Abstract
The pregnane X receptor (PXR, NR1I2) is a nuclear receptor which exerts its regulatory function by heterodimerization with the retinoid-X-receptor α (RXRα, NR2B1) and binding to the promoter and enhancer regions of diverse target genes. PXR is involved in the regulation of drug metabolism and excretion, metabolic and immunological functions and cancer pathogenesis. PXR activity is strongly regulated by the association with coactivator and corepressor proteins. Coactivator proteins exhibit histone acetyltransferase or histone methyltransferase activity or associate with proteins having one of these activities, thus promoting chromatin decondensation and activation of the gene expression. On the contrary, corepressor proteins promote histone deacetylation and therefore favor chromatin condensation and repression of the gene expression. Several studies pointed to clear cell- and ligand-specific differences in the activation of PXR. In this article, we will review the critical role of coactivator and corepressor proteins as molecular determinants of the specificity of PXR-mediated effects. As already known for other nuclear receptors, understanding the complex mechanism of PXR activation in each cell type and under particular physiological and pathophysiological conditions may lead to the development of selective modulators with therapeutic potential.
Highlights
The pregnane X receptor (PXR, NR1I2) is a transcription factor belonging to the superfamily of nuclear receptors
PXR binds as a heterodimer with the retinoid-X-receptor α (RXRα, NR2B1) to response elements characterized by direct repeats (DR) or everted repeats (ER) of nucleotides in the proximal promoters as well as distal and far enhancers of its target genes
We described the interaction of PXR with coactivators and corepressors and the effect of different cellular and pharmacological stimuli
Summary
The pregnane X receptor (PXR, NR1I2) is a transcription factor belonging to the superfamily of nuclear receptors. As well as other members, PXR is characterized by two conserved domains: a DNA-binding domain (DBD), located in the N-terminus of the receptor, and a ligand-binding domain (LBD), located in the C-terminus. Both domains are connected by a hinge region. The special feature of the binding pocket comprises recognition of molecules of different shapes and sizes and, adaption of its size to the structure of the molecule This results in a much higher flexibility of the PXR’s LBD compared to LBDs of other nuclear receptors [2]. Cnosrteitguutleathorusbs which integerxahtiebidt aiftfiesrseune-tsppehcyifsicioelxopgreicssailon(ep.ga.t,tecrhnaanngdeasreinsuhbojercmt toonreegluelvateiolsn)baynddifpfearethntopphhyys-siological signaiollsog(eic.agl.,anmdaplaigthnoapnhtystiroalongsifcoarl mfacatotiros.nT)htuhsa, ctoureltgiumlaatoterlpyroimteipnsaccotnPstXitRuterehguubslawtohricyh function (pFeiugtuis(inFcirgtietgenagu1arrrl)gase.te(eM1te)d..agoiMl.fr,lfoeeomrowreaevnloiinetvgrpgen,hratt,ynhotstheitoetarPlacPoXnkgXsliRRcefoa--cPrclom(oXerrae.Rgegti.-guo,mculnah)eltaaodtnhtriogaaientrtsetuieidnlnrtatighmecteoriaarnotmcneeltoymianociaenmtyilvepmcvaaoecatnlityssoP)tnicaXtouniRntnderspaeatagicpttuheurllooatlmpet-ohaiarsyynispndifgoruollnotimhgcgteaiiicronsaani-dln-gsptehceirfiacmanpneeurt.icIntartgheitsaallrotwicilneg, two teacwkliellPrXeRv-imeewditahteedsgteundeiaecstivinatvioenstiingaacteinll-gatnhdeliignatnedr-aspcteicoifnicbetween PXRmaanndnedr.ifIfnetrheins tarctoicrle,gwuelawtoilrl rpervoietweinthse, sthtuedileisgainnvdesstimgaotidngultahteiningtetrhacetsioenibnettewraeecntions and evenPtuXRal acnedll-d,ilfifgeraenndt -coarnegduglaetnore-psrpoeteciinfisc, tehfefelcigtasn. ds modulating these interactions and eventual cell-, ligand- and gene-specific effects
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