Role of Cofilin 1 pathway and actin dynamics in nuclear retinoid receptor function
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE31665 | GEO | 2011/08/26
SECONDARY ACCESSION(S): PRJNA145391
REPOSITORIES: GEO
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Project description:We have investigated the role of actin dynamics and the effect of actin cytoskeleton modifying agents on retinoid receptor-mediated transactivation. Using Nef, an actin modifying HIV-1 protein, the role of LMK1/CFL1-mediated actin dynamics in receptor function was studied. The effect of Nef expression on transcriptome was investigated following transfection of HEK293 cells with Nef-expressing plasmid. The array data identified Nef-induced inhibition of a number of genes that contain retinoid receptor binding sites in their promoters. The experiment was designed to study the effect of expression of HIV-1 Nef protein on gene expression levels in HEK293 cells. Cells were transfected in three different experiments (each time in duplicate) with Nef expressing plasmid and a plasmid that contained a non-expressing Nef construct (Nef/Stop) as control. The cells were harvested after 36 of transfection and processed for gene array.
2011-08-25 | E-GEOD-31665 | biostudies-arrayexpress
Project description:Cancer cell motility and invasiveness are fundamental characteristics of the malignant phenotype and are regulated through diverse signaling networks involving kinases and transcription factors. In this study, we identify a nuclear hormone receptor (ERα)-protein kinase (ERK5)-cofilin (CFL1) network that specifies the degree of breast cancer cell aggressiveness through coupling of actin reorganization and hormone receptor-mediated transcription. Using dominant negative and constitutively active forms, as well as small molecule inhibitors of ERK5 and MEK5, we show that hormone activation of estrogen receptor-α determines the nuclear versus cytoplasmic localization of the MAPK family member ERK5, which functions as a coregulator of ERα-gene transcription. Notably, ERK5 works with the actin remodeling protein, CFL1, and upon hormone exposure both became localized to transcription factories in the nucleus, verified by immunofluorescence and proximity ligation assays. Both factors facilitated PAF1 recruitment to the RNA Pol II complex and both ERK5 and CFL1 were required for regulation of gene transcription. By contrast, in cells lacking ERα, ERK5 and CFL1 localized to cytoplasmic membrane regions of high actin remodeling, promoting cell motility and invasion, thereby revealing a mechanism likely to contribute to the generally poorer prognosis of ERα-negative breast cancers. Our study uncovers the dynamic interplay of nuclear receptor-mediated transcription and actin reorganization in phenotypes of breast cancer aggressiveness, and highlights new prognostic biomarkers and suggests novel approaches for developing targeted therapies to moderate cancer aggressiveness. MCF-7 human breast adenocarcinoma cells were tranfected with control, and ERK5 siRNA for 72 hours and treated with 0.1% EtOH (Vehicle) or 10 nM E2 for 24 hours, and cDNA microarray analyses were carried out using Affymetrix [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array. siRNA knock-down, ligand treatment
2014-06-03 | E-GEOD-53394 | biostudies-arrayexpress
Project description:Cancer cell motility and invasiveness are fundamental characteristics of the malignant phenotype and are regulated through diverse signaling networks involving kinases and transcription factors. In this study, we identify a nuclear hormone receptor (ERα)-protein kinase (ERK5)-cofilin (CFL1) network that specifies the degree of breast cancer cell aggressiveness through coupling of actin reorganization and hormone receptor-mediated transcription. Using dominant negative and constitutively active forms, as well as small molecule inhibitors of ERK5 and MEK5, we show that hormone activation of estrogen receptor-α determines the nuclear versus cytoplasmic localization of the MAPK family member ERK5, which functions as a coregulator of ERα-gene transcription. Notably, ERK5 works with the actin remodeling protein, CFL1, and upon hormone exposure both became localized to transcription factories in the nucleus, verified by immunofluorescence and proximity ligation assays. Both factors facilitated PAF1 recruitment to the RNA Pol II complex and both ERK5 and CFL1 were required for regulation of gene transcription. By contrast, in cells lacking ERα, ERK5 and CFL1 localized to cytoplasmic membrane regions of high actin remodeling, promoting cell motility and invasion, thereby revealing a mechanism likely to contribute to the generally poorer prognosis of ERα-negative breast cancers. Our study uncovers the dynamic interplay of nuclear receptor-mediated transcription and actin reorganization in phenotypes of breast cancer aggressiveness, and highlights new prognostic biomarkers and suggests novel approaches for developing targeted therapies to moderate cancer aggressiveness.
