Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth

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Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth

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Title: Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth
Author: Cox, Andrew G.; Hwang, Katie L.; Brown, Kristin K.; Evason, Kimberley; Beltz, Sebastian; Tsomides, Allison; O'Connor, Keelin; Galli, Giorgio G.; Yimlamai, Dean; Chhangawala, Sagar; Yuan, Min; Lien, Evan C.; Wucherpfennig, Julia; Nissim, Sahar; Minami, Akihiro; Cohen, David E.; Camargo, Fernando D.; Asara, John M.; Houvras, Yariv; Stainier, Didier Y.R.; Goessling, Wolfram

Note: Order does not necessarily reflect citation order of authors.

Citation: Cox, A. G., K. L. Hwang, K. K. Brown, K. Evason, S. Beltz, A. Tsomides, K. O'Connor, et al. 2016. “Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth.” Nature cell biology 18 (8): 886-896. doi:10.1038/ncb3389. http://dx.doi.org/10.1038/ncb3389.
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Abstract: 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.
Published Version: doi:10.1038/ncb3389
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990146/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:30371109
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