ArticleThe Journal of biological chemistry2008
Cyclin-dependent kinase 2 negatively regulates human pregnane X receptor-mediated CYP3A4 gene expression in HepG2 liver carcinoma cells.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 102 citations in OpenAlex.
- Structure-based machine learning model for discovering pregnane X receptor (PXR) agonists and biological activity validation.Archives of toxicology · 2026Article
- Rifamycin Structural Modifications Attenuate PXR Binding and CYP3A4 Induction.Journal of medicinal chemistry · 2026Article
- Mutation of PXR phosphorylation motif at Ser347 disrupts lipid and bile acid homeostasis in diet-induced metabolic dysfunction-associated steatohepatitis in mice.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- Subtle changes in ligand-receptor interactions dramatically alter transcriptional outcomes of pregnane X receptor modulators.Structure (London, England : 1993) · 2026Article
- PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors.Nature communications · 2025Article
- Insights of direct and indirect regulation of PXR through phosphorylation in fatty liver disease.Molecular pharmacology · 2025Review
- PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network.Structure (London, England : 1993) · 2024Article
- First-in-Class Small Molecule Degrader of Pregnane X Receptor Enhances Chemotherapy Efficacy.Journal of medicinal chemistry · 2024Article
- Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.Nature communications · 2024Article
- A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR.Nucleic acids research · 2024Article
- Identification of human pregnane X receptor antagonists utilizing a high-throughput screening platform.Frontiers in pharmacology · 2024Article
- Ligand flexibility and binding pocket malleability cooperate to allow selective PXR activation by analogs of a promiscuous nuclear receptor ligand.Structure (London, England : 1993) · 2023Article
- The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation.Acta pharmaceutica Sinica. B · 2023Article
- Quantitative Bioactivity Signatures of Dietary Supplements and Natural Products.ACS pharmacology & translational science · 2023Article
- Structure-guided approach to modulate small molecule binding to a promiscuous ligand-activated protein.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Phenobarbital in Nuclear Receptor Activation: An Update.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Screening Method for the Identification of Compounds That Activate Pregnane X Receptor.Current protocols · 2022Article
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- Characterization of human pregnane X receptor activators identified from a screening of the Tox21 compound library.Biochemical pharmacology · 2021Article
10 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The human pregnane X receptor (hPXR) regulates the expression of critical drug metabolism enzymes. One of such enzymes, cytochrome P450 3A4 (CYP3A4), plays critical roles in drug metabolism in hepatocytes that are either quiescent or passing through the cell cycle. It has been well established that the expression of P450, such as CYP3A4, is markedly reduced during liver development or regeneration. Numerous studies have implicated cellular signaling pathways in modulating the functions of nuclear receptors, including hPXR. Here we report that inhibition of cyclin-dependent kinases (Cdks) by kenpaullone and roscovitine (two small molecule inhibitors of Cdks that we identified in a screen for compounds that activate hPXR) leads to activation of hPXR-mediated CYP3A4 gene expression in HepG2 human liver carcinoma cells. Consistent with this finding, activation of Cdk2 attenuates the activation of CYP3A4 gene expression. In vitro kinase assays revealed that Cdk2 directly phosphorylates hPXR. A phosphomimetic mutation of a putative Cdk phosphorylation site, Ser(350), significantly impairs the function of hPXR, whereas a phosphorylation-deficient mutation confers resistance to Cdk2. Using HepG2 that has been stably transfected with hPXR and the CYP3A4-luciferase reporter, enriched in different phases of the cell cycle, we found that hPXR-mediated CYP3A4 expression is greatly reduced in the S phase. Our results indicate for the first time that Cdk2 negatively regulates the activity of hPXR, and suggest an important role for Cdk2 in regulating hPXR activity and CYP3A4 expression in hepatocytes passing through the cell cycle, such as those in fetal or regenerating adult liver.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.