Dumaz Nicolas, Hayward Robert, Martin Jan, Ogilvie Lesley, Hedley Douglas, Curtin John A, Bastian Boris C, Springer Caroline, Marais Richard
Signal Transduction Team, The Institute for Cancer Research, Cancer Research UK Centre of Cell and Molecular Biology, London, United Kingdom.
Cancer Res. 2006 Oct 1;66(19):9483-91. doi: 10.1158/0008-5472.CAN-05-4227.
Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation. We have investigated how cross-talk between these pathways affects melanoma progression. We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling. These data have important implications for the development of therapeutic strategies to treat this life-threatening disease.
黑素细胞需要RAS/RAF/MEK/ERK和环磷酸腺苷（cAMP）信号通路来维持增殖与分化之间的精细平衡。我们研究了这些通路之间的相互作用如何影响黑色素瘤的进展。我们发现cAMP抑制黑素细胞中的CRAF活性，而这对于抑制这些细胞中CRAF的致癌潜能至关重要。因此，单独的BRAF负责向MEK发出信号。然而，当黑色素瘤中的RAS发生突变时，细胞会将其信号传导从BRAF切换为CRAF。这种切换伴随着cAMP信号传导失调，这是使CRAF向MEK发出信号所必需的一步。因此，当黑色素瘤中的RAS发生突变时，RAF同工型的使用会发生根本性转变，并且这种转变发生在cAMP信号传导中断的背景下。这些数据对于开发治疗这种危及生命疾病的治疗策略具有重要意义。
