Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cells
Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cells
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DOI：
10.1038/onc.2009.133
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发表时间：
2009-07-01
期刊：
影响因子：
8
通讯作者：
Ahn, N. G.
中科院分区：
文献类型：
--
作者：
Argast, G. M.;Croy, C. H.;Ahn, N. G.
人类黑色素瘤显示致癌B-Raf突变，其激活B-Raf/MKK/ERK级联。我们筛选了微阵列以确定该途径的细胞靶点，发现B-Raf/MKK/ERK上调的基因与细胞周期调节因子的相关性最高，而下调的基因与轴突导向基因（包括丛蛋白-脑信号蛋白家族成员）的相关性最高。在黑色素瘤细胞和黑素细胞中，丛蛋白B1被丝裂原活化蛋白激酶信号强烈抑制。在原发性黑色素瘤细胞中，丛蛋白B1阻断肿瘤发生，如通过软琼脂中的集落、细胞外基质中的球状体和异种移植肿瘤的生长来测量。肿瘤抑制依赖于丛蛋白B1的C-末端结构域中的残基，其介导受体GT3活化蛋白活性，并且还与AKT抑制相关。有趣的是，在来自匹配的转移性肿瘤的细胞中，对丛蛋白B1的抑制反应减少或不存在，这表明转移性细胞中发生的变化绕过了肿瘤抑制机制。丛状蛋白B1也抑制细胞迁移，但这是在转移性细胞中看到的，而不是在匹配的原代细胞。因此，丛蛋白B1在早期细胞中具有肿瘤抑制功能，尽管抑制晚期细胞中的迁移。我们的研究结果表明，B-Raf/MKK/ERK通过调节丛蛋白B1为黑色素瘤的发生提供了一个允许的环境。Oncogene（2009）28，2697-2709; doi：10.1038/onc.2009.133; 2009年6月1日在线发表
Human melanomas show oncogenic B-Raf mutations, which activate the B-Raf/MKK/ERK cascade. We screened microarrays to identify cellular targets of this pathway, and found that genes upregulated by B-Raf/MKK/ERK showed highest association with cell-cycle regulators, whereas genes downregulated were most highly associated with axon guidance genes, including plexin-semaphorin family members. Plexin B1 was strongly inhibited by mitogen-activated protein kinase signaling in melanoma cells and melanocytes. In primary melanoma cells, plexin B1 blocked tumorigenesis as measured by growth of colonies in soft agar, spheroids in extracellular matrix and xenograft tumors. Tumor suppression depended on residues in the C-terminal domain of plexin B1, which mediate receptor GTPase activating protein activity, and also correlated with AKT inhibition. Interestingly, the inhibitory response to plexin B1 was reduced or absent in cells from a matched metastatic tumor, suggesting that changes occur in metastatic cells which bypass the tumor-suppressor mechanisms. Plexin B1 also inhibited cell migration, but this was seen in metastatic cells and not in matched primary cells. Thus, plexin B1 has tumor-suppressor function in early-stage cells, although suppressing migration in late-stage cells. Our findings suggest that B-Raf/MKK/ERK provides a permissive environment for melanoma genesis by modulating plexin B1. Oncogene (2009) 28, 2697-2709; doi:10.1038/onc.2009.133; published online 1 June 2009