Low energy metabolism protects leukemia stem cells from chemotherapy and immunosurveillance via a SHP-1-PFKP axis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE244234 | GEO | 2023/11/22
REPOSITORIES: GEO
Similar Datasets
Project description:Low energy metabolism protects leukemia stem cells from chemotherapy and immunosurveillance via a SHP-1-PFKP axis
| PRJNA1021957 | ENA
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.
2010-12-10 | E-GEOD-20599 | biostudies-arrayexpress
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.
2023-09-08 | GSE174142 | GEO
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation.
2010-12-10 | GSE20599 | GEO
Project description:Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as programmed cell death protein 1 (PD-1). Blockade of PD-1 signalling leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase Src homology 2 (SH2) domain–containing phosphatase (SHP)-2 is essential for the molecular cascade downstream PD-1, suggesting functional redundancy with the homologous phosphatase SHP-1. Therefore, we investigated the effect of concomitant SHP-1 and 2 deletion in T cells by knocking out these phosphatases under the CD4cre promoter. In vivo results not only indicate that Shp-1/2 deletion is insufficient to ameliorate tumour control, but also that it impairs the therapeutic effects of anti-PD1 treatment, affecting tumour-infiltrating CD8+ T cells. Notably, acute deletion of Shp-1/2 in effector T cells also fails to improve tumour control. In vitro results show that Shp-1/2-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analysis reveals substantial alterations in their proteome, including in apoptosis-related pathways. This data indicates that concomitant ablation of SHP-1/2 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.
2022-09-29 | PXD034897 | Pride
Project description:Goal of this study is to identify annotated and non-annotated genes transcriptionally regulated by small heterodime partner (SHP, Nrob2) expression. Liver 5' capped RNA samples from three SHP -/- and three wild type mice were sequenced with Illumina GAII sequencer.
2013-10-22 | E-GEOD-43893 | biostudies-arrayexpress
Project description:The small heterodimer partner (SHP) regulates fatty acid oxidation and lipogenesis in the liver by regulating peroxisome proliferator-activated receptor (PPAR) γ expression. SHP is also abundantly expressed in the myocardium. Therefore, we investigated the myocardial gene expression in a SHP deletion animal model.
2017-12-01 | E-MTAB-5329 | biostudies-arrayexpress
Project description:THEMIS is critical for conventional T cell development but its precise molecular function remains elusive. Here we show that THEMIS constitutively associates with the phosphatases SHP-1 and SHP-2. This complex requires the adapter GRB2, which bridges SHP to Themis in a Tyr-phosphorylation-independent fashion. Rather, SHP1 and THEMIS engage with the N-SH3 and C-SH3 domains of GRB2, respectively, a configuration that allows GRB2-SH2 to recruit the complex onto LAT. Coherent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knockdown increased TCR-induced TCR- phosphorylation, Erk activation and CD69 expression, however not Lck phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP-1 knockdown. Remarkably, a KI mutation of Lck Ser59, previously suggested to be key in ERK-mediated resistance towards SHP-1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favors T cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T cell development and differentiation.
2015-01-07 | PXD001410 | Pride
Project description:Lysosome-mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that feeding unexpectedly activates intestinal lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the late fed-state gut hormone, fibroblast growth factor-15/19 (FGF15/19). Postprandial intestinal triglycerides (TGs) and apolipoprotein-B48 (ApoB48), the TG-rich chylomicron marker, were elevated in SHP-knockout and FGF15-knockout mice. Genomic analyses in mouse intestine revealed that SHP partners with the key lysosomal activator, transcription factor-EB (TFEB), upregulating autophagy/lipolysis network genes after feeding. In HT29 intestinal cells, FGF19 treatment activated lipophagy in a manner dependent on both SHP and TFEB, reducing TG and ApoB48 levels. Mechanistically, feeding-induced FGF15/19 signaling increases nuclear localization of TFEB and SHP via PKCβ/ζ-mediated phosphorylation, leading to transcriptional induction of Ulk1 and Atgl. Collectively, these results demonstrate that after feeding, FGF15/19-activated SHP and TFEB paradoxically activate gut lipophagy, limiting postprandial TG levels. As excess lipids cause dyslipidemia and obesity, the FGF15/19-SHP-TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity-associated metabolic disease.
2022-04-22 | GSE197549 | GEO
Project description:MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL protein. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins: MLL-AF1p, MLL-AF4, MLL-AF9, MLL-CBP, MLL-EEN, MLL-ENL and MLL-GAS7.
2018-05-25 | PXD009338 | Pride