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.
Cyclophilin D extramitochondrial signaling controls cell cycle progression and chemokine-directed cell motility.
Specimen part
View SamplesWe performed whole-genome stability measurements for MDA-MB-231 and its highly metastatic derivative MDA-LM2. Our goal was to identify post-transcriptonal regulons that are deregulated en route to higher metastatic capacity. Overall design: Cells were pulsed with 4-thiouridine for 2 hours and then RNA was extracted at 0, 2, 4, and 7 hr time-points in quadruplicate from each cell line. 4sU labeling followed by RNA-seq was then used to measure the abundance of transcripts in each population. A decay rate was estimated based on the rate at which transcript abundance was reduced at these time-points.
Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins.
Cell line, Subject, Time
View SamplesSide population (SP) cells isolated from limbal and conjunctival epithelia derive from cells that are slow cycling in vivo, a known feature of tissue stem cells. The purpose of this study was to define the molecular signature of the conjunctival side population cells by global differential gene expression to identify markers and signaling pathways associated with this cell phenotype.
Molecular profiling of conjunctival epithelial side-population stem cells: atypical cell surface markers and sources of a slow-cycling phenotype.
No sample metadata fields
View SamplesThe aim of this study was to identify genes expressed selectively in brown adipose tissue as compared to white adipose tissue from the same animals. This analysis provides a gene set that is brown and white adipose selective.
Transcriptional control of brown fat determination by PRDM16.
Sex, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
VEGF blockade enhances the antitumor effect of BRAFV600E inhibition.
Cell line, Treatment
View SamplesIn this work we investigated the combined effects of the BRAF inhibition and of the VEGF blockade in a preclinical model of melanoma. The purpose of this dataset was to examine the transcriptional responses of a A375 xenograft model to PLX472 and bevacizumab, either as single agents or as combination therapy. We performed species-specific analysis of gene expression to discriminate the effects of the different therapeutic regimens on tumor cells (human) and stromal microenvironment (mouse). Here, Illumina Mouse BeadChips were used to profile the transcriptome after 12 days treatment. We reported that dispensing the dual treatment is more efficient than the single compounds and the occurrence of resistance by modifying the tumor genetic programs regulating myeloid cells recruitment and extracellular matrix remodeling.
VEGF blockade enhances the antitumor effect of BRAFV600E inhibition.
Cell line, Treatment
View SamplesIn this work we investigated the combined effects of the BRAF inhibition and of the VEGF blockade in a preclinical model of melanoma. The purpose of this dataset was to examine the transcriptional responses of a A375 xenograft model to PLX472 and bevacizumab, either as single agents or as combination therapy. We performed species-specific analysis of gene expression to discriminate the effects of the different therapeutic regimens on tumor cells (human) and stromal microenvironment (mouse). Here, Illumina Human BeadChips were used to profile the transcriptome after 12 days treatment. We reported that dispensing the dual treatment is more efficient than the single compounds and the occurrence of resistance by modifying the tumor genetic programs regulating myeloid cells recruitment and extracellular matrix remodeling.
VEGF blockade enhances the antitumor effect of BRAFV600E inhibition.
Cell line, Treatment
View SamplesXbp1 is a major transcription factor in the unfolded protein response. To uncover its function in DCs we generated a conditional KO for Xbp1 in dendritic cells. We here compare the expression of mRNAs in two different splenic DC subpopulations, CD8a and CD11b DCs in both WT and KO mice.
The unfolded-protein-response sensor IRE-1α regulates the function of CD8α+ dendritic cells.
Specimen part
View SamplesTyrosine phosphorylation is a hallmark for activation of Signal Transducer and Activator of Transcription (STAT) proteins, but their transcriptional activity also depends on other secondary modifications. Type I interferons (IFNs) can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Following a genome-wide RNAi screen, we identified the Sin3a complex as an important mediator of this STAT3 transcriptional repression. Sin3a directly interacts with the DNA-binding domain of STAT3 and alters its acetylation status. SIN3A silencing enhances recruitment of STAT3 and enhanceosome components to the SOCS3 promoter, resulting in histone hyperacetylation and enhanced transcription. Conversely, Sin3a is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against Influenza A and hepatitis C viruses. The Sin3a complex therefore acts as a context-dependent STAT1/3 transcriptional switch.
The Sin3a repressor complex is a master regulator of STAT transcriptional activity.
Cell line, Treatment
View SamplesEpigenetic events, including covalent post-translational modification of histones, have frequently been demonstrated to play critical roles in tumor development and progression. The transcriptional coactivator, p300/CBP, possesses both histone acetyltransferase (HAT) activity as well as scaffolding properties that directly influence transcriptional activation of targeted genes. We have used a recently reported small molecule inhibitor of p300 HAT activity, C646, to explore the specific contribution of p300/CBP HAT activity to tumor development and progression. We find that C646 inhibits the growth of lineage-specific tumor cell lines including human melanomas through direct transcriptional regulation of cell cycle regulatory proteins. Further evaluation of the p300 HAT transcriptome in human melanoma cells using comprehensive gene expression profiling reveals that p300 HAT activity globally promotes cell cycle progression, nucleosome assembly, and the DNA damage checkpoint through direct transcriptional regulatory mechanisms. Additionally, C646 promotes sensitivity to DNA damaging agents leading to enhanced apoptosis of melanoma cells following combination treatment with cisplatin. Together our data suggest that p300 HAT activity regulates critical growth regulatory pathways in tumors and may serve as a novel therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents.
Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells.
Cell line, Treatment, Time
View Samples