This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wellbrock, C. Articles by Marais, R. Search for Related Content PubMed PubMed Citation Articles by Wellbrock, C. Articles by Marais, R.

^V599EB-RAF is an Oncogene in Melanocytes

¹ Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, London, United Kingdom, and ² Gene and Oncogene Targeting Team, The Institute of Cancer Research, Sutton, Surrey, United Kingdom

The oncogenic version of B-RAF, ^V599EB-RAF, is found in approximately 70% of human melanomas. However, the role that this oncogene plays in melanoma is unclear because ^V559EB-RAF is also found in approximately 80% of benign nevi. We have examined the role of oncogenic B-RAF in the early stages of melanoma by expressing ^V599EB-RAF in cultured melanocytes. In these cells, ^V599EB-RAF induced constitutive mitogen activated ERK-activating kinase (MEK) and extracellular signal-regulated kinase (ERK) signaling, 12-O-tetradecanoylphorbol-13-acetate-independent growth, and tumorigenicity in nude mice. Intriguingly, in RAS-transformed melanocytes, B-RAF depletion did not block MEK-ERK signaling or cell cycle progression. Similarly, B-RAF depletion blocked MEK-ERK signaling in human melanoma cells harboring oncogenic B-RAF, but not in melanoma cells harboring oncogenic RAS. Thus, although B-RAF can act as a potent oncogene in the early stages of melanoma by signaling through MEK and ERK, it is not required for this signaling in RAS-transformed melanocytes due to innate redundancy within the pathway. These findings have important implications for future therapeutic strategies.

This article has been cited by other articles:

				A Agaimy, L M Terracciano, S Dirnhofer, L Tornillo, A Foerster, A Hartmann, and M P Bihl V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours J. Clin. Pathol., July 1, 2009; 62(7): 613 - 616. [Abstract] [Full Text] [PDF]

				G. Lefevre, N. Babchia, A. Calipel, F. Mouriaux, A.-M. Faussat, S. Mrzyk, and F. Mascarelli Activation of the FGF2/FGFR1 Autocrine Loop for Cell Proliferation and Survival in Uveal Melanoma Cells Invest. Ophthalmol. Vis. Sci., March 1, 2009; 50(3): 1047 - 1057. [Abstract] [Full Text] [PDF]

				J. Yang, S. Zaja-Milatovic, Y.-M. Thu, F. Lee, R. Smykla, and A. Richmond Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy Mol. Cancer Ther., March 1, 2009; 8(3): 636 - 647. [Abstract] [Full Text] [PDF]

				C. A. Pratilas, A. J. Hanrahan, E. Halilovic, Y. Persaud, J. Soh, D. Chitale, H. Shigematsu, H. Yamamoto, A. Sawai, M. Janakiraman, et al. Genetic Predictors of MEK Dependence in Non-Small Cell Lung Cancer Cancer Res., November 15, 2008; 68(22): 9375 - 9383. [Abstract] [Full Text] [PDF]

				J. Leyton, G. Smith, M. Lees, M. Perumal, Q.-d. Nguyen, F. I. Aigbirhio, O. Golovko, Q. He, P. Workman, and E. O. Aboagye Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901 Mol. Cancer Ther., September 1, 2008; 7(9): 3112 - 3121. [Abstract] [Full Text] [PDF]

				Y. Fukuyo, M. Inoue, T. Nakajima, R. Higashikubo, N. T. Horikoshi, C. Hunt, A. Usheva, M. L. Freeman, and N. Horikoshi Oxidative Stress Plays a Critical Role in Inactivating Mutant BRAF by Geldanamycin Derivatives Cancer Res., August 1, 2008; 68(15): 6324 - 6330. [Abstract] [Full Text] [PDF]

				A. Lahoz and A. Hall DLC1: a significant GAP in the cancer genome Genes & Dev., July 1, 2008; 22(13): 1724 - 1730. [Abstract] [Full Text] [PDF]

				M. Cheung, A. Sharma, S. V. Madhunapantula, and G. P. Robertson Akt3 and Mutant V600EB-Raf Cooperate to Promote Early Melanoma Development Cancer Res., May 1, 2008; 68(9): 3429 - 3439. [Abstract] [Full Text] [PDF]

				R. M. Klein, L. S. Spofford, E. V. Abel, A. Ortiz, and A. E. Aplin B-RAF Regulation of Rnd3 Participates in Actin Cytoskeletal and Focal Adhesion Organization Mol. Biol. Cell, February 1, 2008; 19(2): 498 - 508. [Abstract] [Full Text] [PDF]

