Oncogenic BRAF regulates β-Trcp expression and NF-κB activity in human melanoma cells
Oncogenic BRAF regulates β-Trcp expression and NF-κB activity in human melanoma cells
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DOI：
10.1038/sj.onc.1209994
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发表时间：
2007-03-22
期刊：
影响因子：
8
通讯作者：
Fuchs, S. Y.
中科院分区：
文献类型：
--
作者：
Liu, J.;Kumar, K. G. Suresh;Fuchs, S. Y.
BRAF的突变激活是人类恶性黑色素瘤中的常见事件，表明BRAF依赖性信号传导有利于黑色素瘤细胞的生长和存活。先前发表的工作报道，黑色素瘤细胞表现出组成性抗凋亡核因子κ B（NF-κ B）转录因子激活，其抑制剂I κ B的蛋白水解触发。I κ B降解依赖于I κ B激酶（IKK）复合物的磷酸化和随后β-Trcp E3泛素连接酶促进的泛素化。在这里，我们报告说，黑素细胞表达条件致癌形式的BRAF（V600 E）表现出增强的β-Trcp表达，IKK活性增加，并伴随着增加的速度I κ B α降解。相反，在人黑素瘤细胞中，使用广谱Raf抑制剂（BAY 43-9006）或通过RNA干扰选择性敲低BRAF（V600 E）表达来抑制BRAF信号传导导致IKK活性和β-Trcp表达降低、I κ B稳定、NF-κ B转录活性抑制和这些细胞对凋亡的敏感性。总之，这些数据支持了一个模型，其中BRAF在人黑色素瘤中的突变激活有助于组成型诱导NF-κ B活性和增加黑色素瘤细胞的存活。
Mutational activation of BRAF is a frequent event in human malignant melanomas suggesting that BRAF-dependent signaling is conducive to melanoma cell growth and survival. Previously published work reported that melanoma cells exhibit constitutive anti-apoptotic nuclear factor kappa B (NF-kappa B) transcription factor activation triggered by proteolysis of its inhibitor I kappa B. I kappa B degradation is dependent upon its phosphorylation by the I kappa B kinase (IKK) complex and subsequent ubiquitination facilitated by beta-Trcp E3 ubiquitin ligase. Here, we report that melanocytes expressing a conditionally oncogenic form of BRAF(V600E) exhibit enhanced beta-Trcp expression, increased IKK activity and a concomitant increase in the rate of I kappa B alpha degradation. Conversely, inhibition of BRAF signaling using either a broad-spectrum Raf inhibitor (BAY 43-9006) or by selective knock-down of BRAF(V600E) expression by RNA interference in human melanoma cells leads to decreased IKK activity and beta-Trcp expression, stabilization of I kappa B, inhibition of NF-kappa B transcriptional activity and sensitization of these cells to apoptosis. Taken together, these data support a model in which mutational activation of BRAF in human melanomas contributes to constitutive induction of NF-kappa B activity and to increased survival of melanoma cells.