Cancer and Metastasis Reviews

, Volume 24, Issue 1, pp 165–183

The role of B-RAF in melanoma

  • Vanessa C. Gray-Schopfer
  • Silvy da Rocha Dias
  • Richard Marais
Article

Abstract

Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. If detected early, it is easily treated by surgical excision. However, once melanoma metastasises it is notoriously resistant to existing therapies and for many patients the outlook is dismal. Thus a full description of melanoma etiology and a full understanding of the genetic lesions that underlie this disease is required to allow us to develop new and effective therapeutic strategies for its treatment. RAF proteins are a family of serine/threonine-specific protein kinases that form part of a signalling module that regulates cell proliferation, differentiation and survival. In mammals there are three isoforms, A-RAF, B-RAF and C-RAF, and recently it was shown that the B-RAF isoform is mutated in a high proportion of melanomas. In light of these exciting findings, we review what we have learned about B-RAF and its role in cutaneous melanoma.

Keywords

melanocytes melanoma C-RAF B-RAF ERK signalling 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hurst EA, Harbour JW, Cornelius LA: Ocular melanoma: A review and the relationship to cutaneous melanoma. Arch Dermatol 139: 1067–1073, 2003Google Scholar
  2. 2.
    Bauer J, Garbe C: Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data. Pigment Cell Res 16: 297–306, 2003Google Scholar
  3. 3.
    Bliss JM, Ford D, Swerdlow AJ, Armstrong BK, Cristofolini M, Elwood JM, Green A, Holly EA, Mack T, MacKie RM, et al.: Risk of cutaneous melanoma associated with pigmentation characteristics and freckling: Systematic overview of 10 case-control studies. The International Melanoma Analysis Group (IMAGE). Int J Cancer 62: 367–376, 1995.Google Scholar
  4. 4.
    Noonan FP, Recio JA, Takayama H, Duray P, Anver MR, Rush WL, De Fabo EC, Merlino G: Neonatal sunburn and melanoma in mice. Nature 413: 271–272, 2001Google Scholar
  5. 5.
    Lens MB, Dawes M: Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 150: 179–185, 2004Google Scholar
  6. 6.
    Diepgen TL, Mahler V: The epidemiology of skin cancer. Br J Dermatol 146(Suppl 61): 1–6, 2002Google Scholar
  7. 7.
    Clark WH, Jr., Elder DE, Guerry DT, Epstein MN, Greene MH, Van Horn M: A study of tumor progression: The precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 15: 1147–1165, 1984Google Scholar
  8. 8.
    Clark WH, Jr., Elder DE, Guerry DT, Braitman LE, Trock BJ, Schultz D, Synnestvedt M, Halpern AC: Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 81: 1893–1904, 1989PubMedGoogle Scholar
  9. 9.
    Clark WH: Tumour progression and the nature of cancer. Br J Cancer 64: 631–644, 1991Google Scholar
  10. 10.
    Parmiter AH, Nowell PC: Cytogenetics of melanocytic tumors. J Invest Dermatol 100: 254S–258S, 1993Google Scholar
  11. 11.
    Koh HK: Cutaneous melanoma. N Engl J Med 325: 171–182, 1991Google Scholar
  12. 12.
    Mooi WJ: The dysplastic naevus. J Clin Pathol 50: 711–715, 1997Google Scholar
  13. 13.
    Ivanov VN, Bhoumik A, Ronai Z: Death receptors and melanoma resistance to apoptosis. Oncogene 22: 3152–3161, 2003Google Scholar
  14. 14.
    Gilchrest BA, Park HY, Eller MS, Yaar M: Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 63: 1–10, 1996Google Scholar
  15. 15.
    Gilchrest BA, Eller MS, Geller AC, Yaar M: The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med 340: 1341–1348, 1999Google Scholar
  16. 16.
    Takahashi H, Honma M, Ishida-Yamamoto A, Namikawa K, Miwa A, Okado H, Kiyama H, Iizuka H: In vitro and in vivo transfer of bcl-2 gene into keratinocytes suppresses UVB-induced apoptosis. Photochem Photobiol 74: 579–586, 2001Google Scholar
  17. 17.
    Elwood JM, Whitehead SM, Davison J, Stewart M, Galt M: Malignant melanoma in England: Risks associated with naevi, freckles, social class, hair colour, and sunburn. Int J Epidemiol 19: 801–810, 1990Google Scholar
  18. 18.
