Wellbrock Claudia, Ogilvie Lesley, Hedley Douglas, Karasarides Maria, Martin Jan, Niculescu-Duvaz Dan, Springer Caroline J, Marais Richard
Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, London, United Kingdom.
Cancer Res. 2004 Apr 1;64(7):2338-42. doi: 10.1158/0008-5472.can-03-3433.
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.
致癌性的B-RAF，即（V599E）B-RAF，在大约70%的人类黑色素瘤中被发现。然而，这种致癌基因在黑色素瘤中所起的作用尚不清楚，因为在大约80%的良性痣中也发现了（V559E）B-RAF。我们通过在培养的黑素细胞中表达（V599E）B-RAF，研究了致癌性B-RAF在黑色素瘤早期阶段的作用。在这些细胞中，（V599E）B-RAF诱导组成型有丝分裂原活化的ERK激活激酶（MEK）和细胞外信号调节激酶（ERK）信号传导、不依赖12-O-十四烷酰佛波醇-13-乙酸酯的生长以及在裸鼠中的致瘤性。有趣的是，在RAS转化的黑素细胞中，B-RAF缺失并未阻断MEK-ERK信号传导或细胞周期进程。同样，B-RAF缺失在携带致癌性B-RAF的人类黑色素瘤细胞中阻断了MEK-ERK信号传导，但在携带致癌性RAS的黑色素瘤细胞中则没有。因此，尽管B-RAF在黑色素瘤早期阶段可通过MEK和ERK信号传导发挥强大的致癌基因作用，但由于该信号通路中固有的冗余性，在RAS转化的黑素细胞中此信号传导并不需要B-RAF。这些发现对未来的治疗策略具有重要意义。
