The Major Human Pregnane X Receptor (PXR) Splice Variant, PXR.2, Exhibits Significantly Diminished Ligand-Activated Transcriptional Regulation

Lin, Yvonne S.; Yasuda, Kazuto; Assem, Mahfoud; Cline, Cynthia; Barber, Joe; Li, Chia Wei; Kholodovych, Vladyslav; Ni, Ai; Chen, J. Don; Welsh, William J.; Ekins, Sean; Schuetz, Erin G.

doi:10.1124/dmd.108.025213

Cited by 41 publications

(49 citation statements)

References 38 publications

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“…4B). This sequence is absent in the alternatively spliced isoform of PXR, also referred to as PXR.2 (Lin et al, 2009), indicating that p53 specifically associates with the more abundant isoform of PXR, PXR.1. In agreement with previously reported findings, whereas PXR.1 was robustly activated by rifampicin, PXR.2 was not (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The deletion of 37 amino acids (174-210) in the LBD is predicted to make PXR.2 unable to retain certain ligands, thereby altering the ligand and protein partner profile (Lin et al, 2009). It is thus not surprising that the integrity of the PXR protein structure is important to retain certain protein-protein interactions such as PXR-p53 binding, as revealed by the loss of interaction with p53 when the AF-2 domain (Δ421-434) or the N-terminal 99 amino acids of PXR (Δ1-99) were deleted.…”

Section: Discussionmentioning

confidence: 99%

“…The second most abundant isoform, PXR.2 (397 amino acids, also referred to as ), constitutes 7% of the mRNA transcript and has a 37 amino acid deletion in the LBD, resulting in attenuated ligand binding capacity and reduced ligand-mediated transcriptional activity, although there is no loss of association with the PXR response elements in the genome (Dotzlaw et al, 1999;Lin et al, 2009). The physiologic role of PXR.2 has not been fully defined.…”

Section: Introductionmentioning

confidence: 99%

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Tumor Suppressor Protein p53 Negatively Regulates Human Pregnane X Receptor Activity

Elias

Chen

2013

Mol Pharmacol

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The human pregnane X receptor (PXR) regulates genes involved in drug metabolism and disposition. PXR associates with multiple corepressors that attenuate and coactivators that enhance its activity. PXR plays a vital role in the drug metabolism pathway, and a comprehensive examination of PXR-associated proteins will provide greater insight into the regulation of the receptor and possible therapeutic implications. We performed a mass spectrometric screen to identify PXR-associated proteins. Here we report that the tumor suppressor protein p53 can associate with PXR and downregulate its activity. A loss-offunction p53 mutant (R175H) interacts with PXR but does not repress its activity. Mutant p53 can relieve the suppressive effect of wild-type p53 by competing with its interaction with PXR, suggesting that protein-protein interaction is required but not sufficient for p53 to repress PXR activity. Interestingly, a PXR variant with a naturally occurring deletion of a conserved, unique sequence in the ligand binding domain (PXRΔ174-210) did not interact with p53, indicating that the PXR-p53 interaction is specific. Using a chromatin immunoprecipitation assay, we showed that p53 inhibits the binding of PXR to the CYP3A4 promoter. The loss of p53 function in tumor cells leads to aberrant cell proliferation, apoptosis, carcinogenesis, and altered sensitivity to chemotherapeutic drugs, whereas PXR contributes to chemoresistance in many cancer cells. Our findings show for the first time that wild-type p53 can negatively regulate PXR by physically associating with it. Thus, PXR and p53 appear to play important yet opposing roles in the sensitivity of tumor cells to chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor Suppressor Protein p53 Negatively Regulates Human Pregnane X Receptor Activity

Elias

Chen

2013

Mol Pharmacol

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“…Of more importance, PXR.2 has been found to repress the basal expression of CYP3a and MDR1. Whereas PXR.1 is an inducer of genes such as Cyp3a, the PXR.2 isoform has been shown to have a dose-dependent suppressive effect on the basal expression of Cyp3a and Mdr1 (Lin et al, 2009;Matic et al, 2010). The precise function of this major PXR variant remains to be elucidated.…”

Section: Figmentioning

confidence: 99%

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Gahir

Piquette-Miller²

2010

Drug Metab Dispos

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ABSTRACT:The ATP-binding cassette (ABC) drug transporters in the placenta are involved in controlling the exchange of endogenous and exogenous moieties. Pregnane X receptor (PXR) is a nuclear receptor that regulates the hepatic expression of several key ABC transporters, but it is unclear whether PXR is involved in the regulation of these transporters in the placenta. This study explores the role of PXR in the regulation of placental drug transporters. The placental mRNA expression of Mdr1a, Bcrp, and Mrp1, 2, and 3 was

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“…PXR.2 is an alternatively spliced form of PXR that lacks 111 nucleotides encoding 37 amino acids in the ligand-binding domain. Basal CYP2B6 expression levels are increased in untreated PXR.2 cells: however, CYP2B6 induction activity decreased after treatment with rifampin (Lin et al, 2009). Other effects may be linked to the NR1I2 TGT haplotype and basal metabolic activity of CYP2B6.…”

mentioning

confidence: 99%

Effects of Pregnane X Receptor (NR1I2) and CYP2B6 Genetic Polymorphisms on the Induction of Bupropion Hydroxylation by Rifampin

Chung¹,

Cho²,

Lim³

et al. 2010

Drug Metab Dispos

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ABSTRACT:We investigated genetic polymorphisms in the pregnane X receptor (NR1I2) in Korean individuals (n ‫؍‬ 83) and the effects of NR1I2 genotypes on rifampin-mediated induction of bupropion hydroxylation. The pharmacokinetics of bupropion and hydroxybupropion were evaluated after an oral dose of bupropion (150 mg) administered before and after rifampin treatment for 7 days in 35 healthy subjects. The area under the time-concentration curve (AUC) ratio of hydroxybupropion to bupropion in CYP2B6*6 carriers was significantly lower than that in CYP2B6*6 noncarriers in both the basal and rifampin-induced states (p ‫؍‬ 0.012). Among the CYP2B6*6 carriers (n ‫؍‬ 13), the NR1I2 TGT (؊25385T ؉ g.7635G ؉ g.8055T)carriers exhibited a significantly lower AUC ratio, representing the CYP2B6 hydroxylation activity, compared with the TGT noncarriers, in the induced state (11.9 versus 20.3, p ‫؍‬ 0.045). The percent difference in the AUC ratio between the basal and induced states was also significantly different (212% versus 58.8%, p ‫؍‬ 0.006). However, no significant difference was observed among the NR1I2 TGT genotypes for the CYP2B6*6 noncarriers (n ‫؍‬ 22). In conclusion, it is suggested the NR1I2 TGT genotype decreases the bupropion hydroxylation induced by treatment with rifampin, particularly in CYP2B6*6 carriers.

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The Major Human Pregnane X Receptor (PXR) Splice Variant, PXR.2, Exhibits Significantly Diminished Ligand-Activated Transcriptional Regulation

Abstract: ABSTRACT:The pregnane X receptor (PXR; PXR

Cited by 41 publications

References 38 publications

Tumor Suppressor Protein p53 Negatively Regulates Human Pregnane X Receptor Activity

Tumor Suppressor Protein p53 Negatively Regulates Human Pregnane X Receptor Activity

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Effects of Pregnane X Receptor (NR1I2) and CYP2B6 Genetic Polymorphisms on the Induction of Bupropion Hydroxylation by Rifampin

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