Evidence map›Paper›PMID 32205367›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2020

Phosphorylation Modulates the Coregulatory Protein Exchange of the Nuclear Receptor Pregnane X Receptor.

Wenqi Cui, Xunan Shen, Emre Agbas, Brandon Tompkins, Hadley Cameron-Carter, Jeff L Staudinger

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
1.9field-weighted citation impact, top 15% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed, 16 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors at 3 institutions in 1 country.

Wenqi CuiDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota (W.C.); Stowers Institute for Medical Research, Kansas City, Missouri (E.A.); Department of Bioinformatics, University of Georgia, Ethan, Georgia (X.S.); and Kansas City University of Medicine and Biosciences, Joplin, Missouri (B.T., H.C.-C., J.L.S.).
Xunan ShenDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota (W.C.); Stowers Institute for Medical Research, Kansas City, Missouri (E.A.); Department of Bioinformatics, University of Georgia, Ethan, Georgia (X.S.); and Kansas City University of Medicine and Biosciences, Joplin, Missouri (B.T., H.C.-C., J.L.S.).
Emre AgbasDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota (W.C.); Stowers Institute for Medical Research, Kansas City, Missouri (E.A.); Department of Bioinformatics, University of Georgia, Ethan, Georgia (X.S.); and Kansas City University of Medicine and Biosciences, Joplin, Missouri (B.T., H.C.-C., J.L.S.).
Brandon TompkinsDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota (W.C.); Stowers Institute for Medical Research, Kansas City, Missouri (E.A.); Department of Bioinformatics, University of Georgia, Ethan, Georgia (X.S.); and Kansas City University of Medicine and Biosciences, Joplin, Missouri (B.T., H.C.-C., J.L.S.).
Hadley Cameron-CarterDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota (W.C.); Stowers Institute for Medical Research, Kansas City, Missouri (E.A.); Department of Bioinformatics, University of Georgia, Ethan, Georgia (X.S.); and Kansas City University of Medicine and Biosciences, Joplin, Missouri (B.T., H.C.-C., J.L.S.).
Jeff L StaudingerDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota (W.C.); Stowers Institute for Medical Research, Kansas City, Missouri (E.A.); Department of Bioinformatics, University of Georgia, Ethan, Georgia (X.S.); and Kansas City University of Medicine and Biosciences, Joplin, Missouri (B.T., H.C.-C., J.L.S.) JStaudinger@kcumb.edu.
University of Minnesota · USStowers Institute for Medical Research · USUniversity of Georgia · US

Funding

Nuclear Receptors in Liver Health and DiseaseP20GM103549 · NIGMS · UNIVERSITY OF KANSAS MEDICAL CENTER · PI JAESCHKE, HARTMUT W. · 2012 to 2015
$8.1M
Maneuvering of Macrophage Function By Escherichia coli K1R01NS073115 · NINDS · CHILDREN'S HOSPITAL OF LOS ANGELES · PI NEMANI, PRASADARAO V · 2010 to 2014
$1.6M
Inflammation, PXR Modification and Drug DispositionR01DK090558 · NIDDK · UNIVERSITY OF KANSAS LAWRENCE · PI STAUDINGER, JEFFREY L · 2011 to 2014
$1.3M
NIDDK NIH HHS R01 DK090558NIGMS NIH HHS P20 GM103549NINDS NIH HHS R01 NS073115
6 · The paper itself

Abstract

The pregnane X receptor (PXR), or nuclear receptor (NR) 1I2, is a ligand-activated NR superfamily member that is enriched in liver and intestine in mammals. Activation of PXR regulates the expression of genes encoding key proteins involved in drug metabolism, drug efflux, and drug transport. Recent mechanistic investigations reveal that post-translational modifications (PTMs), such as phosphorylation, play a critical role in modulating the bimodal function of PXR-mediated transrepression and transactivation of target gene transcription. Upon ligand binding, PXR undergoes a conformational change that promotes dissociation of histone deacetylase-containing multiprotein corepressor protein complexes while simultaneously favoring recruitment histone acetyl transferase-containing complexes. Here we describe a novel adenoviral vector used to deliver and recover recombinant human PXR protein from primary cultures of hepatocytes. Using liquid chromatography and tandem mass spectrometry we report here that PXR is phosphorylated at amino acid residues threonine 135 (T135) and serine 221 (S221). Biochemical analysis reveals that these two residues play an important regulatory role in the cycling of corepressor and coactivator multiprotein complexes. These data further our foundational knowledge regarding the specific role of PTMs, namely phosphorylation, in regulating the biology of PXR. Future efforts are focused on using the novel tools described here to identify additional PTMs and protein partners of PXR in primary cultures of hepatocytes, an important experimental model system. SIGNIFICANCE STATEMENT: Pregnane X receptor (PXR), or nuclear receptor 1I2, is a key master regulator of drug-inducible CYP gene expression in liver and intestine in mammals. The novel biochemical tools described in this study demonstrate for the first time that in cultures of primary hepatocytes, human PXR is phosphorylated at amino acid residues threonine 135 (T135) and serine 221 (S221). Moreover, phosphorylation of PXR promotes the transrepression of its prototypical target gene CYP3A4 through modulating its interactions with coregulatory proteins.

Indexed as

AnimalsCell Line, TumorCells, CulturedHepatocytesHumansMicePhosphorylationPregnane X ReceptorProtein Processing, Post-TranslationalRatsRats, Sprague-DawleySerineThreonineNr1i2 protein, mouseNr1i2 protein, ratPregnane X ReceptorSerineThreonine

Identifiers

PMID32205367
PMCPMC7228503
OpenAlexW3012890711

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

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.