liu H, Su YC, Becker E, Treisman J, Skolnik EY. A Drosophila TNF-receptor-associated factor (TRAF) binds the ste20 kinases Misshapen and activates Jun kinase. Curr Biol 1999;9:101–104.

    Article  PubMed  CAS  Google Scholar 

  198. Natoli G, Costanzo A, Ianni A, et al. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Science 1997;275:200–203.

    Article  PubMed  CAS  Google Scholar 

  199. Shi CS, Kehrl JH. Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-kappaB, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2-and germinal center kinase related-dependent pathway. J Biol Chem 1997;272:32,102–32,107.

    Article  PubMed  CAS  Google Scholar 

  200. Nishitoh H, Saitoh M, Mochida Y, et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol Cell 1998;2:389–395.

    Article  PubMed  CAS  Google Scholar 

  201. Devin A, Lin Y, Yamaoka S, Li Z, Karin M, Liu ZG. The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF. Mol Cell Biol 2001;21:3986–3994.

    Article  PubMed  CAS  Google Scholar 

  202. Shu HB, Takeuchi M, Goeddel DV. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc Natl Acad Sci USA 1996;93:13,973–13,978.

    Article  PubMed  CAS  Google Scholar 

  203. Wang Y, Wu TR, Cai S, Welte T, Chin YE. Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation. Mol Cell Biol 2000;20:4505–4512.

    Article  PubMed  CAS  Google Scholar 

  204. Habelhah H, Frew IJ, Laine A, et al. Stress-induced decrease in TRAF2 stability is mediated by Siah2. EMBO J 2002;21:5756–5765.

    Article  PubMed  CAS  Google Scholar 

  205. Ivanov VN, Kehrl JH, Ronai Z. Role of TRAF2/GCK in melanoma sensitivity to UV-induced apoptosis. Oncogene 2000;19:933–942.

    Article  PubMed  CAS  Google Scholar 

  206. Ivanov VN, Fodstad O, Ronai Z. Expression of ring finger-deleted TRAF2 sensitizes metastatic melanoma cells to apoptosis via up-regulation of p38, TNFalpha and suppression of NF-kappaB activities. Oncogene 2001;20:2243–2253.

    Article  PubMed  CAS  Google Scholar 

  207. Kunz M, Ibrahim S, Koczan D, et al. Activation of c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) is critical for hypoxia-induced apoptosis of human malignant melanoma. Cell Growth Differ 2001;12:137–145.

    PubMed  CAS  Google Scholar 

  208. Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L. ERK (MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 2003;63:1684–1695.

    PubMed  CAS  Google Scholar 

  209. Fuchs SY, Chen A, Xiong Y, Pan ZQ, Ronai Z. HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin. Oncogene 1999;18:2039–2046.

    Article  PubMed  CAS  Google Scholar 

  210. Yaron A, Hatzubai A, Davis M, et al. Identification of the receptor component of the IkappaBalphaubiquitin ligase. Nature 1998;396:590–594.

    Article  PubMed  CAS  Google Scholar 

  211. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002;109:S81–S96.

    Article  PubMed  CAS  Google Scholar 

  212. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 1996;14:649–683.

    Article  PubMed  CAS  Google Scholar 

  213. McNulty SE, Tohidian NB, Meyskens FL. RelA, p50 and inhibitor of kappa B alpha are elevated in human metastatic melanoma cells and respond aberrantly to ultraviolet light B. Pigment Cell Res 2001;14:456–465.

    Article  PubMed  CAS  Google Scholar 

  214. Meyskens FL Jr, Buckmeier JA, McNulty SE, Tohidian NB. Activation of nuclear factor-kappa B in human metastatic melanoma cells and the effect of oxidative stress. Clin Cancer Res 1999;5:1197–1202.

    PubMed  CAS  Google Scholar 

  215. Devalaraja MN, Wang DZ, Ballard DW, Richmond A. Elevated constitutive IkappaB kinase activity and IkappaB-alpha phosphorylation in Hs294T melanoma cells lead to increased basal MGSA/GROalpha transcription. Cancer Res 1999;59:1372–1377.

    PubMed  CAS  Google Scholar 

  216. Yang J, Richmond A. Constitutive IkappaB kinase activity correlates with nuclear factor-kappaB activation in human melanoma cells. Cancer Res 2001;61:4901–4909.

    PubMed  CAS  Google Scholar 

  217. Dhawan P, Singh AB, Ellis DL, Richmond A. Constitutive activation of Akt/Protein Kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Research 2002;62:7335–7342.

    PubMed  CAS  Google Scholar 

  218. Kashani-Sabet M, Shaikh L, Miller JR 3rd, et al. NF-kappa B in the vascular progression of melanoma. J Clin Oncol 2004;22:617–623.

    Article  PubMed  CAS  Google Scholar 

  219. Kashani-Sabet M, Liu Y, Fong S. Identification of gene function and functional pathways by systemic plasmid-based ribozyme targeting in adult mice. Proc Natl Acad Sci USA 2002;99:3878–3883.

