The Methyl Transferase PRMT1 Functions as Co-Activator of Farnesoid X Receptor (FXR)/9-<i>cis</i> Retinoid X Receptor and Regulates Transcription of FXR Responsive Genes

Rizzo, Giovanni; Renga, Barbara; Antonelli, Elisabetta; Passeri, Daniela; Pellicciari, Roberto; Fiorucci, Stefano

doi:10.1124/mol.105.012104

Cited by 71 publications

(55 citation statements)

References 35 publications

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“…Nevertheless, the binding intensity was found to be boosted upon treatment with GW4064, in agreement with other in vitro studies in a liver cell line, HepG2, where it was shown that FXR binds to its REs weakly in the absence of ligands, and this binding is increased upon ligand treatment (Rizzo et al 2005, Fang et al 2008. Once again, this effect might be due to a ligand-switch effect, and it would be interesting to dissect the binding patterns of FXR upon treatment with natural ligands.…”

Section: Induction-independentsupporting

confidence: 77%

Nuclear receptors and chromatin: an inducible couple

Gadaleta¹,

Magnani²

2013

Journal of Molecular Endocrinology

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The nuclear receptor (NR) family comprises 48 transcription factors (TFs) with essential and diverse roles in development, metabolism and disease. Differently from other TFs, NRs engage with well-defined DNA-regulatory elements, mostly after ligand-induced structural changes. However, NR binding is not stochastic, and only a fraction of the cognate regulatory elements within the genome actively engage with NRs. In this review, we summarize recent advances in the understanding of the interactions between NRs and DNA. We discuss how chromatin accessibility and epigenetic modifications contribute to the recruitment and transactivation of NRs. Lastly, we present novel evidence of the interplay between non-coding RNA and NRs in the mediation of the assembly of the transcriptional machinery.

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Section: Induction-independentsupporting

confidence: 77%

Nuclear receptors and chromatin: an inducible couple

Gadaleta¹,

Magnani²

2013

Journal of Molecular Endocrinology

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“…Other reported SHP inducers include the bile acids [30] and its precursors, 26-hydroxylated bile alcohols, and C 27 bile acids [31], procyanadins, the most abundant polyphenols in red wine, increased liver SHP mRNA levels [32]. Protein arginine methyltransferase type I (PMRT1) was identified as another SHP mRNA expression upregulatory agent [33] and PPARγ coactivator (PGC)-1a has also been reported to induce an elevation of SHP mRNA levels [34].…”

Section: Inducers Of Shp Promoter and Gene Expressionmentioning

confidence: 99%

Molecular Basis of Endocrine Regulation by Orphan Nuclear Receptor Small Heterodimer Partner

2008

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Abstract. Nuclear receptors (NRs) are a unique superfamily of transcription factors (TFs) which are involved in and play a crucial role in almost all aspects of mammalian physiology. Small Heterodimer Partner (SHP; NR0B2), an exceptional member of this superfamily of NRs, have been identified as a key regulatory factor of the transcription of a variety of genes involved in diverse metabolic pathways, and are thereby an important factor in a variety of physiological functions. Since its discovery a decade ago, considerable progress has been made in the elucidation of the underlying mechanism by which SHP regulates various metabolic processes, and the results of previous studies support its importance in the maintenance of metabolic homeostasis. In this review, we have evaluated the current state of understanding of the molecular mechanisms and the resultant physiological interpretations governed by SHP. SMALL Heterodimer Partner is a unique member of the mammalian nuclear receptor superfamily, which is clearly distinct from the conventional nuclear receptors, both structurally and functionally. It is classified into the "orphan" subfamily, due to the absence of any known ligand for this receptor, and appears to function as a transcriptional co-regulator of numerous nuclear receptors and transcription factors. The dosage-sensitive sex reversal-adrenal hypoplasia congenital region gene on the X chromosome, gene-1 (DAX-1; NR0B1) is the closest relative to SHP. Both belong to the same subfamily, and both share considerable functional and structural similarities with SHP. SHP owes its place in the nuclear receptor family to the presence of a putative ligand binding domain (LBD), although it lacks the classical DNA binding domain (DBD) which is generally detected among other nuclear receptors. Intensive research conducted following its discovery last decade has resulted in a clearer understanding of the molecular basis for the inhibitory functions of SHP on a variety of metabolic processes, thereby providing us with ample evidence regarding its importance as a key regulator in a number of signaling pathways [1,2]. Hub-based topological analysis of the nuclear receptor network has demonstrated the extensive connections existing among these receptors as the result of their similarity in terms of interaction and tissue expression, as well as a considerable number of feedback loops that work in concert in this network, with SHP playing a principal role as the hub protein within this network [3]. In this review, we have attempted to survey the entirety of the information available thus far concerning the structural and functional aspects of the orphan nuclear receptor SHP, hoping to acquire a detailed understanding of the physiological significance of the activity of SHP.

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“…The primary amino acid sequence of human FXR shows at least two sumoylation consensus sequences (wKX(E/D); where w represents an hydrophobic amino acid and X refers to any amino acid) (26). To further investigate the role of sumoylation in regulating the expression of target genes by FXR, we generated a human FXR protein mutant lacking the sumoylation consensus sequence located in the LBD of the receptor, position K277 ( Fig.…”

Section: Sumoylation Of Fxr Mediates the Counterregulatory Activitiesmentioning

confidence: 99%

“…26. For luciferase assays, the minimal promoter region containing the NF-B response element from inducible NO synthase (iNOS) or the IL-1␤ gene was amplified and cloned upstream of the luciferase reporter gene into the pGL3 vector (BglII site).…”

Section: Plasmids Cell Culture Transfection and Luciferase Assaysmentioning

confidence: 99%

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The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

Vavassori

Mencarelli²,

Renga³

et al. 2009

The Journal of Immunology

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495

442

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The farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues. In this study we investigated whether FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. Acute (7 days) and chronic (8 wk) colitis were induced in wild-type and FXR−/− mice by intrarectal administration of trinitrobenzensulfonic acid or by 7-day administration of 5% dextran sulfate in drinking water. The results of this experiment demonstrate that FXR is expressed by and exerts counterregulatory effects on cells of innate immunity. Exposure of LPS-activated macrophages to 6-ethyl chenodeoxycholic acid (6E-CDCA; INT-747) a synthetic FXR ligand, results in a reciprocal regulation of NF-κB dependent-genes (TNF-α, IL-1β, IL-6, COX-1, COX-2, and iNOS) and induction of SHP, a FXR-regulated gene. FXR activation stabilizes the nuclear corepressor NCoR on the NF-κB responsive element on the IL-1β promoter. Colon inflammation in Crohn’s disease patients and in rodent models of colitis is associated with a reduced expression of FXR mRNA. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR−/− mice (p < 0.01). In vivo treatment with INT-747 attenuates organ injury and immune cell activation. FXR activation increased the colon expression of I-BABP, FXR, and SHP while reducing IL-1β, IL-2, IL-6, TNF-α, and IFN-γ mRNA expression and attenuating disease severity. In aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that regulate intestinal innate immunity and homeostasis.

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The Methyl Transferase PRMT1 Functions as Co-Activator of Farnesoid X Receptor (FXR)/9-cis Retinoid X Receptor and Regulates Transcription of FXR Responsive Genes

Cited by 71 publications

References 35 publications

Nuclear receptors and chromatin: an inducible couple

Nuclear receptors and chromatin: an inducible couple

Molecular Basis of Endocrine Regulation by Orphan Nuclear Receptor Small Heterodimer Partner

The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

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