The Brn-2 transcription factor links activated BRAF to melanoma proliferation
The Brn-2 transcription factor links activated BRAF to melanoma proliferation
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DOI：
10.1128/mcb.24.7.2923-2931.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Goding, CR
中科院分区：
文献类型：
--
作者：
Goodall, J;Wellbrock, C;Goding, CR
恶性黑色素瘤是一种侵袭性且日益常见的癌症，其特点是 BRAF 突变率极高 (70%)，BRAF 是丝裂原激活蛋白 (MAP) 激酶信号通路的关键组成部分。 BRAF 下游的信号事件如何影响基因表达的潜在程序尚不清楚。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，但在黑色素细胞或成黑素细胞中不表达，并且黑色素细胞中 Brn-2 的过度表达会导致增殖增加。 Ras 和 MAP 激酶信号传导强烈上调 Brn-2 的表达。重要的是，Brn-2 启动子受到激酶激活 BRAF 突变体的刺激，并且内源 Brn-2 表达受到 RNA 干扰介导的 BRAF 下调的抑制。此外，在表达激活的 BRAF 的黑色素瘤细胞中，沉默干扰 RNA 介导的 Brn-2 耗竭会导致增殖减少。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。
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.