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Role of Cofilin 1 pathway and actin dynamics in nuclear retinoid receptor function

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE31665 | GEO | 2011/08/26

SECONDARY ACCESSION(S): PRJNA145391

REPOSITORIES: GEO

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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

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Role of Cofilin 1 pathway and actin dynamics in nuclear retinoid receptor function

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