PXR phosphorylated at Ser350 transduces a glucose signal to repress the estrogen sulfotransferase gene in human liver cells and fasting signal in mouse livers

Hu, Hao; Yokobori, Kosuke; Negishi, Masahiko

doi:10.1016/j.bcp.2020.114197

Cited by 11 publications

(5 citation statements)

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“…The mechanistic studies of PB-mediated indirect activation of CAR led to the realization of the highly conserved Thr-38 like phosphorylation sites existing in the majority of human nuclear receptors. Functional analysis reveals that altering phosphorylation status of PXR (Thr-57, Ser-350), ERα (Ser-216, Ser-236), FXR (Ser-154), RXR (Thr-167), and RORα (Ser-100) can also affect transactivation of these receptors, suggesting phosphorylation/dephosphorylation signaling might be a fundamental function essential for the nuclear receptor superfamily (Pondugula et al, 2009;Hashiguchi et al, 2016;Fashe et al, 2020;Hu et al, 2020;Yi et al, 2022). Thus, in addition to the canonical ligand-based activation, future investigation on the phosphorylation related "indirect activation" for a broad spectrum of In addition to CAR and PXR, PB can influence the activity of several other nuclear receptors affecting homeostasis of estrogen and bile acids.…”

Section: Discussionmentioning

confidence: 99%

“…This perception, however, was challenged when multiple putative phosphorylation sites in PXR were shown to influence its transcriptional activity without direct ligand binding (Negishi et al, 2020). Notably, while hPXR is DMD-MR-2022-000859-R1 one of only 5 human nuclear receptors (out of a total of 48) that does not preserve a Thr-38 like phosphorylation motif in the DBD, several phosphorylation residues including have been identified with many of them located within the LBD (Lin et al, 2008;Pondugula et al, 2009;Elias et al, 2014;Hu et al, 2020). Studies have shown that these residues could be phosphorylated by kinases such as cyclin-dependent kinase 2 (CDK2), PKA, PKC, and vaccinia related kinase 1 (VRK1); and phosphomimetic mutation of T57D and S350D markedly impaired hPXR-mediated CYP3A4 transactivation (Lin et al, 2008;Gotoh et al, 2017;Bulutoglu et al, 2019).…”

Section: Mechanisms Of Pb Activation Of Hpxrmentioning

confidence: 99%

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Phenobarbital in Nuclear Receptor Activation: An Update

Men

Wang

2022

Drug Metab Dispos

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Phenobarbital (PB) is a commonly prescribed anti-epileptic drug that can also benefit newborns from hyperbilirubinemia. Being the first drug demonstrating hepatic induction of cytochrome P450 (CYP), PB has since been broadly used as a model compound to study xenobioticinduced drug metabolism and clearance. Mechanistically, PB-mediated CYP induction is linked to a number of nuclear receptors such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and estrogen receptor α, with CAR being the predominant regulator. Unlike prototypical agonistic ligands, PB-mediated activation of CAR does not involve direct binding with the receptor. Instead, dephosphorylation of threonine 38 in the DNA-binding domain of CAR was delineated as a key signaling event underlying PB-mediated indirect activation of CAR.Further studies revealed that such phosphorylation sites appear to be highly conserved among most human nuclear receptors. Interestingly, while PB is a pan-CAR activator in both animals and humans, PB activates human but not mouse PXR. The species-specific role of PB in gene regulation is a key determinant of its implication in xenobiotic metabolism, drug-drug interactions, energy homeostasis, and cell proliferation. In this review, we summarize the recent progress in our understanding of PB-provoked transactivation of nuclear receptors with a focus on CAR and PXR. Significance statementExtensive studies using PB as a research tool have significantly advanced our understanding of the molecular basis underlying nuclear receptor-mediated drug metabolism, drug-drug interactions, energy homeostasis, and cell proliferation. In particular, CAR has been established as a cell signaling-regulated nuclear receptor in addition to ligand-dependent functionality. This mini-review highlights the mechanisms by which PB transactivates CAR and PXR.