    Tucker MA, Halpern A, Holly EA, Hartge P, Elder DE,Sagebiel RW, Guerry DT, Clark WH, Jr.: Clinically recognized dysplastic nevi. A central risk factor for cutaneous melanoma. Jama 277: 1439–1444, 1997Google Scholar
  19. 19.
    Marais R, Marshall CJ: Control of the ERK MAP kinase cascade by Ras and Raf. Cancer Surv 27: 101–125, 1996Google Scholar
  20. 20.
    Robinson MJ, Cobb MH: Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9: 180–186, 1997CrossRefPubMedGoogle Scholar
  21. 21.
    Sahai E, Olson MF, Marshall CJ: Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. Embo J 20: 755–766, 2001Google Scholar
  22. 22.
    Roux PP, Richards SA, Blenis J: Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity. Mol Cell Biol 23: 4796–4804, 2003Google Scholar
  23. 23.
    Waskiewicz AJ, Flynn A, Proud CG, Cooper JA: Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. Embo J 16: 1909–1920, 1997Google Scholar
  24. 24.
    Marshall CJ: Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation. Cell 80: 179–185, 1995CrossRefPubMedGoogle Scholar
  25. 25.
    Kerkhoff E, Rapp UR: High-intensity Raf signals convert mitotic cell cycling into cellular growth. Cancer Res 58: 1636–1640, 1998Google Scholar
  26. 26.
    Ridley AJ, Paterson HF, Noble M, Land H: Ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation. Embo J 7: 1635–1645, 1988Google Scholar
  27. 27.
    Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M: Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol 17: 5598–5611, 1997Google Scholar
  28. 28.
    Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW: Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 12: 3008–3019, 1998PubMedGoogle Scholar
  29. 29.
    Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW: Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593–602, 1997Google Scholar
  30. 30.
    Marais R, Light Y, Paterson HF, Mason CS, Marshall CJ: Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases. J Biol Chem 272: 4378–4383, 1997Google Scholar
  31. 31.
    Hagemann C, Rapp UR: Isotype-specific functions of Raf kinases. Exp Cell Res 253: 34–46, 1999Google Scholar
  32. 32.
    Barnier JV, Papin C, Eychene A, Lecoq O, Calothy G: The mouse B-raf gene encodes multiple protein isoforms with tissue-specific expression. J Biol Chem 270: 23381–23389, 1995Google Scholar
  33. 33.
    Papin C, Eychene A, Brunet A, Pages G, Pouyssegur J, Calothy G, Barnier JV: B-Raf protein isoforms interact with and phosphorylate Mek-1 on serine residues 218 and 222. Oncogene 10: 1647–1651, 1995Google Scholar
  34. 34.
    Mercer KE, Pritchard CA: Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta 1653: 25–40, 2003Google Scholar
  35. 35.
    Avruch J, Zhang XF, Kyriakis JM: Raf meets Ras: Completing the framework of a signal transduction pathway. Trends Biochem Sci 19: 279–283, 1994Google Scholar
  36. 36.
    Dhillon AS, Pollock C, Steen H, Shaw PE, Mischak H, Kolch W: Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259. Mol Cell Biol 22: 3237–3246, 2002Google Scholar
  37. 37.
    Light Y, Paterson H, Marais R: 14–3–3 antagonizes Ras-mediated Raf-1 recruitment to the plasma membrane to maintain signaling fidelity. Mol Cell Biol 22: 4984–4996, 2002Google Scholar
  38. 38.
    Abraham D, Podar K, Pacher M, Kubicek M, Welzel N, Hemmings BA, Dilworth SM, Mischak H, Kolch W, Baccarini M: Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation. J Biol Chem 275: 22300–22304, 2000Google Scholar
  39. 39.
    Jaumot M, Hancock JF: Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14–3–3 interactions. Oncogene 20: 3949–3958, 2001Google Scholar
  40. 40.
    Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK: Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol 13: 1356–1364, 2003Google Scholar
  41. 41.
    Zhang BH, Guan KL: Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601. Embo J 19: 5429–5439, 2000Google Scholar
  42. 42.
    Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R: Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116: 855–867, 2004CrossRefPubMedGoogle Scholar
  43. 43.
    Garnett MJ, Marais R: Guilty as charged; B-RAF is a human oncogene. Cancer Cell 6: 313–319, 2004Google Scholar
  44. 44.
    Chong H, Lee J, Guan KL: Positive and negative regulation of Raf kinase activity and function by phosphorylation. Embo J 20: 3716–3727, 2001Google Scholar
  45. 45.
