Goodall Jane, Wellbrock Claudia, Dexter Timothy J, Roberts Karen, Marais Richard, Goding Colin R
Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL, United Kingdom.
Mol Cell Biol. 2004 Apr;24(7):2923-31. doi: 10.1128/MCB.24.7.2923-2931.2004.
Malignant melanoma, an aggressive and increasingly common cancer, is characterized by a strikingly high rate (70%) of mutations in BRAF, a key component of the mitogen-activated protein (MAP) kinase signaling pathway. How signaling events downstream from BRAF affect the underlying program of gene expression is poorly understood. We show that the Brn-2 POU domain transcription factor is highly expressed in melanoma cell lines but not in melanocytes or melanoblasts and that overexpression of Brn-2 in melanocytes results in increased proliferation. Expression of Brn-2 is strongly upregulated by Ras and MAP kinase signaling. Importantly, the Brn-2 promoter is stimulated by kinase-activating BRAF mutants and endogenous Brn-2 expression is inhibited by RNA interference-mediated downregulation of BRAF. Moreover, silent interfering RNA-mediated depletion of Brn-2 in melanoma cells expressing activated BRAF leads to decreased proliferation. The results suggest that the high levels of Brn-2 expression observed in melanomas link BRAF signaling to increased proliferation.
恶性黑色素瘤是一种侵袭性且日益常见的癌症，其特征是丝裂原活化蛋白（MAP）激酶信号通路的关键组成部分BRAF的突变率极高（70%）。BRAF下游的信号事件如何影响潜在的基因表达程序，目前还知之甚少。我们发现，Brn-2 POU结构域转录因子在黑色素瘤细胞系中高度表达，但在黑素细胞或成黑素细胞中不表达，并且在黑素细胞中过表达Brn-2会导致增殖增加。Brn-2的表达受到Ras和MAP激酶信号的强烈上调。重要的是，Brn-2启动子受到激酶激活的BRAF突变体的刺激，而内源性Brn-2表达受到RNA干扰介导的BRAF下调的抑制。此外，在表达活化BRAF的黑色素瘤细胞中，沉默干扰RNA介导的Brn-2缺失会导致增殖减少。结果表明，在黑色素瘤中观察到的高水平Brn-2表达将BRAF信号传导与增殖增加联系起来。
