T3 and Glucose Increase Expression of Phosphoenolpyruvate Carboxykinase (Pck1) Leading to Increased ß-Cell Proliferation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA903166 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR22334900_1.fastq.gz | Fastqsanger.gz | |||
| SRR22334900_2.fastq.gz | Fastqsanger.gz | |||
| SRR22334902_1.fastq.gz | Fastqsanger.gz | |||
| SRR22334902_2.fastq.gz | Fastqsanger.gz |
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Project description:Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally down-regulated protein 8, to target proteins, with yet-unknown consequences. Here we show in mice that neddylation in liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver (either pharmacologically or genetically) reduces gluconeogenic capacity and the hyperglycemic actions of counterregulatory hormones (glucagon, adrenaline and glucocorticoids). Further, people with obesity and type 2 diabetes (compared to people with obesity and normoglycemia) display elevated hepatic neddylation levels that correlate positively with fasting glucose levels. Mechanistically, we determined that fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues—K278, K342 and K387. PCK1 is a key control point for gluconeogenesis regulation that can be post-translationally modified by acetylation and phosphorylation, but to date no modifications are known to affect its gluconeogenic capacity. Of note, we find that mutating the three PCK1 lysines that are neddylated reduces its gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely-tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.
2023-10-08 | PXD043054 | Pride
Project description:Phosphoenolpyruvate carboxykinase (PCK1) is a key integrator of hepatic energy metabolism, but its role in hepatic stellate cells (HSCs), the main fibrogenic cells in the liver, remains unknown. We found that PCK1 is reduced in HSCs from fibrotic animals and people with fibrosis, correlating negatively correlated with fibrosis severity. Silencing PCK1 activates human HSCs and increases fibrotic markers, whereas ectopic PCK1 expression blunts transforming growth factor β1-induced activation. Activated HSCs show elevated glycolysis and tricarboxylic acid cycle activity, but PCK1 overexpression reduces acetyl-CoA, limiting tricarboxylic acid cycle intermediates and ameliorating HSCs activation. In mice, HSC-specific PCK1 loss accelerates diet-induced liver fibrosis. Notably, mice lacking PCK1 in HSCs also develop spontaneous fibrosis on a normal diet. These findings show that disrupted cataplerosis from PCK1 loss enhances glycolysis and activates HSCs, promoting liver fibrosis.
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| S-EPMC9731891 | biostudies-literature
Project description:The protein-tyrosine phosphatase SHP-1 (PTPN6) is an important glucose homeostasis modulator. Besides negatively regulating insulin signaling, the specific role of SHP-1 in metabolic control remains poorly understood. We show that SHP-1 acts as a co-activator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene, thereby modulating basal gluconeogenesis in hepatocytes. SHP-1 interacts with RNA polymerase II-subunits and signal transducer and activator of transcription 5 (STAT5), and localizes to the nucleus, where a sub-fraction of SHP-1 associates with chromatin. While SHP-1 binds to the PCK1-promoter, its loss affects RNA polymerase II-recruitment to this and other promoters of genes enriched for glucose metabolism-related functions. SHP-1-downregulation, and similarly STAT5 pharmacological inhibition reduce PCK1-transcript levels correlating with blunted gluconeogenesis. Overall, we identified a novel molecular SHP-1-function, that of a regulator of PCK1-transcription and subsequently hepatic gluconeogenesis, through physical interaction with the transcription machinery, mediated by an Akt-independent mechanism, but independent of STAT5 tyrosine-phosphorylation status.
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Project description:Patients with aggressive prostate cancer generally present with poor outcomes. Identifying the factors regulating prostate cancer aggressiveness may open new avenues in therapy. Specifically, information from prostate cancer patient databases revealed that higher phosphoenolpyruvate carboxykinase isoform 2 (PCK2) levels correlate with more aggressive tumors and lower survival rates. Herein, we show that high tumorigenic prostate cancer cell clones express high levels of PCK2. We found that elevated levels of PCK2 are critical for the glucose metabolic remodeling and the maintenance of tumor-initiating cells (TICs) in aggressive prostate cancer. Our data suggest that PCK2 promotes tumorigenicity by lowering acetyl-CoA levels through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate cancer.
2016-01-04 | GSE76470 | GEO
Project description:We have identified a methanol- and biotin-starvation-inducible zinc finger protein named ROP [repressor of phosphoenolpyruvate carboxykinase (PEPCK)] in the methylotrophic yeast Pichia pastoris. When P.pastoris strain GS115 (wild-type, WT) is cultured in biotin-deficient, glucose ammonium (Bio-) medium, growth is suppressed due to the inhibition of anaplerotic synthesis of oxaloacetate, catalysed by the biotin-dependent enzyme pyruvate carboxylase (PC). Deletion of ROP results in a strain (∆ROP) that can grow under biotin-deficient conditions due to derepression of a biotin- and PC-independent pathway of anaplerotic synthesis of oxaloacetate. Northern analysis as well as microarray expression profiling of RNA isolated from WT and ∆ROP strains cultured in Bio(-) medium indicate that expression of the phosphoenolpyruvate carboxykinase gene (PEPCK) is induced in ∆ROP during biotin- or PC-deficiency even under glucose-abundant conditions. There is an excellent correlation between PEPCK expression and growth of ∆ROP in Bio(-) medium, suggesting that ROP-mediated regulation of PEPCK may have a crucial role in the biotin- and PC-independent growth of the ∆ROP strain. To our knowledge, ROP is the first example, of a zinc finger transcription factor involved in the catabolite repression of PEPCK in yeast cells cultured under biotin- or PC-deficient and glucose-abundant conditions.