    King AJ, Sun H, Diaz B, Barnard D, Miao W, Bagrodia S, Marshall MS: The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature 396: 180–183, 1998Google Scholar
  46. 46.
    Fabian JR, Daar IO, Morrison DK: Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase. Mol Cell Biol 13: 7170–7179, 1993Google Scholar
  47. 47.
    Mason CS, Springer CJ, Cooper RG, Superti-Furga G, Marshall CJ, Marais R: Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. Embo J 18: 2137–2148, 1999Google Scholar
  48. 48.
    King AJ, Wireman RS, Hamilton M, Marshall MS: Phosphorylation site specificity of the Pak-mediated regulation of Raf-1 and cooperativity with Src. FEBS Lett 497: 6–14, 2001Google Scholar
  49. 49.
    Smalley KS: A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer 104: 527–532, 2003Google Scholar
  50. 50.
    Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL, Van Belle P, Elder DE, Herlyn M: Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 63: 756–759, 2003Google Scholar
  51. 51.
    Cohen C, Zavala-Pompa A, Sequeira JH, Shoji M, Sexton DG, Cotsonis G, Cerimele F, Govindarajan B, Macaron N, Arbiser JL: Mitogen-actived protein kinase activation is an early event in melanoma progression. Clin Cancer Res 8: 3728–3733, 2002PubMedGoogle Scholar
  52. 52.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA: Mutations of the BRAF gene in human cancer. Nature 417: 949–954, 2002CrossRefPubMedGoogle Scholar
  53. 53.
    Casula M, Colombino M, Satta MP, Cossu A, Ascierto PA, Bianchi-Scarra G, Castiglia D, Budroni M, Rozzo C, Manca A, Lissia A, Carboni A, Petretto E, Satriano SM, Botti G, Mantelli M, Ghiorzo P, Stratton MR, Tanda F, Palmieri G: BRAF gene is somatically mutated but does not make a major contribution to malignant melanoma susceptibility: The Italian Melanoma Intergroup Study. J Clin Oncol 22: 286–292, 2004Google Scholar
  54. 54.
    Gorden A, Osman I, Gai W, He D, Huang W, Davidson A, Houghton AN, Busam K, Polsky D: Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res 63: 3955–3957, 2003Google Scholar
  55. 55.
    Houben R, Becker JC, Kappel A, Terheyden P, Brocker EB, Goetz R, Rapp UR: Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog 3: 6, 2004Google Scholar
  56. 56.
    Kumar R, Angelini S, Czene K, Sauroja I, Hahka-Kemppinen M, Pyrhonen S, Hemminki K: BRAF mutations in metastatic melanoma: A possible association with clinical outcome. Clin Cancer Res 9: 3362–3368, 2003Google Scholar
  57. 57.
    Kumar R, Angelini S, Hemminki K: Activating BRAF and N-Ras mutations in sporadic primary melanomas: An inverse association with allelic loss on chromosome 9. Oncogene 22: 9217–9224, 2003Google Scholar
  58. 58.
    Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM, Meltzer PS: High frequency of BRAF mutations in nevi. Nat Genet 33: 19–20, 2003CrossRefPubMedGoogle Scholar
  59. 59.
    Yazdi AS, Palmedo G, Flaig MJ, Puchta U, Reckwerth A, Rutten A, Mentzel T, Hugel H, Hantschke M, Schmid-Wendtner MH, Kutzner H, Sander CA: Mutations of the BRAF gene in benign and malignant melanocytic lesions. J Invest Dermatol 121: 1160–1162, 2003Google Scholar
  60. 60.
    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 111: 705–710, 2004Google Scholar
  61. 61.
    Kumar R, Angelini S, Snellman E, Hemminki K: BRAF mutations are common somatic events in melanocytic nevi. J Invest Dermatol 122: 342–348, 2004Google Scholar
  62. 62.
    Mihic-Probst D, Perren A, Schmid S, Saremaslani P, Komminoth P, Heitz PU: Absence of BRAF gene mutations differentiates spitz nevi from malignant melanoma. Anticancer Res 24: 2415–2418, 2004Google Scholar
  63. 63.
    Chin L, Pomerantz J, Polsky D, Jacobson M, Cohen C, Cordon-Cardo C, Horner JW, 2nd, DePinho RA: Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev 11: 2822–2834, 1997PubMedGoogle Scholar
  64. 64.
