Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA121687 | ENA |
REPOSITORIES: ENA
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Project description:(original Title) Phenothiazine Neuroleptics Signal To The Human Insulin Promoter As Revealed By A Novel Human b-Cell Line Based High-Throughput Screen. To address the current deficiency in human beta-cell models, we have developed a cell line from human islets in which the expression of insulin and other beta-cell restricted genes are modulated by an inducible form of the bHLH transcription factor E47. In an effort to probe the global pattern of gene expression in T6PNE in an unbiased fashion, oligonucleotide microarray analysis was performed on T6PNE in the presence and absence of E47 induction and compared against human islets. Our analysis reveals that T6PNE express a substantial percentage of the b-cell specific geneset, and that this is further enhanced by the induction of E47. This cell line, T6PNE, was then screened against a library of known drugs for those that increase insulin promoter activity. Interestingly, members of the phenothiazine class of neuroleptics increased insulin gene expression upon short term exposure. Chronic treatment, however, resulted in suppression of insulin promoter activity, consistent with the effect of phenothiazines observed clinically to induce diabetes in chronically treated patients. In addition to providing insights into previously unrecognized targets and mechanisms of action of phenothiazines, the novel cell line described here provides a broadly applicable platform for mining new molecular drug targets and central regulators of beta-cell differentiated function. Gene expression studies in: Three human islet samples; Five T6PNE samples; Seven T6PNE induced with E47.
2010-08-06 | E-GEOD-18821 | biostudies-arrayexpress
Project description:(original Title) Phenothiazine Neuroleptics Signal To The Human Insulin Promoter As Revealed By A Novel Human b-Cell Line Based High-Throughput Screen. To address the current deficiency in human beta-cell models, we have developed a cell line from human islets in which the expression of insulin and other beta-cell restricted genes are modulated by an inducible form of the bHLH transcription factor E47. In an effort to probe the global pattern of gene expression in T6PNE in an unbiased fashion, oligonucleotide microarray analysis was performed on T6PNE in the presence and absence of E47 induction and compared against human islets. Our analysis reveals that T6PNE express a substantial percentage of the b-cell specific geneset, and that this is further enhanced by the induction of E47. This cell line, T6PNE, was then screened against a library of known drugs for those that increase insulin promoter activity. Interestingly, members of the phenothiazine class of neuroleptics increased insulin gene expression upon short term exposure. Chronic treatment, however, resulted in suppression of insulin promoter activity, consistent with the effect of phenothiazines observed clinically to induce diabetes in chronically treated patients. In addition to providing insights into previously unrecognized targets and mechanisms of action of phenothiazines, the novel cell line described here provides a broadly applicable platform for mining new molecular drug targets and central regulators of beta-cell differentiated function.
2010-08-07 | GSE18821 | GEO
Project description:This model is from the article:
Mass and information feedbacks through receptor endocytosis govern insulin signaling as revealed using a parameter-free modeling framework.
Brannmark C, Palmer R, Glad ST, Cedersund G, Stralfors P.
J Biol Chem.2010 Jun 25;285(26):20171-9.
20421297,
Abstract:
Insulin and other hormones control target cells through a network of signal-mediating molecules. Such networks are extremely complex due to multiple feedback loops in combination with redundancy, shared signal mediators, and cross-talk between signal pathways. We present a novel framework that integrates experimental work and mathematical modeling to quantitatively characterize the role and relation between co-existing submechanisms in complex signaling networks. The approach is independent of knowing or uniquely estimating model parameters because it only relies on (i) rejections and (ii) core predictions (uniquely identified properties in unidentifiable models). The power of our approach is demonstrated through numerous iterations between experiments, model-based data analyses, and theoretical predictions to characterize the relative role of co-existing feedbacks governing insulin signaling. We examined phosphorylation of the insulin receptor and insulin receptor substrate-1 and endocytosis of the receptor in response to various different experimental perturbations in primary human adipocytes. The analysis revealed that receptor endocytosis is necessary for two identified feedback mechanisms involving mass and information transfer, respectively. Experimental findings indicate that interfering with the feedback may substantially increase overall signaling strength, suggesting novel therapeutic targets for insulin resistance and type 2 diabetes. Because the central observations are present in other signaling networks, our results may indicate a general mechanism in hormonal control.
2024-09-02 | BIOMD0000000343 | BioModels
Project description:Human breast cancer cell line MCF-7 is usually sensitive to chemotherapy drug BMS-554417, an insulin receptor (IR) and insulin-like growth factor receptor (IGFR) inhibitor. However, through step-wise increase in BMS-554417 doses in culture media, we were able able to screen and select a single MCF-7 clone that is BMS-554417 resistant. It is cross resistant to BMS-536924. This new line of MCF-7 cells was named as MCF-7R4. The transcriptome profiling of both MCF-7 and MCF-7R4 was performed using Affymetrix HG-U133 plus2.0 GeneChip arrays.
