Impact of glucose metabolism in postnatal cardiomyocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE146924 | GEO | 2021/03/01
REPOSITORIES: GEO
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Project description:Impact of glucose metabolism in postnatal cardiomyocytes
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Project description:Hypothesis: Overexpression of the GLUT1 facilitative glucose transporter, in A7r5 vascular smooth muscle cells, is sufficient and/or necessary to induce alterations in gene expression which influence apoptosis, growth, and proliferation.
2009-10-23 | GSE15713 | GEO
Project description:Hypothesis: Overexpression of the GLUT1 facilitative glucose transporter, in A7r5 vascular smooth muscle cells, is sufficient and/or necessary to induce alterations in gene expression which influence apoptosis, growth, and proliferation. Experiment Overall Design: Scientific Approach: A7r5 rat embryonic vascular smooth muscle cells (VSMCs) (ATCC, CRL-1444) were infected for 72 hours with adenoviral vectors containing human GLUT1 or empty vector controls at a multiplicity of infection of 10 (MOI of 1 = 100 particles/cell) and grown in both high glucose (25mM) and low glucose (5.5mM) media. The human GLUT1 cDNA adenoviral vector and empty vector controls were a gift from Dr Arno Kumagai (University of Michigan). Total RNA was isolated using TRIzol (Invitrogen Life Technologies, Carlsbad, CA), followed by extraction with phenol/chloroform until the interface was clear. Total RNA was further purified using Qiagen RNeasy Mini Kit (Qiagen 74106). Immunoblot analysis was conducted to confirm GLUT1 overexpression at the time of Total RNA isolation (72 hours post-infection) for each condition. Experiment Overall Design: Number of chips: Total RNA was isolated from each of 2 conditions (control cells in low glucose (5.5mM), and GLUT1 overexpressing cells in low glucose), on three separate days and pooled to obtain one sample for each condition. In total we submitted two samples.
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Project description:Glucose uptake increases during B cell activation and plasma cell differentiation. However, conflicting findings regarding the role of glucose at different stages of B cell activation prevents establishing a clear metabolic profile. To determine whether glucose is required for establishing humoral immunity, we deleted the glucose transporter type 1 (GLUT1)-encoding gene (Slc2a1fl/fl) in mature B cells by CD23-mediated Cre expression (GLUT1-cKO). While B cell development was normal, germinal center B cell and antibody-secreting cell numbers (ASCs) were severely reduced in GLUT1-cKO mice. In addition, these mice could hardly mount antigen-specific antibody titers after vaccination. Activation of GLUT1-deficient B cells in vitro was impaired and the remaining plasmablasts abolished glycolysis, relying on mitochondrial activity and fatty acid metabolism. Metabolomics combined with genome-wide transcriptome analysis revealed a dramatically altered anaplerotic balance in GLUT1-deficient ASCs. Although the cells attempt to compensate for glucose deprivation by increasing their mitochondrial mass and the expression of genes responsible for glycolysis, the tricarboxylic acid cycle and the hexosamine synthesis pathways, they lack both the necessary metabolites for energy production and functional mitochondrial respiration. Consequently, protein synthesis was limited in GLUT1-deficient ASCs. Thus, we identified GLUT1 as a critical metabolic player defining the germinal center response and humoral immunity.
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Project description:"Starving cancer to death" is pursued for cancer therapy. An intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. But past attempts are challenged by that cancer cells can somehow tolerate starvation. In addition, during cancer progression, cancer cells may suffer from insufficient nutrient supply, for example due to insufficient angiogenesis. So uncovering mechanism of starvation resistance shall not only shed insight into cancer progression but also benefit cancer therapy. TFE3 is known as a transcription factor capable of activating autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation, which is sensitive to nutrient status. We recently reported TFE3 constitutively localizes to cell nucleus in kidney cancer, promoting cell proliferation even under replete condition. But whether and how TFE3 affects kidney cancer cell sensitivity to starvation is unclear. In this study, we find TFE3 promotes kidney cancer cell resistance to glucose starvation. We show starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through unbiased functional genomic study, we identify genes sensitive to TFE3 protein level, including SLC36A1, a lysosomal amino acid transporter. We find SLC36A1 is overexpressed in kidney cancer, promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is directly upregulated by TFE3 upon starvation, which enhances cellular resistance to starvation. Suppressing TFE3 or SLC36A1 significantly increased cellular sensitivity to GLUT1 inhibitor in kidney cancers. Collectively, we uncover a TFE3-SLC36A1 axis that responds to starvation and enhances starvation tolerance in kidney cancer.
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Project description:"Starving cancer to death" is pursued for cancer therapy. An intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. But past attempts are challenged by that cancer cells can somehow tolerate starvation. In addition, during cancer progression, cancer cells may suffer from insufficient nutrient supply, for example due to insufficient angiogenesis. So uncovering mechanism of starvation resistance shall not only shed insight into cancer progression but also benefit cancer therapy. TFE3 is known as a transcription factor capable of activating autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation, which is sensitive to nutrient status. We recently reported TFE3 constitutively localizes to cell nucleus in kidney cancer, promoting cell proliferation even under replete condition. But whether and how TFE3 affects kidney cancer cell sensitivity to starvation is unclear. In this study, we find TFE3 promotes kidney cancer cell resistance to glucose starvation. We show starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through unbiased functional genomic study, we identify genes sensitive to TFE3 protein level, including SLC36A1, a lysosomal amino acid transporter. We find SLC36A1 is overexpressed in kidney cancer, promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is directly upregulated by TFE3 upon starvation, which enhances cellular resistance to starvation. Suppressing TFE3 or SLC36A1 significantly increased cellular sensitivity to GLUT1 inhibitor in kidney cancers. Collectively, we uncover a TFE3-SLC36A1 axis that responds to starvation and enhances starvation tolerance in kidney cancer.
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