    Papp T, Pemsel H, Zimmermann R, Bastrop R, Weiss DG, Schiffmann D: Mutational analysis of the N-ras, p53, p16INK4a, CDK4, and MC1R genes in human congenital melanocytic naevi. J Med Genet 36: 610–614, 1999Google Scholar
  65. 65.
    Dong J, Phelps RG, Qiao R, Yao S, Benard O, Ronai Z, Aaronson SA: BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res 63: 3883–3885, 2003Google Scholar
  66. 66.
    Loewe R, Kittler H, Fischer G, Fae I, Wolff K, Petzelbauer P: BRAF kinase gene V599E mutation in growing melanocytic lesions. J Invest Dermatol 123: 733–736, 2004Google Scholar
  67. 67.
    Shinozaki M, Fujimoto A, Morton DL, Hoon DS: Incidence of BRAF oncogene mutation and clinical relevance for primary cutaneous melanomas. Clin Cancer Res 10: 1753–1757, 2004Google Scholar
  68. 68.
    Omholt K, Platz A, Kanter L, Ringborg U, Hansson J: NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 9: 6483–6488, 2003Google Scholar
  69. 69.
    Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, Ono T, Albertson DG, Pinkel D, Bastian BC: Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 95: 1878–1890, 2003Google Scholar
  70. 70.
    Lang J, Boxer M, MacKie R: Absence of exon 15 BRAF germline mutations in familial melanoma. Hum Mutat 21: 327–330, 2003Google Scholar
  71. 71.
    Laud K, Kannengiesser C, Avril MF, Chompret A, Stoppa-Lyonnet D, Desjardins L, Eychene A, Demenais F, Lenoir GM, Bressac-de Paillerets B: BRAF as a melanoma susceptibility candidate gene? Cancer Res 63: 3061–3065, 2003Google Scholar
  72. 72.
    Meyer P, Klaes R, Schmitt C, Boettger MB, Garbe C: Exclusion of BRAFV599E as a melanoma susceptibility mutation. Int J Cancer 106: 78–80, 2003Google Scholar
  73. 73.
    Meyer P, Sergi C, Garbe C: Polymorphisms of the BRAF gene predispose males to malignant melanoma. J Carcinog 2: 7, 2003Google Scholar
  74. 74.
    Wojnowski L, Stancato LF, Larner AC, Rapp UR, Zimmer A: Overlapping and specific functions of Braf and Craf-1 proto-oncogenes during mouse embryogenesis. Mech Dev 91: 97–104, 2000Google Scholar
  75. 75.
    Dulon M, Weichenthal M, Blettner M, Breitbart M, Hetzer M, Greinert R, Baumgardt-Elms C, Breitbart EW: Sun exposure and number of nevi in 5- to 6-year-old European children. J Clin Epidemiol 55: 1075–1081, 2002Google Scholar
  76. 76.
    Jhappan C, Noonan FP, Merlino G: Ultraviolet radiation and cutaneous malignant melanoma. Oncogene 22: 3099–3112, 2003CrossRefGoogle Scholar
  77. 77.
    Elwood JM: Melanoma and sun exposure. Semin Oncol 23: 650–666, 1996Google Scholar
  78. 78.
    Cohen Y, Rosenbaum E, Begum S, Goldenberg D, Esche C, Lavie O, Sidransky D, Westra WH: Exon 15 BRAF mutations are uncommon in melanomas arising in nonsun-exposed sites. Clin Cancer Res 10: 3444–3447, 2004Google Scholar
  79. 79.
    Edwards RH, Ward MR, Wu H, Medina CA, Brose MS, Volpe P, Nussen-Lee S, Haupt HM, Martin AM, Herlyn M, Lessin SR, Weber BL: Absence of BRAF mutations in UV-protected mucosal melanomas. J Med Genet 41: 270–272, 2004CrossRefGoogle Scholar
  80. 80.
    El-Shabrawi Y, Radner H, Muellner K, Langmann G, Hoefler G: The role of UV-radiation in the development of conjunctival malignant melanoma. Acta Ophthalmol Scand 77: 31–32, 1999Google Scholar
  81. 81.
    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 111: 757–761, 1998Google Scholar
  82. 82.
    van Elsas A, Zerp S, van der Flier S, Kruse-Wolters M, Vacca A, Ruiter DJ, Schrier P: Analysis of N-ras mutations in human cutaneous melanoma: Tumor heterogeneity detected by polymerase chain reaction/single-stranded conformation polymorphism analysis. Recent Results Cancer Res 139: 57–67, 1995Google Scholar
  83. 83.
