RBM5, 6, and 10 Differentially Regulate NUMB Alternative Splicing to Control Cancer Cell Proliferation
RBM5, 6, and 10 Differentially Regulate NUMB Alternative Splicing to Control Cancer Cell Proliferation
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DOI：
10.1016/j.molcel.2013.11.010
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发表时间：
2013-12-12
期刊：
影响因子：
16
通讯作者：
Valcarcel, Juan
中科院分区：
文献类型：
--
作者：
Bechara, Elias G.;Sebestyen, Endre;Valcarcel, Juan
RBM5是凋亡基因选择性剪接的调节因子，其高度同源的RBM6和RBM10是肺癌中经常缺失或突变的rna结合蛋白。我们报道了RBM5/6和RBM10拮抗调节癌细胞的增殖能力，并在选择性剪接调节中显示出不同的位置效应。我们发现Notch通路调节因子NUMB是这些因子控制细胞增殖的关键靶点。在肺癌中经常改变的NUMB选择性剪接可以调节集落和异种移植物肿瘤的形成，其调节概括或拮抗RBM5, 6和10在细胞集落形成中的作用。在肺癌细胞中发现的RBM10突变破坏NUMB剪接调节以促进细胞生长。我们的研究结果揭示了控制癌细胞增殖的关键遗传回路。
RBM5, a regulator of alternative splicing of apoptotic genes, and its highly homologous RBM6 and RBM10 are RNA-binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation, and its modulation recapitulates or antagonizes the effects of RBM5, 6, and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation.