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GSE41280
Mus musculus
6 Downloadable Samples
Illumina MouseWG-6 v2.0 expression beadchip
Description
Mitochondria control bioenergetics and cell fate decisions, but whether they also participate in extra-organelle signaling is not understood. Here, we show that interference with cyclophilin D (CypD), a mitochondrial matrix protein and apoptosis regulator, causes accelerated cell proliferation and enhanced cell migration and invasion. These responses are associated with global transcriptional changes in CypD-/- cells, predominantly affecting chemokines and their receptors, and resulting in increased activating phosphorylation of Signal Transduction and Activator of Transcription 3 (STAT3). In turn, STAT3 signaling promotes increased proliferation of CypD-/- cells via accelerated S-phase entry and supports Cxcl12-directed paracrine cell motility. Therefore, mitochondria-to-nuclei transcriptional signaling globally affects cell division and motility. As immunosuppressive therapies often target CypD, this pathway may predispose the tissue microenvironment of these patients to oncogenic transformation.
Publication Title
Cyclophilin D extramitochondrial signaling controls cell cycle progression and chemokine-directed cell motility.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The anthracycline, doxorubicin (Dox), is widely used in oncology, but it may it may cause a cardiomyopathy which has dismal prognosis and cannot be effectively prevented. The secretome of multipotent human amniotic fluid-derived stem cells (hAFS) has previously been demonstrated to reduce ischemic cardiac damage. Here, it is shown that the hAFS conditioned medium (hAFS-CM) antagonizes senescence and apoptosis of cardiomyocytes and cardiac progenitor cells, two major features of Dox cardiotoxicity. Mechanistic studies with primary mouse neonatal cardiomyocytes reveal that hAFS-CM inhibition of Dox-elicited senescence and apoptosis is paralleled by decreased DNA damage and is associated with nuclear translocation of NF-kB and upregulation of a set of genes controlled by NF-kB, namely Il6 and Cxcl1, which promote cardiomyocyte survival, and Cyp1b1 and Abcb1, which encode for proteins involved in Dox metabolism and efflux, respectively. The PI3K/Akt signaling cascade, upstream of NF-kB, is potently activated by the hAFS-CM and pre-treatment with a PI3K inhibitor abrogates NF-kB accumulation into the nucleus, modulation of its target genes, and prevention of Dox-initiated senescence and apoptosis in response to the hAFS-CM. This work may lay the ground for the development of a stem cell-based paracrine therapy of chemotherapy-related cardiotoxicity.
Publication Title
The human amniotic fluid stem cell secretome effectively counteracts doxorubicin-induced cardiotoxicity.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The basic helix-loop-helix (bHLH) transcription factors of the Drosophilas atonal-related superfamily Neurogenin3 (Neurog3) and NeuroD1 promote endocrine differentiation in the gastrointestinal tract. Atonal Homolog 8 (Atoh8/Math6) is a newly identified member of the atonal-related family whose expression is induced by Neurog3 and NeuroD1 in cell culture, indicating a possible role for this gene in the endocrine differentiation program downstream of these two pro-endocrine factors. Intriguingly, available experimental evidence based on a reduced number of genes suggests that Atoh8 may negatively regulate Neurog3-targeting events. In this study, we have analyzed global changes in gene expression profiles upon exogenous expression of Atoh8 alone or in combination with Neurog3 in mouse pancreatic duct (mPAC) cells. These cells activate neuroendocrine-specific gene expression in response to Neurog3 and NeuroD1 and thus serve as an optimal model to evaluate the proendocrine activity of Atoh8. We have compared transcriptional profiles between mPAC cells treated with a recombinant adenovirus expressing Atoh8 (Ad-Atoh8) or a control adenovirus encoding B-galactosidase (Ad-Bgal), and between cells treated with Ad-Neurog3+Ad-Bgal or cells treated with Ad-Neurog3+Ad-Atoh8. The results obtained show that Atoh8 exhibits a very modest transcriptional activity in these cells thus confirming that Atoh8 does not function as a proendocrine gene. Furthermore, our data also confirm the ability of Atoh8 to block Neurog3-dependent transcriptional activation events. However, since repression is only seen for a small subset of Neurog3 gene targets, we discard a general role of Atoh8 as a negative regulator of Neurog3 pro-endocrine activity.
Publication Title
Characterization of the transcriptional activity of the basic helix-loop-helix (bHLH) transcription factor Atoh8.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Murine pancreatic beta cell line MIN6 was growth at two different concentrations of glucose (22,2 and 5,5 mM of glucose), 37C, 5% CO2 and was treated at four different concentrations of human amylin (0, 1, 10 and 20 uM) during three different times (2, 12 and 24 hours)
Publication Title
Impairment of the ubiquitin-proteasome pathway is a downstream endoplasmic reticulum stress response induced by extracellular human islet amyloid polypeptide and contributes to pancreatic beta-cell apoptosis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Human strabismic extraocular muscles (EOMs) differ from normal EOMs in structural and functional properties, but the gene expression profile of these two types of human EOM has not been examined. Differences in gene expression may inform about causes and effects of the strabismic condition in humans. Our samples are from human strabismic patients undergoing corrective surgery, and from human organ donors with no history of EOM disease.
Publication Title
Differences in gene expression between strabismic and normal human extraocular muscles.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 14 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Targeting components of the mitogen-activated protein kinase (MAPK) pathway prolongs survival of patients with advanced BRAFV600E melanomas but such an approach is not curative because of the rapid acquisition of numerous resistance mechanisms. Here we analyze melanoma cells that evade MAPK inhibitors by undergoing a senescence-like, slow-growth, phenotype, which leads to acquired resistance. The initial therapeutic response is characterized by an integrated stress response program, including stimulation of autophagic flux, activation of the endoplasmic reticulum machinery, and an enhanced ability of detoxifying reactive oxygen species. Reversibly senescent cells also exhibit an increase in mitochondrial genome copy number and a strong metabolic shift towards oxidative phosphorylation (OxPhos). Inducing mitochondrial dysfunction by co-targeting the MAPK pathway and mitochondrial Hsp90-directed protein folding with specific inhibitors prevented entry of cells into a reversibly senescent state, suppressed mitochondrial energy metabolism and augmented therapy response.
Publication Title
Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors.
Sample Metadata Fields
Disease, Disease stage, Cell line, Time
View Samples- Rattus norvegicus
- 5 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
In obesity an increase in -cell mass occurs to cope with the rise in insulin demand. This -cell plasticity is essential to avoid the onset of hyperglycemia, although the molecular mechanisms that regulate this process remain unclear. This study analyzed the role of adipose tissue in the control of -cell replication. Using a diet-induced model of obesity, we obtained conditioned media from three different white adipose tissue depots. Only in the adipose tissue depot surrounding the pancreas did the diet induce changes that led to an increase in INS1E cells and the islet replication rate. To identify the factors responsible for this proliferative effect, adipose tissue gene expression analysis was conducted by microarrays and quantitative RT-PCR. Of all the differentially expressed proteins, only the secreted ones were studied. IGF binding protein 3 (Igfbp3) was identified as the candidate for this effect. Furthermore, in the conditioned media, although the blockage of IGFBP3 led to an increase in the proliferation rate, the blockage of IGF-I receptor decreased it. Taken together, these data show that obesity induces specific changes in the expression profile of the adipose tissue depot surrounding the pancreas, leading to a decrease in IGFBP3 secretion. This decrease acts in a paracrine manner, stimulating the -cell proliferation rate, probably through an IGF-I-dependent mechanism. This cross talk between the visceral-pancreatic adipose tissue and -cells is a novel mechanism that participates in the control of -cell plasticity. (Endocrinology 153: 177187, 2012)
Publication Title
Role of IGFBP-3 in the regulation of β-cell mass during obesity: adipose tissue/β-cell cross talk.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 19 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 10 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Obesity is associated with an increase in -cell mass in response tothe rising demand for insulin. -cell plasticity is essential to maintaining glucose homeostasis, however,the cellular and molecular mechanisms by which -cell mass is regulated remain poorly understood.Recently, we described the existence of a crosstalk between the peripancreatic adipose tissue and -cells as a novel mechanism that participates in the regulation of -cell plasticity. Here, we identify the secreted frizzled-related protein (Sfrp) 5 as down-regulated in the pancreatic islets of obese rats as well as in the pancreatic islets of human obese patients. Our results demonstrate that the silencing of Sfrp5 induces an increase in -cell proliferation, which we correlate with the activation of Wnt signaling and of the MAPK and PI3 kinase pathways. Together, these findings expand our understanding of the mechanisms underlying -cell proliferation under conditions of obesity. Furthermore, this study opens new insights into the specific targeting of Sfrp5 as a novel therapeutic strategy for balancing -cell mass.
Publication Title
Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 9 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Obesity is associated with an increase in -cell mass in response tothe rising demand for insulin. -cell plasticity is essential to maintaining glucose homeostasis, however,the cellular and molecular mechanisms by which -cell mass is regulated remain poorly understood.Recently, we described the existence of a crosstalk between the peripancreatic adipose tissue and -cells as a novel mechanism that participates in the regulation of -cell plasticity. Here, we identify the secreted frizzled-related protein (Sfrp) 5 as down-regulated in the pancreatic islets of obese rats as well as in the pancreatic islets of human obese patients. Our results demonstrate that the silencing of Sfrp5 induces an increase in -cell proliferation, which we correlate with the activation of Wnt signaling and of the MAPK and PI3 kinase pathways. Together, these findings expand our understanding of the mechanisms underlying -cell proliferation under conditions of obesity. Furthermore, this study opens new insights into the specific targeting of Sfrp5 as a novel therapeutic strategy for balancing -cell mass.
Publication Title
Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat.
Sample Metadata Fields
Specimen part
View Samples