ArticleThe Journal of pharmacology and experimental therapeutics2009
A systematic analysis of predicted phosphorylation sites within the human pregnane X receptor protein.
Article in The Journal of pharmacology and experimental therapeutics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 56 citations in OpenAlex.
- Rifamycin Structural Modifications Attenuate PXR Binding and CYP3A4 Induction.Journal of medicinal chemistry · 2026Article
- Pregnane X receptor (NR1I2) deficiency in mice reveals context-dependent regulation of inflammatory homeostasis.Frontiers in immunology · 2026Review
- Insights of direct and indirect regulation of PXR through phosphorylation in fatty liver disease.Molecular pharmacology · 2025Review
- Nuclear Receptor PXR Confers Irradiation Resistance by Promoting DNA Damage Response Through Stabilization of ATF3.Frontiers in oncology · 2022Article
- Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance.International journal of biological sciences · 2022Review
- Review
- Nuclear receptor phosphorylation in xenobiotic signal transduction.The Journal of biological chemistry · 2020Review
- Phosphorylation Modulates the Coregulatory Protein Exchange of the Nuclear Receptor Pregnane X Receptor.The Journal of pharmacology and experimental therapeutics · 2020Article
- Role of c-Jun-N-Terminal Kinase in Pregnane X Receptor-Mediated Induction of Human Cytochrome P4503A4 In Vitro.Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Mechanisms of xenobiotic receptor activation: Direct vs. indirect.Biochimica et biophysica acta · 2016Review
- Regulation of PXR and CAR by protein-protein interaction and signaling crosstalk.Expert opinion on drug metabolism & toxicology · 2016Review
- Small-molecule modulators of PXR and CAR.Biochimica et biophysica acta · 2016Review
- A SUMO-acetyl switch in PXR biology.Biochimica et biophysica acta · 2016Article
- Tryptophan 299 is a conserved residue of human pregnane X receptor critical for the functional consequence of ligand binding.Biochemical pharmacology · 2016Article
- SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes.Drug metabolism and disposition: the biological fate of chemicals · 2015Article
- Serine 350 of human pregnane X receptor is crucial for its heterodimerization with retinoid X receptor alpha and transactivation of target genes in vitro and in vivo.Biochemical pharmacology · 2015Article
- Effect of erythropoietin on hepatic cytochrome P450 expression and function in an adenine-fed rat model of chronic kidney disease.British journal of pharmacology · 2015Article
- Pregnane X receptor and drug-induced liver injury.Expert opinion on drug metabolism & toxicology · 2014Review
- Stability of the human pregnane X receptor is regulated by E3 ligase UBR5 and serine/threonine kinase DYRK2.The Biochemical journal · 2014Article
- Identification and characterization of phosphorylation sites within the pregnane X receptor protein.Biochemical pharmacology · 2014Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The pregnane X receptor (PXR, NR1I2) regulates the expression of genes that encode drug-metabolizing enzymes and drug transporter proteins in liver and intestine. Understanding the molecular mechanisms that modulate PXR activity is therefore critical for the development of effective therapeutic strategies. Several recent studies have implicated the activation of kinase signaling pathways in the regulation of PXR biological activity, although direct evidence and molecular mechanisms are currently lacking. We therefore sought to characterize potential phosphorylation sites within the PXR protein by use of a rational, comprehensive, and systematic site-directed mutagenesis approach to generate phosphomimetic mutations (Ser/Thr --> Asp) and phospho-deficient mutations (Ser/Thr --> Ala) at 18 predicted consensus kinase recognition sequences in the human PXR protein. Here, we identify amino acid residues Ser8, Thr57, Ser208, Ser305, Ser350, and Thr408 as being critical for biological activity of the PXR protein. Mutations at positions 57 and 408 abolish ligand-inducible PXR activity. Mutations in the extreme N terminus and in the PXR ligand-binding domain at positions Ser8, Ser305, Ser350, and Thr408 decrease the ability of PXR to form heterodimers with retinoid X receptor alpha. Mutations at positions Ser208, Ser305, Ser350, and Thr408 alter PXR-protein cofactor interactions. Finally, the subcellular localization of the PXR protein is profoundly affected by mutations at position Thr408. These data suggest that PXR activity can potentially be regulated by phosphorylation at specific amino acid residues within several predicted consensus kinase recognition sequences to differentially affect PXR biological activity.
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