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Loss of Sirt2 increase and prolongs a chemically induced pancreatitis permissive phenotype and induces spontaneous oncogenic Kras mutations in mouse

ABSTRACT: Loss of Sirt2 increase and prolongs a chemically induced pancreatitis permissive phenotype and induces spontaneous oncogenic Kras mutations in mouse

PROVIDER: PRJNA475959 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7309380.fastq.gz	Fastqsanger.gz
	SRR7309381.fastq.gz	Fastqsanger.gz
	SRR7309382.fastq.gz	Fastqsanger.gz
	SRR7309383.fastq.gz	Fastqsanger.gz
	SRR7309384.fastq.gz	Fastqsanger.gz

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Loss of Sirt2 increase and prolongs a chemically induced pancreatitis permissive phenotype and induces spontaneous oncogenic Kras mutations in mouse

Project description:Transcriptome analysis by RNA-seq in pancreas identified 529 differentially expressed genes between wild-type and Sirt2-deficient mice 2 days after injury and confirmed continuous inflammention and tissue regeneration, as well as delayed tissue reorganization.

2018-11-14 | GSE115758 | GEO

Loss of Sirt2 increases and prolongs a caerulein-induced pancreatitis permissive phenotype and induces spontaneous oncogenic Kras mutations in mice.

Project description:Mice lacking Sirt2 spontaneously develop tumors in multiple organs, as well as when expressed in combination with oncogenic KrasG12D, leading to pancreatic tumors. Here, we report that after caerulein-induced pancreatitis, Sirt2-deficient mice exhibited an increased inflammatory phenotype and delayed pancreatic tissue recovery. Seven days post injury, the pancreas of Sirt2-/- mice display active inflammation, whereas wild-type mice had mostly recovered. In addition, the pancreas from the Sirt2-/- mice exhibited extensive tissue fibrosis, which was still present at six weeks after exposure. The mice lacking Sirt2 also demonstrated an enhanced whole body pro-inflammatory phenotype that was most obvious with increasing age. Importantly, an accumulation of a cell population with spontaneous cancerous KrasG12D mutations was observed in the Sirt2-/- mice that is enhanced in the recovering pancreas after exposure to caerulein. Finally, transcriptome analysis of the pancreas of the Sirt2-/- mice exhibited a pro-inflammatory genomic signature. These results suggest that loss of Sirt2, as well as increased age, enhanced the immune response to pancreatic injury and induced an inflammatory phenotype permissive for the accumulation of cells carrying oncogenic Kras mutations.

| S-EPMC6220268 | biostudies-literature

Essential Role of Sirt2 in Type I Interferon Signaling

Project description:We provide evidence for the essential role of Sirt2 in IFN mediated signaling. Our studies demonstrate that SIRT2 controls expression of key interferon stimulated genes (ISGs) that mediate important biological functions, including anti-viral and antineoplastic responses.

2015-12-31 | GSE66033 | GEO

Sirt2 Inhibition Reprograms T Cell Metabolism to Confer Superior Anti-Tumor Immunity

Project description:Metabolism is a key driver of T cell functions, and the switch from oxidative-phosphorylation to aerobic glycolysis is a hallmark of T cell activation. However, the mechanisms underlying the metabolic switch remain unclear. Here, we report that the Sirtuin-2 (Sirt2) deacetylase protein functions as a metabolic checkpoint that harnesses T cell effector functions and impairs anti-tumor immunity. Specifically, upregulation of Sirt2 expression in human tumor-infiltrating T lymphocytes (TILs) negatively correlates with response to Nivolumab and TIL therapy in non-small cell lung cancer. Mechanistically, Sirt2 suppresses aerobic glycolysis by deacetylating key glycolytic enzymes. Accordingly, Sirt2-deficient T cells manifest increased glycolysis, display enhanced proliferation and effector functions, and have superior anti-tumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and enhanced effector functions. These findings indicate Sirt2 as an actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.

2020-09-16 | GSE151421 | GEO

Deacetylation of Sirt2 regulates PKM2 ubiquitination and its effect on liver glucose metabolism

Project description:In order to explore the effects of SIRT2 on the liver metabolic function of mice under metabolic stress, we constructed SIRT2 knockout mice.

2023-04-08 | GSE229161 | GEO

transcriptome analysis of SIRT2 dependent genes modulated during infection by Listeria monocytogenes

Project description:tissue culture cells were treated with an inhibitor to the deacetylase SIRT2 (AGK2) and infected with Listeria monocytogenes

2013-06-01 | E-MEXP-3912 | biostudies-arrayexpress

The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription

Project description:Aberrant expression of IL-17A together with abated IL-2 production by effector CD4+ T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here we report that Sirtuin 2 (SIRT2), a member of the family of NAD+-dependent histone deacetylases, suppresses IL-2 production by CD4+ T cells while it promotes their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K and the activation of the mTORC1/HIF-1α/RORγt pathway and the generation of Th17 cells differentiation. Additionally, SIRT2 is responsible for the deacetylation of c-Jun and histones on the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, binds directly to the Sirt2 promoter and promotes its transcription. AK-7, a SIRT2 inhibitor limited the ability of adoptively transferred antigen-specific CD4+ T cells to cause autoimmune encephalomyelitis and disease in the lupus-prone MRL/lpr mice. Finally, CD4+ T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4+ T cells from patients with SLE attenuated their ability to differentiate into Th17 cells and promoted IL-2–producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential for the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new therapies for SLE.

2022-03-30 | GSE199496 | GEO

Differentially expressed RNA levels in the liver of aged LoxP and SIRT2-KOhep mice

Project description:To investigate the differentially expressed RNA levels in the liver of aged LoxP and SIRT2-KOhep mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of liver of aged LoxP and SIRT2-KOhep mice

2023-04-30 | GSE228204 | GEO

Sirt2 inhibition reprograms T cell metabolism for optimal anti-tumor immunity: Sirt2 Interacting Proteins

Project description:Growing evidence indicates that metabolism is a key driver of T cell functions. A switch from oxidative phosphorylation to aerobic glycolysis is a hallmark of T cell activation and is required to meet metabolic demands of proliferation and effector functions. However, the mechanisms underlying the metabolic switch in T cells remain unclear. Here, we identify Sirt2 as a crucial immune checkpoint coordinating metabolic and functional fitness of T cells. Sirt2 is induced upon T cell activation and increases in late maturation stages. Sirt2 negatively regulates glycolysis by targeting key glycolytic enzymes. Remarkably, Sirt2 knockout T cells exhibit profound upregulation of aerobic glycolysis with enhanced proliferation and effector function and thus effectively reject tumor challenge in vivo. Furthermore, pharmacologic inhibition of Sirt2 in human tumor infiltrating lymphocytes demonstrated a similar phenotype. Taken together, our results demonstrate Sirt2 as an actionable target to reprogram T cell metabolism to augment immunotherapy.

2020-06-15 | PXD012811 | Pride

Sirt2 inhibition reprograms T cell metabolism for optimal anti-tumor immunity: Sirt2 Interacting Proteins 2

2020-07-03 | PXD020150 | Pride