2014-06-03 | GSE53394 | GEO
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Project description:Intronic hexanucleotide expansions in C9ORF72 are common in ALS and FTLD, but it is unknown whether loss of function, toxicity by the expanded RNA or dipeptides from non ATG-initiated translation are responsible for the pathophysiology. We determined the interactome of C9ORF72 in motoneurons and found that C9ORF72 is present in a complex with cofilin and other actin binding proteins. Phosphorylation of cofilin is enhanced in C9ORF72 depleted motoneurons, in patient derived lymphoblastoid cells, iPS cell derived motoneurons and post-mortem brain samples from ALS patients. C9ORF72 modulates the activity of the small GTPases Arf6 and Rac1, resulting in enhanced activity of LIMK1/2. This results in reduced axonal actin dynamics in C9ORF72 depleted motoneurons. Dominant negative Arf6 rescues this defect, suggesting that C9ORF72 acts as a modulator of small GTPases in a pathway that regulates axonal actin dynamics.
2016-09-30 | PXD004913 | Pride
Project description:Role of Cofilin 1 pathway and actin dynamics in nuclear retinoid receptor function
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Project description:Remodeling of the actin cytoskeleton through actin dynamics (assembly and disassembly of filamentous actin) is known to be essential for numerous basic biological processes. In addition, recent in vitro studies provided evidence that actin dynamics participate in the control of gene expression. A spontaneous mouse mutant, corneal disease 1 (corn1), is deficient for a regulator of actin dynamics, destrin (DSTN; also known as actin depolymerizing factor or ADF), and develops epithelial hyperproliferation and neovascularization in the cornea. Dstncorn1 mice exhibit the actin dynamics defect in the corneal epithelial cells as evidenced by increased filamentous actin, offering an in vivo model to investigate the physiological significance of the transcriptional regulation by actin dynamics. To examine the effect of the Dstncorn1 mutation on gene expression, we performed a microarray analysis using the cornea from Dstncorn1 and wild-type control mice. A dramatic alteration of gene expression was observed in the Dstncorn1 cornea, with 1,226 annotated genes differentially expressed. Functional annotation of these genes revealed that most significantly enriched functional categories are associated with actin and/or cytoskeleton. Among genes that belong to these categories, a considerable number of serum response factor (SRF) target genes were found, indicating the existence of the actin-SRF pathway of transcriptional regulation in vivo. A comparative study using an allelic mutant strain, Dstncorn1-2J, with milder corneal phenotypes also suggested that the severity of the actin dynamics defect correlates with the level of gene expression changes. Our study provides evidence that actin dynamics have a strong impact on gene expression in vivo. Keywords: Comparative gene expression
2008-05-30 | GSE9743 | GEO
Project description:We describe a new mutant allele of the ACTIN2 gene with enhanced actin dynamics, displaying a broad array of twisting and bending phenotypes that resemble BR-treated plants. Moreover, auxin transcriptional regulation is enhanced on the mutant background, supporting the idea that shaping actin filaments is sufficient to modulate BR-mediated auxin responsiveness. The actin cytoskeleton thus functions as a scaffold for integration of auxin and BR signaling pathways. Three biological replicates were performed for each sample (wild-type and actin2-5) and hybridized to the the Affymetrix ATH1 GeneChips.
2012-11-21 | E-GEOD-27077 | biostudies-arrayexpress
Project description:Neddylation is the post-translational protein modification that is most closely related to
ubiquitination. The Ubiquitin-like protein NEDD8 is mostly studied for its role in activating
the Cullin-RING E3 Ubiquitin ligases, however little is known about other NEDD8 targets.
We developed serial NEDD8-Ubiquitin Substrate Profiling (sNUSP), a method that
employs Nedd8-R74K knock-in cells allowing discrimination of endogenous NEDD8- and
Ubiquitin-modification sites by mass spectrometry after Lys-C digestion and K-GG-
peptide enrichment. Using sNUSP, we identified 607 neddylation sites dynamically
regulated by the neddylation inhibitor MLN4924 and the de-neddylating enzyme
NEDP1/SENP8. Among the candidates, we characterized lysine 112 (K112) of the Actin
regulator Cofilin as a novel neddylation event. Global inhibition of neddylation in
developing neurons leads to cytoskeletal defects, altered Actin dynamics and neurite
growth impairments and site-specific neddylation of Cofilin at K112 regulates neurite
outgrowth. These data show that Cofilin neddylation contributes to the regulation of
neuronal Actin dynamics.
2019-12-12 | MSV000084683 | MassIVE