				C. Spittle, M. R. Ward, K. L. Nathanson, P. A. Gimotty, E. Rappaport, M. S. Brose, A. Medina, R. Letrero, M. Herlyn, and R. H. Edwards Application of a BRAF Pyrosequencing Assay for Mutation Detection and Copy Number Analysis in Malignant Melanoma J. Mol. Diagn., September 1, 2007; 9(4): 464 - 471. [Abstract] [Full Text] [PDF]

				W. Goessling, T. E. North, and L. I. Zon New Waves of Discovery: Modeling Cancer in Zebrafish J. Clin. Oncol., June 10, 2007; 25(17): 2473 - 2479. [Full Text] [PDF]

				D. Liu, Z. Liu, S. Condouris, and M. Xing BRAF V600E Maintains Proliferation, Transformation, and Tumorigenicity of BRAF-Mutant Papillary Thyroid Cancer Cells J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2264 - 2271. [Abstract] [Full Text] [PDF]

				L. A. Fecher, S. D. Cummings, M. J. Keefe, and R. M. Alani Toward a Molecular Classification of Melanoma J. Clin. Oncol., April 20, 2007; 25(12): 1606 - 1620. [Abstract] [Full Text] [PDF]

				J. Yang, W.-H. Pan, G. A. Clawson, and A. Richmond Systemic Targeting Inhibitor of {kappa}B Kinase Inhibits Melanoma Tumor Growth Cancer Res., April 1, 2007; 67(7): 3127 - 3134. [Abstract] [Full Text] [PDF]

				S. Y. Sharp, K. Boxall, M. Rowlands, C. Prodromou, S. M. Roe, A. Maloney, M. Powers, P. A. Clarke, G. Box, S. Sanderson, et al. In vitro Biological Characterization of a Novel, Synthetic Diaryl Pyrazole Resorcinol Class of Heat Shock Protein 90 Inhibitors Cancer Res., March 1, 2007; 67(5): 2206 - 2216. [Abstract] [Full Text] [PDF]

				R. J. Abi-Habib, R. Singh, S. H. Leppla, J. J. Greene, Y. Ding, B. Berghuis, N. S. Duesbery, and A. E. Frankel Systemic Anthrax Lethal Toxin Therapy Produces Regressions of Subcutaneous Human Melanoma Tumors in Athymic Nude Mice Clin. Cancer Res., December 15, 2006; 12(24): 7437 - 7443. [Abstract] [Full Text] [PDF]

				N. Dumaz, R. Hayward, J. Martin, L. Ogilvie, D. Hedley, J. A. Curtin, B. C. Bastian, C. Springer, and R. Marais In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling Cancer Res., October 1, 2006; 66(19): 9483 - 9491. [Abstract] [Full Text] [PDF]

				M. Kono, I. S. Dunn, P. J. Durda, D. Butera, L. B. Rose, T. J. Haggerty, E. M. Benson, and J. T. Kurnick Role of the Mitogen-Activated Protein Kinase Signaling Pathway in the Regulation of Human Melanocytic Antigen Expression Mol. Cancer Res., October 1, 2006; 4(10): 779 - 792. [Abstract] [Full Text] [PDF]

				A. Sharma, M. A. Tran, S. Liang, A. K. Sharma, S. Amin, C. D. Smith, C. Dong, and G. P. Robertson Targeting Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase in the Mutant (V600E) B-Raf Signaling Cascade Effectively Inhibits Melanoma Lung Metastases Cancer Res., August 15, 2006; 66(16): 8200 - 8209. [Abstract] [Full Text] [PDF]

				L. Chin, L. A. Garraway, and D. E. Fisher Malignant melanoma: genetics and therapeutics in the genomic era. Genes & Dev., August 15, 2006; 20(16): 2149 - 2182. [Abstract] [Full Text] [PDF]

				C. Petti, A. Molla, C. Vegetti, S. Ferrone, A. Anichini, and M. Sensi Coexpression of NRASQ61R and BRAFV600E in Human Melanoma Cells Activates Senescence and Increases Susceptibility to Cell-Mediated Cytotoxicity. Cancer Res., July 1, 2006; 66(13): 6503 - 6511. [Abstract] [Full Text] [PDF]

				K. S.M. Smalley, N. K. Haass, P. A. Brafford, M. Lioni, K. T. Flaherty, and M. Herlyn Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases Mol. Cancer Ther., May 1, 2006; 5(5): 1136 - 1144. [Abstract] [Full Text] [PDF]

				A. Calipel, F. Mouriaux, A.-L. Glotin, F. Malecaze, A.-M. Faussat, and F. Mascarelli Extracellular Signal-regulated Kinase-dependent Proliferation Is Mediated through the Protein Kinase A/B-Raf Pathway in Human Uveal Melanoma Cells J. Biol. Chem., April 7, 2006; 281(14): 9238 - 9250. [Abstract] [Full Text] [PDF]

