Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth.
Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth.
复制标题
DOI：
10.1038/ncb3389
复制
发表时间：
2016-08
影响因子：
21.3
通讯作者：
Goessling W
中科院分区：
文献类型：
--
作者：
Cox AG;Hwang KL;Brown KK;Evason K;Beltz S;Tsomides A;O'Connor K;Galli GG;Yimlamai D;Chhangawala S;Yuan M;Lien EC;Wucherpfennig J;Nissim S;Minami A;Cohen DE;Camargo FD;Asara JM;Houvras Y;Stainier DYR;Goessling W
河马途径是器官大小和肿瘤发生的重要调节因子。然而，目前尚不清楚河马信号如何提供快速增长所需的细胞构建块。在这里，我们证明了表达激活形式的河马途径效应器YAP1(也称为YAP)的转基因斑马鱼会形成增大的肝脏，并容易形成肝脏肿瘤。转录学和代谢组学研究表明，YAP1重新编程谷氨酰胺代谢。YAP1直接增强谷氨酰胺合成酶(GLUL)的表达和活性，提高谷氨酰胺的稳态水平，增强从头合成嘌呤和嘧啶过程中氮的相对同位素富集性。GLUL的基因或药物抑制会减少氮在核苷酸中的同位素聚集，抑制肝肿大和肝癌细胞的生长。因此，YAP驱动的肝脏生长很容易受到核苷酸的抑制。总之，我们的发现表明，YAP1通过重新编程氮代谢来刺激核苷酸生物合成，整合了组织发育和肿瘤发生过程中的合成代谢需求。
The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signaling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumor formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances glutamine synthetase (glul) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during de novo purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppresses hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis.