School of Biological Sciences and National Creative Research Center, Seoul National University, Seoul, 151-742, Korea.
Cell. 2009 Dec 11;139(6):1096-108. doi: 10.1016/j.cell.2009.11.020.
How body size is determined is a long-standing question in biology, yet its regulatory mechanisms remain largely unknown. Here, we find that a conserved microRNA miR-8 and its target, USH, regulate body size in Drosophila. miR-8 null flies are smaller in size and defective in insulin signaling in fat body that is the fly counterpart of liver and adipose tissue. Fat body-specific expression and clonal analyses reveal that miR-8 activates PI3K, thereby promoting fat cell growth cell-autonomously and enhancing organismal growth non-cell-autonomously. Comparative analyses identify USH and its human homolog, FOG2, as the targets of fly miR-8 and human miR-200, respectively. USH/FOG2 inhibits PI3K activity, suppressing cell growth in both flies and humans. FOG2 directly binds to p85alpha, the regulatory subunit of PI3K, and interferes with the formation of a PI3K complex. Our study identifies two novel regulators of insulin signaling, miR-8/miR-200 and USH/FOG2, and suggests their roles in adolescent growth, aging, and cancer.
生物体大小如何确定是生物学中的一个长期存在的问题，但其调控机制在很大程度上仍然未知。在这里，我们发现一种保守的 microRNA miR-8 及其靶标 USH 调节果蝇的体型。miR-8 缺失的果蝇体型较小，且其脂肪体（果蝇中相当于肝脏和脂肪组织的器官）中的胰岛素信号受损。脂肪体特异性表达和克隆分析表明，miR-8 激活了 PI3K，从而促进脂肪细胞的自主生长，并增强了机体的非自主生长。比较分析确定了 USH 及其人类同源物 FOG2 分别是果蝇 miR-8 和人类 miR-200 的靶标。USH/FOG2 抑制 PI3K 活性，抑制果蝇和人类中的细胞生长。FOG2 直接与 PI3K 的调节亚基 p85alpha 结合，并干扰 PI3K 复合物的形成。我们的研究确定了胰岛素信号的两个新调节因子，miR-8/miR-200 和 USH/FOG2，并表明它们在青少年生长、衰老和癌症中的作用。
