Centre de Regulació Genòmica, Dr. Aiguader, 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain.
Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain.
Mol Cell. 2013 Dec 12;52(5):720-33. doi: 10.1016/j.molcel.2013.11.010.
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.
RBM5 是凋亡基因可变剪接的调节因子，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。我们报告 RBM5/6 和 RBM10 拮抗调节癌细胞的增殖能力，并在可变剪接调节中显示出不同的位置效应。我们确定 Notch 途径调节剂 NUMB 是这些因子在控制细胞增殖中的关键靶标。NUMB 的可变剪接在肺癌中经常改变，可调节集落和异种移植肿瘤的形成，其调节可再现或拮抗 RBM5、6 和 10 在细胞集落形成中的作用。在肺癌细胞中鉴定的 RBM10 突变会破坏 NUMB 剪接调节以促进细胞生长。我们的结果揭示了控制癌细胞增殖的关键遗传回路。
