Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA138801 | ENA |
REPOSITORIES: ENA
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Project description:Differential retinoic acid responses across testicular development in vitro
| PRJNA1391353 | ENA
Project description:Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90 % of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested deregulation of the retinoic acid (RA) pathway in high-risk WT. This could be validated in a large independent tumor set. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/intermediate risk, suggesting a beneficial impact of RA on advanced WT. To investigate the possible mode of action of retinoids as a novel therapeutic agent we treated primary tumor cell cultures with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid / HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. Although some of the effects appear to be reversible, these findings provide further evidence of a potential utility of retinoids in Wilms tumor treatment. total samples analysed are 2
2012-04-20 | E-GEOD-28807 | biostudies-arrayexpress
Project description:Wilms tumors are genetically heterogeneous kidney tumors whose cells of origin are unknown. Tumors with WT1 mutations and concomitant loss of the wild-type allele represent a distinct subgroup, frequently associated with mutations in CTNNB1. Here we describe the establishment and characterization of long-term cell cultures derived from five individual Wilms tumors with WT1 mutations. Three of these tumor cell lines also had CTNNB1 mutations and an activated canonical Wnt signaling pathway as measured by β-catenin/TCF transcriptional activity. Four of the five Wilms cell lines had a stable normal karyotype for at least 25 passages, and four lines showed loss of heterozygosity of chromosome 11p due to mitotic recombination in 11p11. Gene expression profiling revealed that the Wilms tumor cell lines are highly similar to human mesenchymal stem cells (MSCs) and FACS analysis demonstrated expression of MSC-specific surface proteins CD105, CD90 and CD73. The stem cell like nature of the Wilms tumor cells is further supported by their adipogenic, chondrogenic, osteogenic and myogenic differentiation potentials. By generating multipotent mesenchymal precursors from paraxial mesoderm (PAM) in tissue culture using embryonal stem cells, gene expression profiles of PAM and MSCs were described. Using these published gene sets we found coexpression of a large number of genes in Wilms tumor cell lines, PAM and MSCs. Lineage plasticity is indicated by the simultaneous expression of genes from the mesendodermal and neuroectodermal lineages. We conclude that Wilms tumors with WT1 mutations have specific traits of PAM, which is the source of kidney stromal cells.
2010-02-01 | GSE18058 | GEO
Project description:Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90 % of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested deregulation of the retinoic acid (RA) pathway in high-risk WT. This could be validated in a large independent tumor set. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/intermediate risk, suggesting a beneficial impact of RA on advanced WT. To investigate the possible mode of action of retinoids as a novel therapeutic agent we treated primary tumor cell cultures with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid / HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. Although some of the effects appear to be reversible, these findings provide further evidence of a potential utility of retinoids in Wilms tumor treatment.
2012-04-21 | GSE28807 | GEO
Project description:Haffez2017 - RAR interaction with synthetic
analogues
This model is described in the article:
The molecular basis of the
interactions between synthetic retinoic acid analogues and the
retinoic acid receptors
Hesham Haffez, David R. Chisholm,
Roy Valentine, Ehmke Pohl, Christopher Redfern and Andrew
Whiting
MedChemComm
Abstract:
All-trans-retinoic acid (ATRA) and its synthetic analogues
EC23 and EC19 direct cellular differentiation by interacting as
ligands for the retinoic acid receptor (RARα,
β and γ) family of nuclear receptor
proteins. To date, a number of crystal structures of natural
and synthetic ligands complexed to their target proteins have
been solved, providing molecular level snap-shots of ligand
binding. However, a deeper understanding of receptor and ligand
flexibility and conformational freedom is required to develop
stable and effective ATRA analogues for clinical use.
Therefore, we have used molecular modelling techniques to
define RAR interactions with ATRA and two synthetic analogues,
EC19 and EC23, and compared their predicted biochemical
activities to experimental measurements of relative ligand
affinity and recruitment of coactivator proteins. A
comprehensive molecular docking approach that explored the
conformational space of the ligands indicated that ATRA is able
to bind the three RAR proteins in a number of conformations
with one extended structure being favoured. In contrast the
biologically-distinct isomer, 9-cis-retinoic acid (9CRA),
showed significantly less conformational flexibility in the RAR
binding pockets. These findings were used to inform docking
studies of the synthetic retinoids EC23 and EC19, and their
respective methyl esters. EC23 was found to be an excellent
mimic for ATRA, and occupied similar binding modes to ATRA in
all three target RAR proteins. In comparison, EC19 exhibited an
alternative binding mode which reduces the strength of key
polar interactions in RARα/γ but is
well-suited to the larger RARβ binding pocket. In
contrast, docking of the corresponding esters revealed the loss
of key polar interactions which may explain the much reduced
biological activity. Our computational results were
complemented using an in vitro binding assay based on FRET
measurements, which showed that EC23 was a strongly binding,
pan-agonist of the RARs, while EC19 exhibited specificity for
RARβ, as predicted by the docking studies. These
findings can account for the distinct behaviour of EC23 and
EC19 in cellular differentiation assays, and additionally, the
methods described herein can be further applied to the
understanding of the molecular basis for the selectivity of
different retinoids to RARα, β and
γ.
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2024-09-02 | BIOMD0000000629 | BioModels
Project description:Characterization of retinoic acid-regulated microRNAs
| PRJNA106491 | ENA
Project description:We report the microRNA profiles of the mouse embryonic stem cell (E14IV), which have been deleted for tumour suppressor Wilms' Tumour 1 (WT1), and induced with retinoic acid. Additionally, cells that had an inducibe WT1 expression where also used to compare the microRNA profile during different time points of WT1 induction.
2024-03-26 | GSE169684 | GEO
Project description:UBE3A Deficiency Downregulates Retinoic Acid Signalling Pathway
| PRJNA714431 | ENA
Project description:Pyrydopyrazine A2 induced in vitro the differentiation of leukemic cells (HoxA9-Meis1) into macrophages, we decided to perform a transcriptomic study in order to analyze the GM-CSF pathway regulation. We therefore compared effect with A2 to cells treated with Retinoic acid and D3 Vitamin, a combination known to induce also differentiation of leukemic cells. HoxA9-Meis1 murine AML cells were treated in vitro during 24h, with Pyrydopyrazine( A2) at 3.4μM or a combination of all-trans Retinoic Acid (RA) and 1α-hydroxy-D3 Vitamin (D3V), 10μM each. Gene expression signature was compared to untreated control. One sample was tested for each condition
2015-09-02 | E-GEOD-72635 | biostudies-arrayexpress
Project description:Gliomas are immunologically cold tumors that can be broken into several categories based on either RNA expression profiles or methylation profiles, with isocitrate dehydrogenase (IDH) mutations defining a major segregration between types. IDH mutant gliomas often exhibit defects in the retinoic acid pathway. We treated mice harboring IDH mutant gliomas with all-trans retinoic acid, and found that this treatment cause reductions in tumor growth and a swith in immune profiles in the tumor microenvironment.
2024-04-19 | GSE172387 | GEO