Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Genes Dev. 2018 Jul 1;32(13-14):903-908. doi: 10.1101/gad.315804.118. Epub 2018 Jun 27.
Loss of function of the DIS3L2 exoribonuclease is associated with Wilms tumor and the Perlman congenital overgrowth syndrome. LIN28, a Wilms tumor oncoprotein, triggers the DIS3L2-mediated degradation of the precursor of let-7, a microRNA that inhibits Wilms tumor development. These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation. Here we examine new DIS3L2-deficient cell lines and mouse models, demonstrating that DIS3L2 loss has no effect on mature let-7 levels. Rather, analysis of -null nephron progenitor cells, a potential cell of origin of Wilms tumors, reveals up-regulation of , a growth-promoting gene strongly associated with Wilms tumorigenesis. These findings nominate a new potential mechanism underlying the pathology associated with DIS3L2 deficiency.
DIS3L2 外切核酸酶功能丧失与肾母细胞瘤和 Perlman 先天性过度生长综合征有关。LIN28 是一种肾母细胞瘤癌蛋白，可触发 DIS3L2 介导的 let-7 前体降解，let-7 是一种抑制肾母细胞瘤发育的 microRNA。这些观察结果导致推测 DIS3L2 介导的肿瘤抑制归因于 let-7 的调节。在这里，我们研究了新的 DIS3L2 缺陷细胞系和小鼠模型，表明 DIS3L2 缺失对成熟 let-7 水平没有影响。相反，对 -null 肾祖细胞的分析，一种潜在的肾母细胞瘤起源细胞，揭示了生长促进基因的上调，与肾母细胞瘤的发生密切相关。这些发现为 DIS3L2 缺陷相关病理学提供了一个新的潜在机制。