2011-10-14 | GSE32948 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) has been reported to be less effective to immune checkpoint inhibitors, which may be associated with metabolic reprogramming of tumor cells and abnormal tumor microenvironment. Here, we aim to investigate the role of gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC and its interplay with the tumor microenvironment. Hepatocyte-specific phosphatase and tensin homolog (Pten) and Pck1 biallelic knockout mice were established to induce MASH-HCC. Single-cell RNA sequencing and multiparametric flow cytometry were performed to analyze the immune landscape alterations. PCK1 is downregulated in tumors tissues compared with adjacent non-cancerous tissues from patients with MASH-HCC. Hepatocyte-specific Pck1 knockout mice exhibited markedly increased tumorigenesis in dietary models and genetic models of spontaneous MASH-HCC, together with inhibited effector function of tumor-infiltrating CD8+ T cells. Mechanistically, PCK1 deficiency induces the accumulation of endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which can be taken up by CD8+ T cells and activate the p38 mitogen-activated protein kinase pathway, ultimately leading to CD8+ T cells dysfunction. Notably, PCK1 restoration or 12-HETE inhibition combined with anti-PD1 treatment increases the antitumor capability of CD8+ T cells and suppresses MASH-HCC development. This study reveals the pivotal role of the hepatic cell-intrinsic enzyme PCK1 in mediating CD8+ T cell dysfunction via 12-HETE-p38 signaling in MASH-HCC. PCK1 could be a metabolic checkpoint to enhance the efficacy of anti-PD1 immunotherapy in MASH-HCC.
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Project description:Patients with aggressive prostate cancer generally present with poor outcomes. Identifying the factors regulating prostate cancer aggressiveness may open new avenues in therapy. Specifically, information from prostate cancer patient databases revealed that higher phosphoenolpyruvate carboxykinase isoform 2 (PCK2) levels correlate with more aggressive tumors and lower survival rates. Herein, we show that high tumorigenic prostate cancer cell clones express high levels of PCK2. We found that elevated levels of PCK2 are critical for the glucose metabolic remodeling and the maintenance of tumor-initiating cells (TICs) in aggressive prostate cancer. Our data suggest that PCK2 promotes tumorigenicity by lowering acetyl-CoA levels through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate cancer. 2 subclones have been isolated from DU145 cells. The epithelial like (EL) clone has a high tumorigenicity ability and enriched tumor initiating cells than mesenchymal like (ML) clone. Genes with differential expression pattern between these two clones were detected by gene micorarray.
2016-01-04 | E-GEOD-76470 | biostudies-arrayexpress
Project description:We have identified a methanol- and biotin-starvation-inducible zinc finger protein named ROP [repressor of phosphoenolpyruvate carboxykinase (PEPCK)] in the methylotrophic yeast Pichia pastoris. When P.pastoris strain GS115 (wild-type, WT) is cultured in biotin-deficient, glucose ammonium (Bio-) medium, growth is suppressed due to the inhibition of anaplerotic synthesis of oxaloacetate, catalysed by the biotin-dependent enzyme pyruvate carboxylase (PC). Deletion of ROP results in a strain (∆ROP) that can grow under biotin-deficient conditions due to derepression of a biotin- and PC-independent pathway of anaplerotic synthesis of oxaloacetate. Northern analysis as well as microarray expression profiling of RNA isolated from WT and ∆ROP strains cultured in Bio(-) medium indicate that expression of the phosphoenolpyruvate carboxykinase gene (PEPCK) is induced in ∆ROP during biotin- or PC-deficiency even under glucose-abundant conditions. There is an excellent correlation between PEPCK expression and growth of ∆ROP in Bio(-) medium, suggesting that ROP-mediated regulation of PEPCK may have a crucial role in the biotin- and PC-independent growth of the ∆ROP strain. To our knowledge, ROP is the first example, of a zinc finger transcription factor involved in the catabolite repression of PEPCK in yeast cells cultured under biotin- or PC-deficient and glucose-abundant conditions. Agilent one-color experiment,Organism: Pichia pastoris ,Custom Pichia pastoris Gene Expression 8x15k array designed by Genotypic Technology Pvt. Ltd. (Agilent -AMADID: 25088 ) , Labeling kit: Agilent Quick-Amp labeling Kit (p/n5190-0442)
2011-10-13 | E-GEOD-32948 | biostudies-arrayexpress