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Nat Cell Biol. 2016 Aug;18(8):886-896. doi: 10.1038/ncb3389. Epub 2016 Jul 18.

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

Author information

1
Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
2
Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA.
3
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
4
University of Utah, Salt Lake City, UT.
5
Boston Children's Hospital, Harvard Medical School, Boston, MA.
6
Weill Cornell Medical College and New York Presbyterian Hospital, NY.
7
Harvard Stem Cell Institute, Cambridge, MA.
8
Max Planck Institute, Bad Nauheim, Germany.
9
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
10
Broad Institute of MIT and Harvard, Cambridge, MA.
#
Contributed equally

Abstract

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.

PMID:
27428308
PMCID:
PMC4990146
DOI:
10.1038/ncb3389
[Indexed for MEDLINE]
Free PMC Article

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