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RNA-seq analysis of whole liver derived from endothelial specific TAK1 conditional knockout mice.

ABSTRACT: In this study we show that TGFβ-activated kinase 1 (TAK1), is crucial for ensuring EC survival on TNFα stimulation. EC-specific TAK1-knockout in adult mice resulted in rapid death of the animal due to destruction of intestinal and liver blood vessels. TNFα from myeloid cells responding to intestinal microbiota was responsible for EC death in the intestine and liver. Our results illuminate mechanisms ensuring survival of intestinal and liver EC under physiological conditions

ORGANISM(S): Mus musculus

PROVIDER: GSE115190 | GEO | 2019/01/11

REPOSITORIES: GEO

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Hepatocyte-Specific TAK1 Deficiency Drives RIPK1 Kinase-dependent Inflammation to Promote Liver Fibrosis and Hepatocellular Carcinoma

Project description:Transforming growth factor beta-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1_Hep mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using kinase dead knock-in D138N mutation in Tak1_Hep mice inhibits the expression of liver tumor biomarkers, liver fibrosis and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single cell RNA-seq, we discover that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-non-autonomously, in the development of liver fibrosis and HCC, independent of cell death and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.

2020-07-08 | GSE148859 | GEO

TAK1-dependent checkpoint in dendritic cell survival regulates immune homeostasis and function

Project description:Homeostatic control of dendritic cell (DC) survival is crucial for a productive adaptive immune response, but the molecular mechanism is not well defined. Moreover, how DCs influence homeostasis of the immune system under steady state remains unclear. Combining DC-specific and inducible deletion systems, we report here that the kinase TAK1 is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c+ cells diminished DC populations, especially the CD8+ and CD103+ DC subsets in the lymphoid and non-lymphoid organs, respectively. This was associated with increased apoptosis of DCs, whereas DC proliferation and differentiation from precursors appeared largely normal. In addition, acute deletion of TAK1 caused DC apoptosis, indicating a direct role of TAK1 in actively maintaining DC survival. TAK1 deficiency impaired activities of the pro-survival NF-kB and AKT pathways but upregulated expression of the pro-apoptotic molecule Bim. Under steady state, loss of TAK1 in DCs resulted in a myeloid proliferative disorder, and altered homeostasis of T cells. In response to antigen stimulation, TAK1-deficient DCs were impaired for T cell priming and regulatory T cell generation. Therefore, TAK1 orchestrates a pro-survival checkpoint in DCs that affects the homeostasis and function of the immune system RNA extracted from three replicate samples of wild-type and Map3k7 (TAK1) knockout dendritic cells was analyzed on Affymetrix gene expression arrays

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TAK1-dependent checkpoint in dendritic cell survival regulates immune homeostasis and function

2012-01-23 | GSE34417 | GEO

Gene expression profile of WT and TAK1 KO livers.

Project description:The effect of ablation of Tak1 gene in the liver was characterized. RNA was extracted from 1-month-old WT and hepatocyte specific TAK1-deleted mice

2014-12-22 | E-GEOD-51962 | biostudies-arrayexpress

Chromosomal aberrations in Tak1-/- mice

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2010-03-31 | GSE19105 | GEO

Gene expression profile of WT and TAK1 KO livers.

Project description:The effect of ablation of Tak1 gene in the liver was characterized.

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TAK1 deficient liver parenchymal cells with Rip3 double knockout TAK1LPC

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TAK1 deficient liver parenchymal cells with Rip3 double knockout TAK1LPC

Project description:Genomic copy number profiling of TAK1 deficient liver parenchymal cells with Rip3 double knockout Sample vs. Reference (pool of 4 normal liver tissues)

2013-05-01 | E-GEOD-45206 | biostudies-arrayexpress

Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance

Project description:The nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. TAK1-deficient (TAK1-/-) mice are resistant to the development of age- and high fat diet (HFD)-induced metabolic syndrome. Biochemical analysis showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1-/- mice compared to wild type (WT) mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver of TAK1-/- mice. Moreover, TAK1-/- mice exhibit reduced infiltration of inflammatory cells and expression of inflammatory genes in adipose tissue and were resistant to the development of glucose intolerance and insulin resistance. TAK1-/- mice consume more oxygen and produce more carbon dioxide than WT mice suggesting a higher rate of energy expenditure. Together, these results indicate that TAK1 plays a critical role in the regulation of energy and lipid homeostasis and potentiates the development of metabolic syndrome. Our study suggests that TAK1 might provide a novel therapeutic target in the management of metabolic syndrome. For microarray liver total RNAs were purified from WT and TAK1 KO mice and applied on Agilent mouse genome chip. Liver from 1 year old- WT and TAK1 KO mice.

2010-09-30 | E-GEOD-21903 | biostudies-arrayexpress

Baseline RNA-sequencing data of 12 glioblastoma stem cell lines sensitive or resistant to TAK1 inhibition

Project description:Poor survival and lack of response to current treatment modalities in adult human glioblastomas is attributed to the persistence of a subpopulation of glioma stem cells (GSCs). To identify novel approaches to therapeutically target GSCs, we performed CRISPR/Cas9 knockout screens in GSCs and identified the kinase TAK1 as an important selective survival factor in 50% of the tested GSCs. In sensitive cells, knockout of TAK1 leads to induction of caspase-dependent apoptosis via the RIPK1/Caspase 8/FADD complex due to constitutive, low-level secretion of tumor necrosis factor alpha (TNF-a) and stimulation of TNF receptor 1. Furthermore, we show that expression of genes involved in immune signaling and a mesenchymal signature predict the sensitivity and response of GSCs to TAK1 inhibition. In summary, we have identified TAK1 as a new therapeutic target for mesenchymal GBM and a potential gene signature for selection of patients benefitting from TAK1 targeted therapy.

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