    Dumaz N, Drougard C, Sarasin A, Daya-Grosjean L: Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. Proc Natl Acad Sci U S A 90: 10529–10533, 1993Google Scholar
  84. 84.
    Palmedo G, Hantschke M, Rutten A, Mentzel T, Hugel H, Flaig MJ, Yazdi AS, Sander CA, Kutzner H: The T1796A mutation of the BRAF gene is absent in Spitz nevi. J Cutan Pathol 31: 266–270, 2004Google Scholar
  85. 85.
    Joshi PC, Carraro C, Pathak MA: Involvement of reactive oxygen species in the oxidation of tyrosine and dopa to melanin and in skin tanning. Biochem Biophys Res Commun 142: 265–274, 1987Google Scholar
  86. 86.
    Bennett DC: Human melanocyte senescence and melanoma susceptibility genes. Oncogene 22: 3063–3069, 2003Google Scholar
  87. 87.
    Sherr CJ, McCormick F: The RB and p53 pathways in cancer. Cancer Cell 2: 103–112, 2002Google Scholar
  88. 88.
    Pavey SJ, Cummings MC, Whiteman DC, Castellano M, Walsh MD, Gabrielli BG, Green A, Hayward NK: Loss of p16 expression is associated with histological features of melanoma invasion. Melanoma Res 12: 539–547, 2002Google Scholar
  89. 89.
    Gruis NA, van der Velden PA, Bergman W, Frants RR: Familial melanoma; CDKN2A and beyond. J Investig Dermatol Symp Proc 4: 50–54, 1999Google Scholar
  90. 90.
    Daniotti M, Oggionni M, Ranzani T, Vallacchi V, Campi V, Di Stasi D, Torre GD, Perrone F, Luoni C, Suardi S, Frattini M, Pilotti S, Anichini A, Tragni G, Parmiani G, Pierotti MA, Rodolfo M: BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene 23: 5968–5977, 2004Google Scholar
  91. 91.
    Wu H, Goel V, Haluska F G: PTEN signaling pathways in melanoma. Oncogene 22: 3113–3122, 2003Google Scholar
  92. 92.
    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 62: 7335–7342, 2002Google Scholar
  93. 93.
    Pollock PM, Walker GJ, Glendening JM, Que Noy T, Bloch NC, Fountain JW, Hayward NK: PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines. Melanoma Res 12: 565–575, 2002Google Scholar
  94. 94.
    Tsao H, Zhang X, Fowlkes K, Haluska FG: Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res 60: 1800–1804, 2000Google Scholar
  95. 95.
    Tsao H, Goel V, Wu H, Yang G, Haluska FG: Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol 122: 337–341, 2004Google Scholar
  96. 96.
    Samuels Y, Velculescu VE: Oncogenic Mutations of PIK3CA in Human Cancers. Cell Cycle 3: 2004Google Scholar
  97. 97.
    Knowles MA, Hornigold N, Pitt E: Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours. Biochem Soc Trans 31: 597–602, 2003Google Scholar
  98. 98.
    Guldberg P, thor Straten P, Ahrenkiel V, Seremet T, Kirkin AF, Zeuthen J: Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma. Oncogene 18: 1777–1780, 1999Google Scholar
  99. 99.
    Rowan A, Bataille V, MacKie R, Healy E, Bicknell D, Bodmer W, Tomlinson I: Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic malignant melanomas. J Invest Dermatol 112: 509–511, 1999Google Scholar
  100. 100.
    Ikenoue T, Hikiba Y, Kanai F, Aragaki J, Tanaka Y, Imamura J, Imamura T, Ohta M, Ijichi H, Tateishi K, Kawakami T, Matsumura M, Kawabe T, Omata M: Different effects of point mutations within the B-Raf glycine-rich loop in colorectal tumors on mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase and nuclear factor kappaB pathway and cellular transformation. Cancer Res 64: 3428–3435, 2004Google Scholar
  101. 101.
    Medrano EE, Yang F, Boissy R, Farooqui J, Shah V, Matsumoto K, Nordlund JJ, Park HY: 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 5: 497–509, 1994Google Scholar
  102. 102.
    Busca R, Abbe P, Mantoux F, Aberdam E, Peyssonnaux C, Eychene A, Ortonne JP, Ballotti R: Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes. Embo J 19: 2900–2910, 2000CrossRefPubMedGoogle Scholar
  103. 103.
