Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tsirvouli2023 - PsoriaSys model: a multiscale psoriasis model

ABSTRACT: The PsoriaSys model represent molecular and cellular interactions in the psoriatic microenvironment. The model is able to simulate the dynamics of keratinocyte proliferation in response to psoriatic triggers and perturbations. Dynamic simulations coupled with network graph metrics were used to identify target pairs with high influence on the system's behavior. Two target pairs, namely the combinatorial inhibition of neutrophil activation with PGE2 production or STAT3 activation, were predicted to reduce keratinocyte hyperproliferation at similar levels as IL-17 inhibition, which is the current standard treatment for moderate-to-severe cases.

SUBMITTER: Eirini Tsirvouli

PROVIDER: MODEL2308300001 | BioModels | 2024-06-14

REPOSITORIES: BioModels

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	MODEL2308300001?filename=PsoriaSys.bnd	Other
	MODEL2308300001?filename=PsoriaSys.cfg	Other
	MODEL2308300001?filename=PsoriaSys.sbml	Other
	MODEL2308300001?filename=PsoriaSys.upp	Other

Items per page:

1 - 4 of 4

Similar Datasets

The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome

Project description:Transcription factor recruitment to genomic sites of action is primarily due to direct protein:DNA interactions. The subsequent recruitment of co-regulatory complexes leads to either transcriptional activation or repression. In contrast to this canonical scheme, some transcription factors such as the glucocorticoid receptor (GR) behave as transcriptional repressors when recruited to target genes through protein tethering. We have investigated the genome-wide prevalence of tethering between GR and Stat3 and found non-reciprocal interactions, namely that GR tethering to DNA-bound Stat3 results in transcriptional repression whereas Stat3 tethering to GR results in synergism. Further, other schemes of GR and Stat3 co-recruitment to regulatory modules result in transcriptional synergism, including neighbouring and composite binding sites. The results indicate extensive transcriptional interactions between Stat3 and GR; further, they provide a genome-wide assessment of transcriptional regulation by tethering and a molecular basis for integration of signals mediated by GR and Stats in health and disease. ChIP-seq analysis of Stat3 and GR binding sites in pituitary corticotroph AtT-20 cell model. Five independant ChIPs were pooled prior library preparation for each contitions: STAT3 (LIF), STAT3 (Dex+LIF), GR (Dex+LIF), GR (Dex) and control IgG.

2012-06-06 | E-GEOD-37235 | biostudies-arrayexpress

NFATc1 integrates STAT3 inflammatory signals to promote Kras(G12D)-driven carcinogenesis in the pancreas.

Project description:Inflammatory transcription networks have been linked with the development of pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrate that NFATc1 is both necessary and sufficient to drive progression of KrasG12D-initiated PDAC, particularly in the context of inflammation. Significantly, nuclear NFATc1 accelerates PDAC development in KrasG12D mice, whereas conditional NFATc1 deletion or pharmacological inhibition attenuates inflammation-mediated carcinogenesis. Mechanistically, NFATc1 induces STAT3 expression, complex formation and signal integration in PDAC. Genome-wide ChIP-sequencing and expression analysis in cells derived from c.n.NFATc1;KrasG12D mice identified combinatorial NFATc1/STAT3 binding at chromatin enhancer sites and subsequent regulation of key molecules involved in oncogenic signaling, growth and inflammation. Together, this study supports the relevance of inflammatory transcription factor networks in pancreatic carcinogenesis and provides a theoretical platform for therapeutic targeting of NFATc1 nucleoprotein complexes in PDAC. NFATc1 ChIP followed by high throughput sequencing in primary murine pancreatic cancer cells (referred to as NKC cells) derived from transgenic mice with pancreas-specific constitutive activation of NFATc1 and KrasG12D mutation in the presence or absence of STAT3 shRNA; 2 ChIP samples (scramble DNA and shSTAT3 DNA) and 1 unenriched input control from the same chromatin pool.