				A. Chiloeches and R. Marais Is BRAF the Achilles' Heel of Thyroid Cancer? Clin. Cancer Res., March 15, 2006; 12(6): 1661 - 1664. [Full Text] [PDF]

				Y. Newbatt, S. Burns, R. Hayward, S. Whittaker, R. Kirk, C. Marshall, C. Springer, E. Mcdonald, Cancer Genome Project, R. Marais, et al. Identification of Inhibitors of the Kinase Activity of Oncogenic V600EBRAF in an Enzyme Cascade High-Throughput Screen J Biomol Screen, March 1, 2006; 11(2): 145 - 154. [Abstract] [PDF]

				V. Balan, D. T. Leicht, J. Zhu, K. Balan, A. Kaplun, V. Singh-Gupta, J. Qin, H. Ruan, M. J. Comb, and G. Tzivion Identification of Novel In Vivo Raf-1 Phosphorylation Sites Mediating Positive Feedback Raf-1 Regulation by Extracellular Signal-regulated Kinase Mol. Biol. Cell, March 1, 2006; 17(3): 1141 - 1153. [Abstract] [Full Text] [PDF]

				O. M. Grbovic, A. D. Basso, A. Sawai, Q. Ye, P. Friedlander, D. Solit, and N. Rosen V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors PNAS, January 3, 2006; 103(1): 57 - 62. [Abstract] [Full Text] [PDF]

				K. Mercer, S. Giblett, S. Green, D. Lloyd, S. DaRocha Dias, M. Plumb, R. Marais, and C. Pritchard Expression of Endogenous Oncogenic V600EB-raf Induces Proliferation and Developmental Defects in Mice and Transformation of Primary Fibroblasts Cancer Res., December 15, 2005; 65(24): 11493 - 11500. [Abstract] [Full Text] [PDF]

				S. da Rocha Dias, F. Friedlos, Y. Light, C. Springer, P. Workman, and R. Marais Activated B-RAF Is an Hsp90 Client Protein That Is Targeted by the Anticancer Drug 17-Allylamino-17-Demethoxygeldanamycin Cancer Res., December 1, 2005; 65(23): 10686 - 10691. [Abstract] [Full Text] [PDF]

				V. Emuss, M. Garnett, C. Mason, The Cancer Genome Project, and R. Marais Mutations of C-RAF Are Rare in Human Cancer because C-RAF Has a Low Basal Kinase Activity Compared with B-RAF Cancer Res., November 1, 2005; 65(21): 9719 - 9726. [Abstract] [Full Text] [PDF]

				L Zhuang, C S Lee, R A Scolyer, S W McCarthy, A A Palmer, X D Zhang, J F Thompson, L P Bron, and P Hersey Activation of the extracellular signal regulated kinase (ERK) pathway in human melanoma J. Clin. Pathol., November 1, 2005; 58(11): 1163 - 1169. [Abstract] [Full Text] [PDF]

				J. Zhu, V. Balan, A. Bronisz, K. Balan, H. Sun, D. T. Leicht, Z. Luo, J. Qin, J. Avruch, and G. Tzivion Identification of Raf-1 S471 as a Novel Phosphorylation Site Critical for Raf-1 and B-Raf Kinase Activities and for MEK Binding Mol. Biol. Cell, October 1, 2005; 16(10): 4733 - 4744. [Abstract] [Full Text] [PDF]

				R. J. Abi-Habib, J. O. Urieto, S. Liu, S. H. Leppla, N. S. Duesbery, and A. E. Frankel BRAF status and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin Mol. Cancer Ther., September 1, 2005; 4(9): 1303 - 1310. [Abstract] [Full Text] [PDF]

				C. Wellbrock and R. Marais Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation J. Cell Biol., August 29, 2005; 170(5): 703 - 708. [Abstract] [Full Text] [PDF]

				S. Bloethner, B. Chen, K. Hemminki, J. Muller-Berghaus, S. Ugurel, D. Schadendorf, and R. Kumar Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines Carcinogenesis, July 1, 2005; 26(7): 1224 - 1232. [Abstract] [Full Text] [PDF]

				N. H. Tran, X. Wu, and J. A. Frost B-Raf and Raf-1 Are Regulated by Distinct Autoregulatory Mechanisms J. Biol. Chem., April 22, 2005; 280(16): 16244 - 16253. [Abstract] [Full Text] [PDF]

				A. M. Mirza, S. Gysin, N. Malek, K.-i. Nakayama, J. M. Roberts, and M. McMahon Cooperative Regulation of the Cell Division Cycle by the Protein Kinases RAF and AKT Mol. Cell. Biol., December 15, 2004; 24(24): 10868 - 10881. [Abstract] [Full Text] [PDF]

				S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, et al. 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., October 1, 2004; 64(19): 7099 - 7109. [Abstract] [Full Text] [PDF]