    Dumaz N, Marais R: Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. J Biol Chem 278: 29819–29823, 2003Google Scholar
  104. 104.
    Sidovar MF, Kozlowski P, Lee JW, Collins MA, He Y, Graves LM: Phosphorylation of serine 43 is not required for inhibition of c-Raf kinase by the cAMP-dependent protein kinase. J Biol Chem 275: 28688–28694, 2000Google Scholar
  105. 105.
    Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ, Sturgill TW: Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3′,5′-monophosphate. Science 262: 1065–1069, 1993PubMedGoogle Scholar
  106. 106.
    Wellbrock C, Ogilvie L, Hedley D, Karasarides M, Martin J, Niculescu-Duvaz D, Springer CJ, Marais R: V599EB-RAF is an oncogene in melanocytes. Cancer Res 64: 2338–2342, 2004Google Scholar
  107. 107.
    Johnson LN, Lowe ED, Noble ME, Owen DJ: The eleventh datta lecture. The structural basis for substrate recognition and control by protein kinases. FEBS Lett 430: 1–11, 1998Google Scholar
  108. 108.
    Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O’Hagan R, Pantginis J, Zhou H, Horner JW, 2nd, Cordon-Cardo C, Yancopoulos GD, DePinho RA: Essential role for oncogenic Ras in tumour maintenance. Nature 400: 468–472, 1999Google Scholar
  109. 109.
    Calipel A, Lefevre G, Pouponnot C, Mouriaux F, Eychene A, Mascarelli F: Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK pathway. J Biol Chem 278: 42409–42418, 2003Google Scholar
  110. 110.
    Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA: Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res 63: 5198–5202, 2003Google Scholar
  111. 111.
    Karasarides M, Chiloeches A, Hayward R, Niculescu-Duvaz D, Scanlon I, Friedlos F, Ogilvie L, Hedley D, Martin J, Marshall CJ, Springer CJ, Marais R: B-RAF is a therapeutic target in melanoma. Oncogene 23: 6292–6298, 2004Google Scholar
  112. 112.
    Sumimoto H, Miyagishi M, Miyoshi H, Yamagata S, Shimizu A, Taira K, Kawakami Y: Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Oncogene 23: 6031–6039, 2004Google Scholar
  113. 113.
    Bennett DC, Cooper PJ, Hart IR: A line of non-tumorigenic mouse melanocytes, syngeneic with the B16 melanoma and requiring a tumour promoter for growth. Int J Cancer 39: 414–418, 1987Google Scholar
  114. 114.
    Sviderskaya EV, Hill SP, Evans-Whipp TJ, Chin L, Orlow SJ, Easty DJ, Cheong SC, Beach D, DePinho RA, Bennett DC: p16(Ink4a) in melanocyte senescence and differentiation. J Natl Cancer Inst 94: 446–454, 2002Google Scholar
  115. 115.
    Mattei S, Colombo MP, Melani C, Silvani A, Parmiani G, Herlyn M: Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes. Int J Cancer 56: 853–857, 1994Google Scholar
  116. 116.
    Lazar-Molnar E, Hegyesi H, Toth S, Falus A: Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 12: 547–554, 2000Google Scholar
  117. 117.
    Nesbit M, Nesbit HK, Bennett J, Andl T, Hsu MY, Dejesus E, McBrian M, Gupta AR, Eck SL, Herlyn M: Basic fibroblast growth factor induces a transformed phenotype in normal human melanocytes. Oncogene 18: 6469–6476, 1999Google Scholar
  118. 118.
    Sviderskaya EV, Gray-Schopfer VC, Hill SP, Smit NP, Evans-Whipp TJ, Bond J, Hill L, Bataille V, Peters G, Kipling D, Wynford-Thomas D, Bennett DC: p16/cyclin-dependent kinase inhibitor 2A deficiency in human melanocyte senescence, apoptosis, and immortalization: Possible implications for melanoma progression. J Natl Cancer Inst 95: 723–732, 2003Google Scholar
  119. 119.
    Wilson DJ, Alessandrini A, Budd RC: MEK1 activation rescues Jurkat T cells from Fas-induced apoptosis. Cell Immunol 194: 67–77, 1999CrossRefPubMedGoogle Scholar
  120. 120.
    Erhardt P, Schremser EJ, Cooper GM: B-Raf inhibits programmed cell death downstream of cytochrome c release from mitochondria by activating the MEK/Erk pathway. Mol Cell Biol 19: 5308–5315, 1999Google Scholar
  121. 121.
