SKI activates Wnt/beta-catenin signaling in human melanoma.
SKI activates Wnt/beta-catenin signaling in human melanoma.
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发表时间：
2003
期刊：
影响因子：
11.2
通讯作者：
Dahu Chen;Wei-dong Xu;E. Bales;C. Colmenares;Maralice Conacci-Sorrell;S. Ishii;E. Stavnezer;J. Campisi;D. Fisher;A. Ben-Ze'ev;E. Medrano
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文献类型：
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作者：
Dahu Chen;Wei-dong Xu;E. Bales;C. Colmenares;Maralice Conacci-Sorrell;S. Ishii;E. Stavnezer;J. Campisi;D. Fisher;A. Ben-Ze'ev;E. Medrano
癌蛋白SKI的过表达与体内人黑素瘤的进展相关。已知SKI通过在p21（Waf-1）启动子处与Smad 2和Smad 3形成抑制性转录复合物来削减肿瘤生长因子β的生长抑制活性。在这里，我们表明SKI也通过激活Wnt信号通路刺激生长。从酵母双杂交筛选和免疫沉淀研究，我们确定了蛋白质FHL 2/DRAL作为一种新的SKI结合伴侣。FHL 2是一种仅含LIM的蛋白质，可与β-连环蛋白结合，并可作为Wnt信号通路的转录抑制因子或激活因子发挥作用。SKI增强了黑色素瘤细胞中FHL 2和/或β-连环蛋白调节的基因启动子的激活。SKI靶点包括小眼症相关转录因子和Nr-CAM，这两种蛋白质与黑色素瘤细胞存活、生长、运动和转化相关。SKI和FHL 2在ski（-/-）黑素细胞中的瞬时过表达协同增强细胞生长，SKI在克隆形成性差的人黑色素瘤细胞系中的稳定过表达足以刺激快速增殖，减少细胞周期G（1）期的细胞数量，并显著增加克隆形成性、集落大小和运动性。总之，这些结果表明，通过靶向肿瘤生长因子β和β-连环蛋白途径的成员，SKI调节黑色素瘤生长，存活和侵袭所需的关键事件。
Overexpression of the oncoprotein SKI correlates with the progression of human melanoma in vivo. SKI is known to curtail the growth inhibitory activity of tumor growth factor beta through the formation of repressive transcriptional complexes with Smad2 and Smad3 at the p21(Waf-1) promoter. Here, we show that SKI also stimulates growth by activating the Wnt signaling pathway. From a yeast two-hybrid screen and immunoprecipitation studies, we identified the protein FHL2/DRAL as a novel SKI binding partner. FHL2, a LIM-only protein, binds beta-catenin and can function as either a transcriptional repressor or activator of the Wnt signaling pathway. SKI enhanced the activation of FHL2 and/or beta-catenin- regulated gene promoters in melanoma cells. Among the SKI targets were microphthalmia-associated transcription factor and Nr-CAM, two proteins associated with melanoma cell survival, growth, motility, and transformation. Transient overexpression of SKI and FHL2 in ski(-/-) melanocytes synergistically enhanced cell growth, and stable overexpression of SKI in a poorly clonogenic human melanoma cell line was sufficient to stimulate rapid proliferation, decreasing the number of cells in the G(1) phase of the cell cycle, and dramatically increasing clonogenicity, colony size and motility. Taken together, these results suggest that by targeting members of the tumor growth factor beta and beta-catenin pathways, SKI regulates crucial events required for melanoma growth, survival, and invasion.