2014-06-30 | E-GEOD-39969 | biostudies-arrayexpress

Expression data from DU145 cells treated with STAT3 siRNA

Project description:Activation of Signal Transducer and Activator of Transcription 3 (STAT3) is common in prostate cancers. STAT3 may induce cell proliferation and resistance to apoptosis, as well as promote tumor angiogenesis, invasion, and migration by activating gene expression. Many STAT3-dependent transcriptional responses are mediated through protein-protein interactions that involve the amino-terminal domain (N-domain). In this study, we found that inhibition of the STAT3 N-domain using novel inhibitor ST3-Hel2A-2 induces apoptotic death in prostate cancer cells. The cell death was accomponied by robust activation of pro-apoptotic gene. Using chromatin immunoprecipitation and tiling human promoter arrays (ChIP-chip), we have defined genome-wide targets of STAT3 in DU145 prostate cancer cells. We found that upregulated pro-apoptotic genes were bound by STAT3 in prostate cancer cells, and that STAT3 binding was decreased following inhibition of the STAT3 N-domain. STAT3 siRNA knockdow confirmed specificity of STAT3 binding and changes in gene expression. DU145 cells were treated with STAT3 siRNA or scrambled siRNA for 48hr. Total RNA has been extracted and prepared for hybridization on Affymetrix HG-U133A 2.0 arrays.

2010-12-07 | E-GEOD-25867 | biostudies-arrayexpress

Expression data from DU145 cells treated with ST3-Hel2A-2 STAT3 N-domain inhibitor coupled to analysis of genome-wide STAT3 binding sites

Project description:Activation of Signal Transducer and Activator of Transcription 3 (STAT3) is common in prostate cancers. STAT3 may induce cell proliferation and resistance to apoptosis, as well as promote tumor angiogenesis, invasion, and migration by activating gene expression. Many STAT3-dependent transcriptional responses are mediated through protein-protein interactions that involve the amino-terminal domain (N-domain). In this study, we found that inhibition of the STAT3 N-domain using novel inhibitor ST3-Hel2A-2 induces apoptotic death in prostate cancer cells. The cell death was accomponied by robust activation of pro-apoptotic gene. Using chromatin immunoprecipitation and tiling human promoter arrays (ChIP-chip), we have defined genome-wide targets of STAT3 in DU145 prostate cancer cells. We found that upregulated pro-apoptotic genes were bound by STAT3 in prostate cancer cells, and that STAT3 binding was decreased following inhibition of the STAT3 N-domain. DU145 cells were treated with ST3-Hel2A-2 or DMSO as a control for 3 hr. Total RNA has been extracted and prepared for hybridization on Affymetrix HG-U133A 2.0 arrays.

2010-12-07 | E-GEOD-25866 | biostudies-arrayexpress

Inhibition of Met results in concomitant inhibition of Akt and STAT3 signaling pathways, while abrogation of negative feedback permits Erk reactivation

Project description:Amplification and activation of the Met receptor tyrosine kinase occurs up to 23% of gastric cancers, suggesting that Met is a therapeutic target in these cancers. However, the steady-state signaling events that occur during chronic Met activation, and mechanisms for resistance to Met small-molecule inhibitors, are poorly understood. Here we show that multiple gastric cancer cell lines harboring MET amplifications are dependent on Met signaling for proliferation and anchorage-independent growth. In these cells, short-term inhibition of Met leads to coordinated changes in gene expression; these include a rapid loss in expression of immediate-early genes, followed by decreased expression of genes involved in cell cycle and proliferation. Activation of Ras-Erk, PI3K-Akt and STAT3 pathways is attenuated by acute Met inhibition. STAT3 inhibition alone, but not individual inhibition of Mek or Akt, is sufficient to abrogate Met-dependent growth of these cells. However, following chronic Met inhibition, reactivation of Mek-dependent Erk phosphorylation occurs even in the presence of Met inhibitor corresponding with a downregulation of Erk negative regulators DUSP4/6. This provides a mechanism for the emergence of drug resistance. Our findings provide insights into innate resistance to a small-molecule Met inhibitor and highlight rational combination therapies that could be evaluated in clinical trials. Time series experiment, four cell lines, 2 treatments