    Pritchard CA, Hayes L, Wojnowski L, Zimmer A, Marais RM, Norman JC: B-Raf acts via the ROCKII/LIMK/cofilin pathway to maintain actin stress fibers in fibroblasts. Mol Cell Biol 24: 5937–5952, 2004Google Scholar
  122. 122.
    Rutter JL, Mitchell TI, Buttice G, Meyers J, Gusella JF, Ozelius LJ, Brinckerhoff CE: A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res 58: 5321–5325, 1998Google Scholar
  123. 123.
    Ye S, Dhillon S, Turner SJ, Bateman AC, Theaker JM, Pickering RM, Day I, Howell WM: Invasiveness of cutaneous malignant melanoma is influenced by matrix metalloproteinase 1 gene polymorphism. Cancer Res 61: 1296–1298, 2001Google Scholar
  124. 124.
    Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100: 57–70, 2000CrossRefPubMedGoogle Scholar
  125. 125.
    Bollag G, Freeman S, Lyons JF, Post LE: Raf pathway inhibitors in oncology. Curr Opin Investig Drugs 4: 1436–1441, 2003PubMedGoogle Scholar
  126. 126.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64: 7099–7109, 2004Google Scholar
  127. 127.
    Ahmad T, Eisen T: Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res 10: 6388S-6392S, 2004Google Scholar
  128. 128.
    Flaherty KT: New molecular targets in melanoma. Curr Opin Oncol 16: 150–154, 2004Google Scholar
  129. 129.
    Dai Y, Yu C, Singh V, Tang L, Wang Z, McInistry R, Dent P, Grant S: Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. Cancer Res 61: 5106–5115, 2001Google Scholar
  130. 130.
    Tsavachidou D, Coleman ML, Athanasiadis G, Li S, Licht JD, Olson MF, Weber BL: SPRY2 is an inhibitor of the ras/extracellular signal-regulated kinase pathway in melanocytes and melanoma cells with wild-type BRAF but not with the V599E mutant. Cancer Res 64: 5556–5559, 2004Google Scholar
  131. 131.
    Frattini M, Ferrario C, Bressan P, Balestra D, De Cecco L, Mondellini P, Bongarzone I, Collini P, Gariboldi M, Pilotti S, Pierotti MA, Greco A: Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene 23: 7436–7440, 2004Google Scholar
  132. 132.
    Pavey S, Johansson P, Packer L, Taylor J, Stark M, Pollock PM, Walker GJ, Boyle GM, Harper U, Cozzi SJ, Hansen K, Yudt L, Schmidt C, Hersey P, Ellem KA, O’Rourke MG, Parsons PG, Meltzer P, Ringner M, Hayward NK: Microarray expression profiling in melanoma reveals a BRAF mutation signature. Oncogene 23: 4060–4067, 2004Google Scholar
  133. 133.
    Ruas M, Peters G: The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1378: F115–177, 1998CrossRefPubMedGoogle Scholar
  134. 134.
    Bartkova J, Lukas J, Guldberg P, Alsner J, Kirkin AF, Zeuthen J, Bartek J: The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res 56: 5475–5483, 1996Google Scholar
  135. 135.
    Sauter ER, Yeo UC, von Stemm A, Zhu W, Litwin S, Tichansky DS, Pistritto G, Nesbit M, Pinkel D, Herlyn M, Bastian BC: Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res 62: 3200–3206, 2002PubMedGoogle Scholar
  136. 136.
    Polsky D, Young AZ, Busam KJ, Alani RM: The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in early melanomas. Cancer Res 61: 6008–6011, 2001Google Scholar
  137. 137.
    Straume O, Sviland L, Akslen LA: Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma. Clin Cancer Res 6: 1845–1853, 2000Google Scholar
  138. 138.
    Straume O, Akslen LA: Alterations and prognostic significance of p16 and p53 protein expression in subgroups of cutaneous melanoma. Int J Cancer 74: 535–539, 1997Google Scholar
  139. 139.
    Albino AP, Vidal MJ, McNutt NS, Shea CR, Prieto VG, Nanus DM, Palmer JM, Hayward NK: Mutation and expression of the p53 gene in human malignant melanoma. Melanoma Res 4: 35–45, 1994Google Scholar
  140. 140.
