雅普1
生物合成
谷氨酰胺
新陈代谢
河马信号通路
效应器
嘧啶代谢
癌变
细胞生物学
转录组
生物
生物化学
转录因子
嘌呤
基因表达
基因
氨基酸
酶
作者
Andrew G. Cox,Katie L. Hwang,Kristin K. Brown,Kimberley Evason,Sebastian Beltz,Allison Tsomides,Keelin O’Connor,Giorgio Galli,Dean Yimlamai,Sagar Chhangawala,Min Yuan,Evan C. Lien,Julia Wücherpfennig,Sahar Nissim,Akihiro Minami,David E. Cohen,Fernando D. Camargo,John M. Asara,Yariv Houvras,Didier Y.R. Stainier,Wolfram Goessling
摘要
The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signalling 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 tumour 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, suppressing 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.
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