Med14 phosphorylation shapes genomic response to GLP-1 agonist [snRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1273752 | ENA |
REPOSITORIES: ENA
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Project description:Under feeding conditions, increases in circulating glucose concentrations trigger the release of glucagon-like peptide (GLP-1) from intestinal L cells. GLP-1 promotes insulin secretion and pancreatic beta cell viability in part via triggering of the beta cell GLP-1 receptor and subsequent induction of the cAMP signaling pathway, leading to the protein kinase A (PKA) mediated phosphorylation of CREB and induction of CREB target genes. By contrast with the acute effects of this pathway on immediate early CREB target genes, which attenuate the cAMP-CREB response, sustained exposure of beta cells to GLP-1 agonist (exenatide-4; Ex-4) or adenyl cyclase activator (Forskolin; FSK) stimulates the expression of beta cell specific CREB target genes with delayed kinetics. In a proteomic screen for transcriptional co-regulators that mediate the long-term effects of GLP-1, we identified Med14, a backbone subunit of the Mediator complex. Exposure to either Ex-4 or FSK stimulates Med14 phosphorylation at Ser983, corresponding to a conserved PKA recognition site (RRXS) that is located within an intrinsically disordered region of Med14. Phosphorylation of Med14 is essential for maintenance of enhancers that drive induction of beta cell-specific and diabetes-linked genes. Mutation of Med14 at Ser983 to alanine decreased beta cell numbers and repressed growth factor signaling in primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.
2025-06-17 | GSE299282 | GEO
Project description:Under feeding conditions, increases in circulating glucose concentrations trigger the release of glucagon-like peptide (GLP-1) from intestinal L cells. GLP-1 promotes insulin secretion and pancreatic beta cell viability in part via triggering of the beta cell GLP-1 receptor and subsequent induction of the cAMP signaling pathway, leading to the protein kinase A (PKA) mediated phosphorylation of CREB and induction of CREB target genes. By contrast with the acute effects of this pathway on immediate early CREB target genes, which attenuate the cAMP-CREB response, sustained exposure of beta cells to GLP-1 agonist (exenatide-4; Ex-4) or adenyl cyclase activator (Forskolin; FSK) stimulates the expression of beta cell specific CREB target genes with delayed kinetics. In a proteomic screen for transcriptional co-regulators that mediate the long-term effects of GLP-1, we identified Med14, a backbone subunit of the Mediator complex. Exposure to either Ex-4 or FSK stimulates Med14 phosphorylation at Ser983, corresponding to a conserved PKA recognition site (RRXS) that is located within an intrinsically disordered region of Med14. Phosphorylation of Med14 is essential for maintenance of enhancers that drive induction of beta cell-specific and diabetes-linked genes. Mutation of Med14 at Ser983 to alanine decreased beta cell numbers and repressed growth factor signaling in primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.
2025-06-17 | GSE299281 | GEO
Project description:Under feeding conditions, increases in circulating glucose concentrations trigger the release of glucagon-like peptide (GLP-1) from intestinal L cells. GLP-1 promotes insulin secretion and pancreatic beta cell viability in part via triggering of the beta cell GLP-1 receptor and subsequent induction of the cAMP signaling pathway, leading to the protein kinase A (PKA) mediated phosphorylation of CREB and induction of CREB target genes. By contrast with the acute effects of this pathway on immediate early CREB target genes, which attenuate the cAMP-CREB response, sustained exposure of beta cells to GLP-1 agonist (exenatide-4; Ex-4) or adenyl cyclase activator (Forskolin; FSK) stimulates the expression of beta cell specific CREB target genes with delayed kinetics. In a proteomic screen for transcriptional co-regulators that mediate the long-term effects of GLP-1, we identified Med14, a backbone subunit of the Mediator complex. Exposure to either Ex-4 or FSK stimulates Med14 phosphorylation at Ser983, corresponding to a conserved PKA recognition site (RRXS) that is located within an intrinsically disordered region of Med14. Phosphorylation of Med14 is essential for maintenance of enhancers that drive induction of beta cell-specific and diabetes-linked genes. Mutation of Med14 at Ser983 to alanine decreased beta cell numbers and repressed growth factor signaling in primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.
2025-06-17 | GSE299399 | GEO
Project description:Under feeding conditions, increases in circulating glucose concentrations trigger the release of glucagon-like peptide (GLP-1) from intestinal L cells. GLP-1 promotes insulin secretion and pancreatic beta cell viability in part via triggering of the beta cell GLP-1 receptor and subsequent induction of the cAMP signaling pathway, leading to the protein kinase A (PKA) mediated phosphorylation of CREB and induction of CREB target genes. By contrast with the acute effects of this pathway on immediate early CREB target genes, which attenuate the cAMP-CREB response, sustained exposure of beta cells to GLP-1 agonist (exenatide-4; Ex-4) or adenyl cyclase activator (Forskolin; FSK) stimulates the expression of beta cell specific CREB target genes with delayed kinetics. In a proteomic screen for transcriptional co-regulators that mediate the long-term effects of GLP-1, we identified Med14, a backbone subunit of the Mediator complex. Exposure to either Ex-4 or FSK stimulates Med14 phosphorylation at Ser983, corresponding to a conserved PKA recognition site (RRXS) that is located within an intrinsically disordered region of Med14. Phosphorylation of Med14 is essential for maintenance of enhancers that drive induction of beta cell-specific and diabetes-linked genes. Mutation of Med14 at Ser983 to alanine decreased beta cell numbers and repressed growth factor signaling in primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.
2025-06-17 | GSE299280 | GEO
Project description:Med14 phosphorylation shapes genomic response to GLP-1 agonist [ATAC-seq]
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Project description:Med14 phosphorylation shapes genomic response to GLP-1 agonist [RNA-seq]
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2021-09-10 | PXD028452 |
Project description:Obesity and its co-morbidities, such as diabetes and hypertension, can significantly reduce a person’s quality of life and place huge pressure on healthcare resources. When we eat a meal our gut and brain release hormones to control the amount of food and fluid we ingest to prevent overeating. One of these hormones is called glucagon-like peptide 1 (GLP-1) and is released from intestinal cells in response to food intake, but also produced and released in the brain. Drug analogues of GLP-1 are already in use in the clinic to treat both diabetes and obesity. The aim of this work was to obtain fundamental knowledge about a GLP-1 receptor population in nerve terminals of the posterior pituitary gland. We have investigated the pharmacological actions of GLP-1 using a selective receptor agonist called liraglutide, a drug that is approved for diabetes and obesity treatment in humans. Our work has focussed on the phosphoproteome of the neurointermediate lobe (posterior pituitary + intermediate lobe) of the rat pituitary gland 30 minutes after intraperitoneal injection of liraglutide (100 µg/kg) compared to vehicle controls (n = 6 animals per group). New understanding of this GLP-1 receptor population is essential for our knowledge of current treatments of diabetes and obesity that use stable peptide analogues in humans.
2023-03-02 | PXD037495 | Pride
Project description:GLP-1 agonists are potent glucose-lowering agents, however, their effect on adolescent organisms needs to be clarified Transgenic pigs expressing a dominant-negative GLP receptor randomly assigned for a 90 day treatment trial with liraglutide (0.6-1.8 mg per day)/placebo
2015-12-31 | E-GEOD-56427 | biostudies-arrayexpress