    Article  PubMed  CAS  Google Scholar 

  220. Chinenov Y, Kerppola TK. Close encounters of many kinds: Fos-Jun interactions that mediate transcription regulatory specificity. Oncogene 2001;20:2438–2452.

    Article  PubMed  CAS  Google Scholar 

  221. Vogt PK. Fortuitous convergences: the beginnings of JUN. Nature Rev Cancer 2002;2:465–469.

    Article  CAS  Google Scholar 

  222. Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1991;1072:129–157.

    PubMed  CAS  Google Scholar 

  223. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol 2002;4:131–136.

    Article  CAS  Google Scholar 

  224. Angel P, Szabowski A, Schorpp-Kistner M. Function and regulation of AP-1 subunits in skin physiology and pathology. Oncogene 2001;20:2413–2423.

    Article  PubMed  CAS  Google Scholar 

  225. Yamanishi DT, Buckmeier JA, Meyskens FL Jr. Expression of c-Jun, JunB, and c-Fos protooncogenes in human primary melanocytes and metastatic melanomas. J Invest Dermatol 1991;97:349–353.

    Article  PubMed  CAS  Google Scholar 

  226. 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.

    Article  PubMed  CAS  Google Scholar 

  227. Madireddi MT, Dent P, Fisher PB. AP-1 and C/EBP transcription factors contribute to mda-7 gene promoter activity during human melanoma differentiation. J Cell Physiol 2000;185:36–46.

    Article  PubMed  CAS  Google Scholar 

  228. Fisher PB, Gopalkrishnan RV, Chada S, et al. mda-7/IL-24, a novel cancer selective apoptosis inducing cytokine gene: from the laboratory into the clinic. Cancer Biol Ther 2003;2:S23–S37.

    PubMed  CAS  Google Scholar 

  229. Bhoumik A, Gangi L, Ronai Z. Inhibition of melanoma growth and metastasis by ATF2-derived peptides. Cancer Res 2004;64:8222–8230.

    Article  PubMed  CAS  Google Scholar 

  230. van Dam H, Castellazzi M. Distinct roles of Jun: Fos and Jun: ATF dimers in oncogenesis. Oncogene 2001;20:2453–2464.

    Article  PubMed  CAS  Google Scholar 

  231. Kaszubska W, Hooft van Huijsduijnen R, Ghersa P, et al. Cyclic AMP-independent ATF family members interact with NF-kappa B and function in the activation of the E-selectin promoter in response to cytokines. Mol Cell Biol 1993;13:7180–7190.

    PubMed  CAS  Google Scholar 

  232. Kim SJ, Wagner S, Liu F, O’Reilly MA, Robbins PD, Green MR. Retinoblastoma gene product activities expression of the human TGF-beta 2 gene through transcription factor ATF-2. Nature 1992;358:331–334.

    Article  PubMed  CAS  Google Scholar 

  233. Gupta S, Campbell D, Derijard B, Davis RJ. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 1995;267:389–393.

    Article  PubMed  CAS  Google Scholar 

  234. Tsai EY, Jain J, Pesavento PA, Rao A, Goldfeld AE. Tumor necrosis factor alpha gene regulation in activated T cells involves ATF-2/Jun and NFATp. Mol Cell Biol 1996;16:459–467.

    PubMed  CAS  Google Scholar 

  235. Shimizu M, Nomura Y, Suzuki H, et al. Activation of the rat cyclin A promoter by ATF2 and Jun family members and its suppression by ATF4. Exp Cell Res 1998;239:93–103.

    Article  PubMed  CAS  Google Scholar 

  236. van Dam H, Duyndam M, Rottier R, et al. Heterodimer formation of cJun and ATF-2 is responsible for induction of c-Jun by the 243 amino acid adenovirus E1A protein. EMBO 1993;12:479–487.

    Google Scholar 

  237. Huguier S, Baguet J, Perez S, van Dam H, Castellazzi M. Transcription factor ATF2 cooperates with v-Jun to promote growth factor-independent proliferation in vitro and tumor formation in vivo. Mol Cell Biol 1998;18:7020–7029.

    PubMed  CAS  Google Scholar 

  238. van Dam H, Huguier S, Kooistra K, et al. Autocrine growth and anchorage independence: two complementing Jun-controlled genetic programs of cellular transformation. Genes Dev 1998;12:1227–1239.

    PubMed  Google Scholar 

  239. Bhoumik A, Jones N, Ronai Z. Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity. Proc Natl Acad Sci USA 2004;101:4222–4227.

    Article  PubMed  CAS  Google Scholar 

  240. Ronai Z, Yang YM, Fuchs SY, Adler V, Sardana M, Herlyn M. ATF2 confers radiation resistance to human melanoma cells. Oncogene 1998;16:523–531.

    Article  PubMed  CAS  Google Scholar 

  241. Ivanov VN, Bhoumik A, Ronai Z. Death receptors and melanoma resistance to apoptosis. Oncogene 2003;22:3152–3161.

    Article  PubMed  CAS  Google Scholar 

  242. Berger A, Harriet K, Ning L, et al. Subcellular localization of activating transcription factor 2 in melanoma specimens predicts patient survival. Cancer Res 2003;63:8103–8107.