2009-11-06 | GSE18912 | GEO
Project description:Objective: The developmental effects of mutations in genes associated with monogenic diabetes on human pancreas development is not well understood. More specifically, if insulin gene recessive mutations influence the human endocrine lineage segregation still needs to be investigated. Methods: We generated a novel knock-in H2B-Cherry reporter human induced pluripotent stem cell (iPSCs) line expressing no insulin upon differentiation to stem cell-derived (SC-) β cells in vitro. This cell line enabled us to have a model mimicking the extremely reduced insulin levels in patients with recessive insulin mutations. We combined immunostaining, Western blotting and proteomics analysis to characterize the SC-islets from this iPSC line. Furthermore, we leveraged FACS analysis and imaging to explore the impact of insulin shortage on human endocrine cell induction, composition and proliferation. Results: We found that lack of insulin hampers insulin receptor (IR) signaling in SC-islets but increases the IR sensitivity. Furthermore, insulin deficiency showed no effects on human endocrine lineage induction. However, lack of insulin skewed the SC-islet cell composition. We found an increased in SC-β cell number at the expense of SC-α cell differentiation in the absence of insulin. Finally, insulin shortage reduced the rate of SC-β cell proliferation but had no impact of the expansion of SC-α cells. Conclusions: We provided evidence of the developmental impacts of reduced insulin levels on human β cell characteristics and endocrine lineage formation. These findings help to better understand the pathomechanisms of recessive insulin mutations during embryonic development and also shed some lights on the possible physiological function of this hormone coordinating human islet cell composition and architecture during endocrinogenesis.
2024-01-17 | PXD045366 | Pride
Project description:Insulin expression is restricted to the pancreatic beta cells, which are physically or functionally depleted in diabetes. Identifying targetable pathways repressing insulin in non-beta cells, particularly in the developmentally related glucagon-secreting alpha cells, is an important aim of regenerative medicine. Here, we performed an RNA interference screen in the murine alpha cell line, alphaTC1, to identify silencers of insulin expression. We discovered that knockdown of the splicing factor Smndc1 (Survival Motor Neuron Domain Containing 1) triggered a global repression of alpha cell gene-expression programs in favor of increased beta cell markers. Mechanistically, Smndc1 knockdown upregulated the key beta cell transcription factor Pdx1, by modulating the activities of the BAF and Atrx families of chromatin remodeling complexes. SMNDC1’s repressive role was conserved in human pancreatic islets, its loss triggering enhanced insulin secretion and PDX1 expression. Our study identifies Smndc1 as a key factor connecting splicing and chromatin remodeling to the control of insulin expression in human and mouse islet cells.
2022-07-01 | PXD030363 | Pride
Project description:Insulin expression is restricted to the pancreatic beta cells, which are physically or functionally depleted in diabetes. Identifying targetable pathways repressing insulin in non-beta cells, particularly in the developmentally related glucagon-secreting alpha cells, is an important aim of regenerative medicine. Here, we performed an RNA interference screen in the murine alpha cell line, alphaTC1, to identify silencers of insulin expression. We discovered that knockdown of the splicing factor Smndc1 (Survival Motor Neuron Domain Containing 1) triggered a global repression of alpha cell gene-expression programs in favor of increased beta cell markers. Mechanistically, Smndc1 knockdown upregulated the key beta cell transcription factor Pdx1, by modulating the activities of the BAF and Atrx families of chromatin remodeling complexes. SMNDC1’s repressive role was conserved in human pancreatic islets, its loss triggering enhanced insulin secretion and PDX1 expression. Our study identifies Smndc1 as a key factor connecting splicing and chromatin remodeling to the control of insulin expression in human and mouse islet cells.
2022-07-01 | PXD030361 | Pride
Project description:Insulin expression is restricted to the pancreatic beta cells, which are physically or functionally depleted in diabetes. Identifying targetable pathways repressing insulin in non-beta cells, particularly in the developmentally related glucagon-secreting alpha cells, is an important aim of regenerative medicine. Here, we performed an RNA interference screen in the murine alpha cell line, alphaTC1, to identify silencers of insulin expression. We discovered that knockdown of the splicing factor Smndc1 (Survival Motor Neuron Domain Containing 1) triggered a global repression of alpha cell gene-expression programs in favor of increased beta cell markers. Mechanistically, Smndc1 knockdown upregulated the key beta cell transcription factor Pdx1, by modulating the activities of the BAF and Atrx families of chromatin remodeling complexes. SMNDC1’s repressive role was conserved in human pancreatic islets, its loss triggering enhanced insulin secretion and PDX1 expression. Our study identifies Smndc1 as a key factor connecting splicing and chromatin remodeling to the control of insulin expression in human and mouse islet cells.
2022-07-01 | PXD030362 | Pride
Project description:Human breast cancer cell line MCF-7 is usually sensitive to chemotherapy drug BMS-554417, an insulin receptor (IR) and insulin-like growth factor receptor (IGFR) inhibitor. However, through step-wise increase in BMS-554417 doses in culture media, we were able able to screen and select a single MCF-7 clone that is BMS-554417 resistant. It is cross resistant to BMS-536924. This new line of MCF-7 cells was named as MCF-7R4. The transcriptome profiling of both MCF-7 and MCF-7R4 was performed using Affymetrix HG-U133 plus2.0 GeneChip arrays. Five replicates of MCF-7 and five replicates of MCF-7R4 were profiled.
2009-11-05 | E-GEOD-18912 | biostudies-arrayexpress
Project description:The study was completed to compare expression profiles of primary human beta cells (in the form of adult human islets), to the expression profile of hESC-derived beta-like cells. A HES3 line modified by homologous recombination to express GFP under the insulin promoter allowed us to FACS sort the hESC-derived cells into purified insulin-positive (presumably beta-like cells), and insulin-negative populations.
2012-09-09 | GSE40709 | GEO