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

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 report that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 develop enlarged livers and are prone to liver tumor formation. Transcriptomic profiling reveals that Yap1 reprograms genes involved in glutamine metabolism.

ORGANISM(S): Danio rerio

PROVIDER: GSE82246 | GEO | 2016/08/02

SECONDARY ACCESSION(S): PRJNA324425

REPOSITORIES: GEO

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

Project description: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 report that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 develop enlarged livers and are prone to liver tumor formation. Transcriptomic profiling reveals that Yap1 reprograms genes involved in glutamine metabolism. Analysis of gene expression in WT and lf:Yap transgenic zebrafish livers.

2016-08-02 | E-GEOD-82246 | biostudies-arrayexpress

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

Project description: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.

| S-EPMC4990146 | biostudies-literature

Gene expression profile of YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line (SK-Hep1)

Project description:Hippo signaling pathway is pivotally involved in human cancer. Among the Hippo components, YAP1 is highly active while function of MST1,2 and SAV1 was lost in liver cancer. Based on systematic analysis, we identified KLF5 as YAP1 binding partner in silico. To investigate KLF5 in liver cancer, we performed the gene expression microarray after knocked down YAP1, TEAD1 and KLF5 in SK-Hep1 cell line. To identify the role of YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line, we performed microarray after knocking down YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line (3 siLuc, 3 siYAP1, 3 siTEAD1, 3 siKLF5)

2013-12-31 | E-GEOD-32597 | biostudies-arrayexpress

Hippo reprograms the transcriptional response to Ras signalling

Project description:Mutations that lead to hyperactivation of Ras signaling are hallmarks of carcinomas. During development, signaling via Ras mediates cell fate decisions and cellular differentiation without causing hyper-proliferation. What determines whether Ras activation leads to differentiation or proliferation remains unknown. Here we show that the Hippo pathway reprograms the cellular response to Ras signaling in Drosophila. While hyperactivation of Ras signaling alone promotes cellular differentiation, additional loss of Hippo signaling drives aggressive hyper-proliferation. Transcriptome analysis combined with ChIP-nexus confirmed that the magnitude and specificity of Ras target gene expression strongly depends on the activity status of the Hippo pathway. This is because Hippo signaling directly regulates the expression of two key downstream transcription factors of the Ras pathway: the ETS-domain transcription factor Pointed and the transcriptional repressor Capicua. Our results highlight how independent signaling pathways can impinge on each other at the level of transcription factors, thereby providing a safety mechanism to keep proliferation in check under normal developmental conditions.

2017-09-26 | GSE96868 | GEO

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

Project description:The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about how Yap target genes mediate these growth effects. Here, we show that defects in hepatic progenitor potential and liver growth in yap-/- mutant zebrafish are caused by impaired glucose transport and nucleotide biosynthesis: transcriptomic and metabolomic analyses reveal that Yap directly regulates expression of glucose transporter glut1, causing decreased glycolytic flux into anabolic nucleotide biosynthesis in yap-/- mutants and impaired glucose tolerance in adults. Nucleotide supplementation improved Yap-deficient phenotypes, indicating functional importance of glucose-fuelled nucleotide biosynthesis. Yap-regulated Glut1 expression and glucose uptake are conserved in mammals. Our results identify Glut1 as a direct Yap target enhancing glucose uptake and utilization for anabolic nucleotide biosynthesis, which are required for organ growth. Our findings demonstrate the central role of Hippo signalling in metabolic homeostasis

2018-08-25 | GSE119024 | GEO

Maternal slimming reprograms metabolic gene expression in mice offspring

Project description:This SuperSeries is composed of the following subset Series: GSE40471: Maternal slimming reprograms metabolic gene expression in mice offspring (NimbleGen expression) GSE40477: Maternal slimming reprograms metabolic gene expression in mice offspring (NimbleGen methylation) GSE40478: Maternal slimming reprograms metabolic gene expression in mice offspring (mRNA-Seq) Refer to individual Series

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Gene espression Profile by YAP1 and TAZ

Project description:The Hippo signaling pathway is evolutionarily well conserved, and all core components have one or more mammalian orthologs, including MST1/2 (Hippo), SAV1 (Salvador), LATS1/2 (Warts), MOB1 (Mats), YAP1/TAZ (Yorkie), and TEAD1/2/3/4 (Scalloped) (Halder and Johnson, 2011; Pan, 2007; Dong et al., 2007; Saucedo and Edgar, 2007). When Hippo signaling is active, YAP1/TAZ is phosphorylated by LATS1/2 and sequestered by 14-3-3 proteins in cytoplasm. When Hippo signaling is absent, unphosphorylated YAP1/TAZ enters the nucleus and increases transcriptional activation of genes involved in cell proliferation and survival. The indispensability of the Hippo pathway in restricting cell growth and proliferation has prompted speculation that many members of the pathway might be involved in tumorigenesis. To see the effect of YAP1 and TAZ in HCC cell, we generated gene expression profile.

2014-12-31 | GSE54617 | GEO

RNA-seq data set of EGFR mutant human non-small cell lung cancer cell lines PC9, HCC827, HCC4006 after NF2 knockout, YAP1 or WWTR1 overexpression or osimertinib treatment

Project description:Experiment was designed to study the effect of Hippo pathway on osimertinib resistance in non-small cell lung cancer cell lines. The specific comparisons investigated were: PC-9: NTC vs NF2 KO, EV vs YAP1 OE, EV vs WWTR1 OE, EV DMSO treated vs EV osimertinib treated HCC827: NTC vs NF2 KO, EV vs YAP1 OE, EV vs WWTR1 OE,EV DMSO treated vs EV osimertinib treated HCC4006: NTC vs NF2 KO, EV vs YAP1 OE, EV vs WWTR1 OE, EV DMSO treated vs EV osimertinib treated

2024-07-01 | E-MTAB-13831 | biostudies-arrayexpress

Gene expression profile of mouse liver cancer (Sav1 and Mst1/2 Knockout models)

Project description:Hippo pathway is evolutionarily well conserved. All core components of the pathway identified to date have one or more mammalian orthologs, including MST1/2 (Hippo), SAV1 (Salvador, also known as WW45), LATS1/2 (Warts), MOB1 (Mats), YAP1 and its paralog WWTR1 (also known as TAZ) (Yorkie), and TEAD1/2/3/4 (Scalloped). Ectopic over-expression of YAP1 in mouse liver led to develop hepatocellular carcinoma (HCC). HCC is the third most common cause of cancer-related death in the world, and accounts for an estimated 600,000 deaths annually. Lack of molecular classification and clinical heterogeneity of this malignant disease hampered the development of standardized treatment. To investigate roles of Hippo pathway in liver carcinogenesis, we generated liver-specific Mst1/2 -/- and Sav1 -/- mouse models and collected gene expression data from them. Our study provided new understanding on molecular characteristics of HCC. Sav1 and Mst1/2 Knockout models

2014-08-23 | E-GEOD-32510 | biostudies-arrayexpress

Gene expression profile of YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line (SK-Hep1)

2013-12-31 | GSE32597 | GEO