    PubMed  CAS  Google Scholar 

  243. Bhoumik A, Ivanov V, Ronai Z. Activating transcription factor 2-derived peptides alter resistance of human tumor cell lines to ultraviolet irradiation and chemical treatment. Clin Cancer Res 2001;7:331–342.

    PubMed  CAS  Google Scholar 

  244. Bhoumik A, Huang TG, Ivanov V, et al. An ATF2-derived peptide sensitizes melanomas to apoptosis and inhibits their growth and metastasis. J Clin Investig 2002;110:643–650.

    Article  PubMed  CAS  Google Scholar 

  245. Massagué J. TGFβ signal transduction. Annu Rev Biochem 1998;67:753–791.

    Article  PubMed  Google Scholar 

  246. Schier AF, Shen MM. Nodal signalling in vertebrate development. Nature 2000;403:385–389.

    Article  PubMed  CAS  Google Scholar 

  247. Whitman M. SMADs and early developmental signaling by the TGFβ superfamily. Genes Dev 1998;12:2445–2462.

    PubMed  CAS  Google Scholar 

  248. Massagué J, Blain SW, Lo RS. TGF-β signaling in growth control, cancer and heritable disorders. Cell 2000;103:295–309.

    Article  PubMed  Google Scholar 

  249. Myatt N, Aristodemou P, Neale MH. Abnormalities of the transforming growth factor-beta pathway in ocular melanoma. J Pathol 2000;192:511–518.

    Article  PubMed  CAS  Google Scholar 

  250. Berking C, Takemoto R, Schaider H, et al. Transforming growth factor-beta1 increases survival of human melanoma through stroma remodeling. Cancer Res 2001;61:8306–8316.

    PubMed  CAS  Google Scholar 

  251. Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene 2003;22:3113–3122.

    Article  PubMed  CAS  Google Scholar 

  252. Persad S, Troussard AA, McPhee TR, Mulholland DJ, Dedhar S. Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation. J Cell Biol 2001;153:1161–1174.

    Article  PubMed  CAS  Google Scholar 

  253. Hajduch E, Alessi DR, Hemmings BA, Hundal HS. Constitutive activation of protein kinase B by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells. Diabetes 1998;47:1006–1013.

    Article  PubMed  CAS  Google Scholar 

  254. van Weeren PC, de Bruyn KM, de Vries-Smits AM, van Lint J, Burgering BM. Essential role for protein kinase B (PKB) in insulin-induced glycogen synthase kinase 3 inactivation: characterization of dominant-negative mutant of PKB. J Biol Chem 1998;273:13,150–13,156.

    Article  PubMed  Google Scholar 

  255. Rudin CM, Holmlund J, Fleming GF, et al. Phase I trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer. Clin Cancer Res 2001;7:1214–1220.

    PubMed  CAS  Google Scholar 

  256. Mercer KE, Pritchard CA. Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta 2003;165:25–40.

    Google Scholar 

  257. Collisson EA, De A, Suzuki H, Gambhir SS, Kolodney MS. Treatment of metastatic melanoma with an orally available inhibitor of the Ras-Raf-MAPK cascade. Cancer Res 2003;63:5669–5673.

    PubMed  CAS  Google Scholar 

  258. Karasarides M, Chiloeches A, Hayward R, et al. B-RAF is a therapeutic target in melanoma. Oncogene 2004;23:6292–6298.

    Article  PubMed  CAS  Google Scholar 

  259. Bedogni B, O’Neill MS, Welford SM, et al. Topical treatment with inhibitors of the phosphatidylinositol 3′-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways reduces melanoma development in severe combined immunodeficient mice. Cancer Res 2004;64:2552–2560.

    Article  PubMed  CAS  Google Scholar 

  260. Sumimoto H, Miyagishi M, Miyoshi H, et al. Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Oncogene 2004;23:6031–6039.

    Article  PubMed  CAS  Google Scholar 

  261. Pavey S, Johansson P, Packer L, et al. Microarray expression profiling in melanoma reveals a BRAF mutation signature. Oncogene 2000;23:4060–4067.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY

    Pablo López Bergam, Anindita Bhoumik & Ze’ev Ronai

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  1. Pablo López Bergam
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  2. Anindita Bhoumik
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  3. Ze’ev Ronai
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Editors and Affiliations

  1. Laboratory of Cell Biology National Cancer Institute, National Institutes of Health, Bethesda, MD

    Vincent J. Hearing PhD

  2. Department of Surgery, University of California, San Francisco

    Stanley P. L. Leong MD

  3. School of Medicine, San Francisco, CA

    Stanley P. L. Leong MD

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© 2006 Humana Press Inc., Totowa, N.J.

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Bergam, P.L., Bhoumik, A., Ronai, Z. (2006). Altered Signal Transduction in Melanoma. In: Hearing, V.J., Leong, S.P.L. (eds) From Melanocytes to Melanoma. Humana Press. https://doi.org/10.1007/978-1-59259-994-3_7

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  • DOI: https://doi.org/10.1007/978-1-59259-994-3_7

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-459-3

  • Online ISBN: 978-1-59259-994-3

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