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Section: Discussionmentioning

confidence: 99%

Section: Mechanisms Of Pb Activation Of Hpxrmentioning

confidence: 99%

Phenobarbital in Nuclear Receptor Activation: An Update

Men

Wang

2022

Drug Metab Dispos

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“…Dephosphorylated SGK2 conversely augments PXR-mediated transactivation of gluconeogenic genes in human liver cells, thereby enhancing gluconeogenesis [58]. In one of the recent studies, fasting-activated PXR interacts with vaccinia virus-related kinase 1 (VRK1) and phosphorylates S350 of PXR, further inhibits the sulfotransferase (SULT1E1) activity, modulating glucose metabolism [59]. Phosphomimic mutation at T290 (T290D) makes PXR protein remain in the cytoplasm whereas phosphorylation at S350 may alter the binding with RXRα and its co-activators, attenuating transactivation of UGT1A1 by roscovitine [60].…”

Section: Pxr Contains Numerous Serine (S) / Threonine (T) Amino Acids and Can Be Phosphorylated And Implicated In Cellular Stress Responsmentioning

confidence: 99%

Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance

Niu¹,

Wu²,

Li³

et al. 2022

Int. J. Biol. Sci.

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Pregnane x receptor (PXR) as a nuclear receptor is well-established in drug metabolism, however, it has pleiotropic functions in regulating inflammatory responses, glucose metabolism, and protects normal cells against carcinogenesis. Most studies focus on its transcriptional regulation, however, PXR can regulate gene expression at the translational level. Emerging evidences have shown that PXR has a broad protein-protein interaction network, by which is implicated in the cross signaling pathways. Furthermore, the interactions between PXR and some critical proteins (e.g., p53, Tip60, p300/CBP-associated factor) in DNA damage pathway highlight its potential roles in this field. A thorough understanding of how PXR maintains genome stability and prevents carcinogenesis will help clinical diagnosis and finally benefit patients. Meanwhile, due to the regulation of CYP450 enzymes CYP3A4 and multidrug resistance protein 1 (MDR1), PXR contributes to chemotherapeutic drug resistance. It is worthy of note that the co-factor of PXR such as RXRα, also has contributions to this process, which makes the PXR-mediated drug resistance more complicated. Although single nucleotide polymorphisms (SNPs) vary between individuals, the amino acid substitution on exon of PXR finally affects PXR transcriptional activity. In this review, we have summarized the updated mechanisms that PXR protects the human body against carcinogenesis, and major contributions of PXR with its co-factors have made on multidrug resistance. Furthermore, we have also reviewed the current promising antagonist and their clinic applications in reversing chemoresistance. We believe our review will bring insight into PXR-targeted cancer therapy, enlighten the future study direction, and provide substantial evidence for the clinic in future.

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“…Poly (ADP-ribosyl) ation and SUMOylation of PXR stimulates its activity by influencing PXR protein stability and dimerization (Cui et al, 2015, Priyanka et al, 2016, Wang C. et al, 2018a. However, PXR phosphorylation, acetylation, and ubiquitination inhibit PXR activity by regulating its subcellular localization, co-regulatory interaction, and degradation (Biswas et al, 2011, Cui et al, 2020, Hu et al, 2020, Rana et al, 2013. There is mounting evidence that non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), modulate the function and expression of PXR posttranscriptionally (Smutny et al, 2021).…”

Section: Pxr and Its Ligandsmentioning

confidence: 99%

The Function of Xenobiotic Receptors in Metabolic Diseases

Zhang

Jia

et al. 2022

Drug Metab Dispos

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Metabolic diseases are a series of metabolic disorders that include obesity, diabetes, insulin resistance, hypertension, and hyperlipidemia. The increased prevalence of metabolic diseases has resulted in higher mortality and mobility rates over the past decades, and this has led to extensive research focusing on the underlying mechanisms. Xenobiotic receptors (XRs) are a series of xenobioticsensing nuclear receptors that regulate their downstream target genes expression, thus defending the body from xenobiotic and endotoxin attacks. XR activation is associated with the development of a number of metabolic diseases such as obesity, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and cardiovascular diseases, thus suggesting an important role for XRs in modulating metabolic diseases.However, the regulatory mechanism of XRs in the context of metabolic disorders under different nutrient conditions is complex and remains controversial. This review summarizes the effects of XRs on different metabolic components (cholesterol, lipids, glucose, and bile acids) in different tissues during metabolic diseases. As chronic inflammation plays a critical role in the initiation and progression of metabolic diseases, we also discuss the impact of XRs on inflammation to comprehensively recognize the role of XRs in metabolic diseases. This will provide new ideas for treating metabolic diseases by targeting XRs.

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PXR phosphorylated at Ser350 transduces a glucose signal to repress the estrogen sulfotransferase gene in human liver cells and fasting signal in mouse livers

Cited by 11 publications

References 43 publications

Phenobarbital in Nuclear Receptor Activation: An Update

Phenobarbital in Nuclear Receptor Activation: An Update

Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance

The Function of Xenobiotic Receptors in Metabolic Diseases

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