V599EB-RAF is an oncogene in melanocytes.
The oncogenic version of B-RAF, (V599E)B-RAF, is found in approximately 70% of human melanomas. However, the role that this oncogene plays in melanoma is unclear because (V559E)B-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 (V599E)B-RAF in cultured melanocytes. In these cells, (V599E)B-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.
Wellbrock
Claudia
C
Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, London, United Kingdom.
Ogilvie
Lesley
L
Hedley
Douglas
D
Karasarides
Maria
M
Martin
Jan
J
Niculescu-Duvaz
Dan
D
Springer
Caroline J
CJ
Marais
Richard
R
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000473:pathology / Q000502:physiology*; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009857:Oncogenes; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D002273:Carcinogens; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D013755:Tetradecanoylphorbol Acetate