    Baldi A, Santini D, Russo P, Catricala C, Amantea A, Picardo M, Tatangelo F, Botti G, Dragonetti E, Murace R, Tonini G, Natali PG, Baldi F, Paggi MG: Analysis of APAF-1 expression in human cutaneous melanoma progression. Exp Dermatol 13: 93–97, 2004Google Scholar
  141. 141.
    Borner C, Schlagbauer Wadl H, Fellay I, Selzer E, Polterauer P, Jansen B: Mutated N-ras upregulates Bcl-2 in human melanoma in vitro and in SCID mice. Melanoma Res 9: 347–350, 1999Google Scholar
  142. 142.
    Demunter A, Ahmadian MR, Libbrecht L, Stas M, Baens M, Scheffzek K, Degreef H, De Wolf-Peeters C, van Den Oord JJ: A novel N-ras mutation in malignant melanoma is associated with excellent prognosis. Cancer Res 61: 4916–4922, 2001Google Scholar
  143. 143.
    Chen D, Xu W, Bales E, Colmenares C, Conacci-Sorrell M, Ishii S, Stavnezer E, Campisi J, Fisher DE, Ben-Ze’ev A, Medrano EE: SKI activates Wnt/beta-catenin signaling in human melanoma. Cancer Res 63: 6626–6634, 2003Google Scholar
  144. 144.
    Bush JA, Li G: The role of Bcl-2 family members in the progression of cutaneous melanoma. Clin Exp Metastasis 20: 531–539, 2003Google Scholar
  145. 145.
    Bar-Eli M: Gene regulation in melanoma progression by the AP-2 transcription factor. Pigment Cell Res 14: 78–85, 2001CrossRefPubMedGoogle Scholar
  146. 146.
    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 57: 3660–3663, 1997Google Scholar
  147. 147.
    Kraehn GM, Utikal J, Udart M, Greulich KM, Bezold G, Kaskel P, Leiter U, Peter RU: Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases. Br J Cancer 84: 72–79, 2001Google Scholar
  148. 148.
    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 92: 839–842, 2001Google Scholar
  149. 149.
    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 132: 20–24, 2002Google Scholar
  150. 150.
    Worm J, Christensen C, Gronbaek K, Tulchinsky E, Guldberg P: Genetic and epigenetic alterations of the APC gene in malignant melanoma. Oncogene 23: 5215–5226, 2004Google Scholar
  151. 151.
    Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen KL, Vinson VL, Gumpper KL, Ellis L, El-Naggar A, Frazier M, Jasser S, Langford LA, Lee J, Mills GB, Pershouse MA, Pollack RE, Tornos C, Troncoso P, Yung WK, Fujii G, Berson A, Steck PA: MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57: 5221–5225, 1997Google Scholar
  152. 152.
    Walker GJ, Hayward NK: Pathways to melanoma development: Lessons from the mouse. J Invest Dermatol 119: 783–792, 2002Google Scholar
  153. 153.
    Li G, Satyamoorthy K, Herlyn M: N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res 61: 3819–3825, 2001Google Scholar
  154. 154.
    Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL: BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62: 6997–7000, 2002Google Scholar
  155. 155.
    Reifenberger J, Knobbe CB, Sterzinger AA, Blaschke B, Schulte KW, Ruzicka T, Reifenberger G: Frequent alterations of Ras signaling pathway genes in sporadic malignant melanomas. Int J Cancer 109: 377–384, 2004CrossRefPubMedGoogle Scholar
  156. 156.
    Rimoldi D, Salvi S, Lienard D, Lejeune FJ, Speiser D, Zografos L, Cerottini JC: Lack of BRAF mutations in uveal melanoma. Cancer Res 63: 5712–5715, 2003Google Scholar
  157. 157.
    Domingo E, Espin E, Armengol M, Oliveira C, Pinto M, Duval A, Brennetot C, Seruca R, Hamelin R, Yamamoto H, Schwartz S, Jr.: Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. Genes Chromosomes Cancer 39: 138–142, 2004Google Scholar
  158. 158.
    Oliveira C, Pinto M, Duval A, Brennetot C, Domingo E, Espin E, Armengol M, Yamamoto H, Hamelin R, Seruca R, Schwartz S, Jr.: BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene 22: 9192–9196, 2003.Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Vanessa C. Gray-Schopfer
    • 1
  • Silvy da Rocha Dias
    • 1
  • Richard Marais
    • 1
  1. 1.Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular BiologyThe Institute of Cancer ResearchLondonUK

Personalised recommendations