Dataset Information

Regulation of the nongenomic actions of retinoid X receptor-? by targeting the coregulator-binding sites.

ABSTRACT: Retinoid X receptor-? (RXR?), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXR? ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXR? remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXR? can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXR? have been identified, which mediate the regulation of the nongenomic actions of RXR? by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXR? in the RXR? signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXR? regulation by targeting alternate binding sites on its surface.

SUBMITTER: Zhang XK

PROVIDER: S-EPMC4571313 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Publications

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites.

Zhang Xiao-kun XK Su Ying Y Chen Liqun L Chen Fan F Liu Jie J Zhou Hu H

Acta pharmacologica Sinica 20141201 1

Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeuti ...[more]

PMID: 25434990

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Project description:Using a chromatin immunoprecipitation-paired end diTag cloning and sequencing strategy, we mapped estrogen receptor alpha (ERalpha) binding sites in MCF-7 breast cancer cells. We identified 1,234 high confidence binding clusters of which 94% are projected to be bona fide ERalpha binding regions. Only 5% of the mapped estrogen receptor binding sites are located within 5 kb upstream of the transcriptional start sites of adjacent genes, regions containing the proximal promoters, whereas vast majority of the sites are mapped to intronic or distal locations (>5 kb from 5' and 3' ends of adjacent transcript), suggesting transcriptional regulatory mechanisms over significant physical distances. Of all the identified sites, 71% harbored putative full estrogen response elements (EREs), 25% bore ERE half sites, and only 4% had no recognizable ERE sequences. Genes in the vicinity of ERalpha binding sites were enriched for regulation by estradiol in MCF-7 cells, and their expression profiles in patient samples segregate ERalpha-positive from ERalpha-negative breast tumors. The expression dynamics of the genes adjacent to ERalpha binding sites suggest a direct induction of gene expression through binding to ERE-like sequences, whereas transcriptional repression by ERalpha appears to be through indirect mechanisms. Our analysis also indicates a number of candidate transcription factor binding sites adjacent to occupied EREs at frequencies much greater than by chance, including the previously reported FOXA1 sites, and demonstrate the potential involvement of one such putative adjacent factor, Sp1, in the global regulation of ERalpha target genes. Unexpectedly, we found that only 22%-24% of the bona fide human ERalpha binding sites were overlapping conserved regions in whole genome vertebrate alignments, which suggest limited conservation of functional binding sites. Taken together, this genome-scale analysis suggests complex but definable rules governing ERalpha binding and gene regulation.

Dataset Information

Regulation of the nongenomic actions of retinoid X receptor-? by targeting the coregulator-binding sites.

Publications

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites.

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