2014-05-19 | E-GEOD-54532 | biostudies-arrayexpress

SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3-BASED GLIOMA PATIENT STRATIFICATION AND APPLICATION IN PRECISION ONCOLOGY

Project description:Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors fare more poorly than the proneural subtype. We focused on STAT3 because its activation precedes the proneural-mesenchymal transition. We first established a STAT3 gene signature that stratifies GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigated STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. Additionally, we defined the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells. This allows us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. We demonstrate that dual inhibition of IGF-1R and STAT3 sensitized STAT3-low cells and improved survival in mice. Our study underscores the importance of serially profiling tumors so as to accurately target individuals who may demonstrate molecular subtype switching

2019-06-20 | GSE117905 | GEO

The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome

2012-06-07 | GSE37235 | GEO

PIAS3 induction of apoptosis in non-small cell lung cancer cells is p53-independent and has STAT3-independent mediator.

Project description:Protein inhibitor of activated STAT3 (PIAS3) is an endogenous inhibitor of STAT3 that negatively regulates STAT3 transcriptional activity and cell growth and demonstrates limited expression in the majority of human squamous cell carcinomas of the lung. In the present study we sought to determine if PIAS3 inhibits cell growth in non-small cell lung cancer (NSCLC) cell lines by induction of apoptosis and further determine the dependence of PIAS3 activity on p53 status by using both wild-type and p53-null cells. Our results demonstrate that over-expression of PIAS3 promotes caspase 3 activation and PARP cleavage. Furthermore, the expression of pro-survival family members Bcl-xL and Bcl-2 is decreased. These effects were observed after both transient and regulated expression of exogenous PIAS3 and were independent of p53 status. Furthermore, while p53 can promote apoptosis by inhibition of STAT3 activity, PIAS3 inhibition of STAT3 activity was also p53 independent. Microarray experiments were performed to further investigate the STAT3-dependence of PIAS3-induced apoptosis by comparing the apoptotic gene expression signature induced by PIAS3 over-expression with that induced by STAT3 siRNA. The results showed that a subset of apoptotic genes, including CIDEC and DAPK2, were uniquely expressed only after PIAS3 expression. Thus, PIAS3 may represent a promising lung cancer therapeutic target because of its p53-independent efficacy as well as its potential to synergize with direct STAT3 inhibitors. The expression profiles of genes related to apoptosis in A549 cell line transfected with pCMV5 vector encoding human PIAS3 compared with that induced by STAT3 siRNA Cells in all three groups were grown in serum-free medium, then stimulated with EGF, then one group transfected with pCMV5 vector encoding human PIAS3, second group was induced by STAT3 siRNA, third group considered as control.

2012-12-19 | E-GEOD-42979 | biostudies-arrayexpress

Genome wide analysis of STAT3-mediated transcription and binding sites in mouse female germ stem cell (ChIP-seq)

Project description:Activation of JAK-STAT3 signaling by leukemia inhibitory factor (LIF) is required for maintaining self-renewal of mouse embryonic stem cells (mESCs). STAT3 perform cell type-specific roles in different cell type, here we revisit the role of STAT3 using mouse female germ stem cell (mFGSCs). We applied CRISPR/Cas9 system to generate Stat3 knockout FGSCs and then observed cell growth inhibition and cell cycle arrest in KO cell line. By combining genome wide ChIP-Seq and RNA-Seq, we identified 5990 STAT3 binding sites and discovered serval genes specific regulated by STAT3 that were involved in stem cell proliferation and female gonad development in FGSCs. In general, we identify key roles of STAT3 for sustains self-renewal and proliferation for FGSCs in this study.

2017-12-20 | E-MTAB-6163 | biostudies-arrayexpress

Genome wide analysis of STAT3-mediated transcription and binding sites in mouse female germ stem cell (RNA-seq)

2017-12-20 | E-MTAB-6162 | biostudies-arrayexpress