Raptor determines β-cell identity and plasticity independent of metabolic state
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE130792 | GEO | 2019/05/08
REPOSITORIES: GEO
Similar Datasets
Project description:Raptor determines β-cell identity and plasticity independent of metabolic state
| PRJNA541439 | ENA
Project description:Compromised ?-cell identity is emerging as an important contributor to ?-cell failure in diabetes; however, the precise mechanism independent of hyperglycemia is under investigation. We have previously reported that mTORC1/Raptor regulates functional maturation in ?-cells. In the present study, we find that diabetic ?-cell specific Raptor-deficient mice (?RapKOGFP) show reduced ?-cell mass, loss of ?-cell identity and acquisition of ?-cell features; which are not reversible upon glucose normalization. Deletion of Raptor directly impairs ?-cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to ?-cell failure. Moreover, loss of Raptor activates ?-cell transcription factor MafB (via modulating C/EBP? isoform ratio) and several ?-cell enriched genes i.e. Etv1 and Tspan12, thus initiates ?- to ?-cell reprograming. The present findings highlight mTORC1 as a metabolic rheostat for stabilizing ?-cell identity and repressing ?-cell program at normoglycemic level, which might present therapeutic opportunities for treatment of diabetes.
| S-EPMC7242325 | biostudies-literature
Project description:Naïve T cells respond to antigen stimulation by exiting from quiescence into clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that Raptor/mTORC1-dependent metabolic reprogramming is a central determinant of this transitional process. Loss of Raptor abrogates T cell priming and Th2 cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells. mTORC1 coordinates multiple metabolic programs in T cells including glycolysis, lipid synthesis and oxidative phosphorylation to mediate antigen-triggered exit from quiescence. mTORC1 further links glucose metabolism to the initiation of Th2 differentiation by orchestrating cytokine receptor expression and cytokine responsiveness. Activation of Raptor/mTORC1 integrates T cell receptor (TCR) and CD28 co-stimulatory signals in antigen-stimulated T cells. Our studies identify a Raptor/mTORC1-dependent pathway linking signal-dependent metabolic reprogramming to quiescence exit, and this in turn coordinates lymphocyte activation and fate decisions in adaptive immunity. We used microarrays to explore the gene expression profiles differentially expressed in CD4+ T-cells from wild-type (WT) and CD4(cre) x Raptor(fl/fl) mice before and after stimulation with anti CD3/CD28 antibodies.
2014-01-27 | E-GEOD-51668 | biostudies-arrayexpress
Project description:Naïve T cells respond to antigen stimulation by exiting from quiescence into clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that Raptor/mTORC1-dependent metabolic reprogramming is a central determinant of this transitional process. Loss of Raptor abrogates T cell priming and Th2 cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells. mTORC1 coordinates multiple metabolic programs in T cells including glycolysis, lipid synthesis and oxidative phosphorylation to mediate antigen-triggered exit from quiescence. mTORC1 further links glucose metabolism to the initiation of Th2 differentiation by orchestrating cytokine receptor expression and cytokine responsiveness. Activation of Raptor/mTORC1 integrates T cell receptor (TCR) and CD28 co-stimulatory signals in antigen-stimulated T cells. Our studies identify a Raptor/mTORC1-dependent pathway linking signal-dependent metabolic reprogramming to quiescence exit, and this in turn coordinates lymphocyte activation and fate decisions in adaptive immunity.
2014-01-27 | GSE51668 | GEO
Project description:mTORC1 to AMPK Switching Underlies β-Cell Metabolic Plasticity During Maturation and Diabetes
| PRJNA547067 | ENA
Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment. The hepatic transcriptional response in mice on high fat diet treated with metformin was largely ablated by AMPK-deficiency under the conditions examined, indicating the essential role of this kinase and its targets in metformin action in vivo.
2023-08-10 | GSE157049 | GEO
Project description:Independent phenotypic plasticity axes define mammalian metabolic and obesity sub-types
| PRJNA847415 | ENA
Project description:The mammalian target of rapamycin complex 1 (mTORC1) is a key nutrient-sensing hub and a master regulator of cellular growth and metabolism. Activation of mTORC1 by amino acids and growth factors requires its recruitment to the lysosomes. Furthermore, lysosomal distribution has been shown to be intimately involved in the control of mTORC1, where localisation of lysosomes near plasma membrane increases mTORC1 activity. However, the underlying mechanisms by which lysosomal positioning impacts on mTORC1 signalling are not well understood. To understand better the spatial associations of mTORC1, we analysed the proximal ‘interactome’ of the constitutive component of mTORC1, Raptor, using BioID2-based proximity labelling and MS-based proteomics.
2021-09-08 | PXD012795 | Pride
Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment.
2023-08-10 | GSE157048 | GEO
Project description:Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/-CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs. The CA1 OSCC cell line was sub-cloned to derive 4 clonal sub-lines, termed pEMT-P, pEMT-S, Epi-S and Epi-P (here 18, 23, 7 and 4 respectively).
2016-01-12 | E-GEOD-74578 | biostudies-arrayexpress