Linked Life Data

20060928

Source:http://linkedlifedata.com/resource/pubmed/id/20060928

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2010-3-9
pubmed:abstractText
The orphan nuclear receptor pregnane X receptor regulates enzymes and transport proteins involved in the detoxification and clearance of numerous endobiotic and xenobiotic compounds, including pharmaceutical agents. Multiple alternatively spliced pregnane X receptor isoforms have been identified which are significantly expressed in humans and mice (up to 30% of the total pregnane X receptor transcript), however, little is known about their biological action. We explored functional differences between the major mouse pregnane X receptor isoforms mPXR(431) and mPXR(Delta171-211) that lacks 41 amino acids adjacent to the ligand-binding pocket. Transient transfection assays showed that mPXR(Delta171-211) reduced the basal transcription of cytochrome P450 3A4 and the drug transporter P-glycoprotein/Multi Drug Resistance Protein 1 and directly repressed the regulatory effects of mPXR(431) on these genes. Replacement of the mPXR(Delta171-211) DNA-binding domain with that of GAL4 showed mPXR(Delta171-211) retained its repressive role independent of binding to PXR responsive elements located within the cytochrome P450 3A4 and Multi Drug Resistance Protein 1 regulatory regions. Use of the histone deacetylase inhibitor, trichostatin A, demonstrated that the repressive function of mPXR(Delta171-211) acts independently of histone acetylation state. Protein interaction assays revealed mPXR(Delta171-211) and mPXR(431) differentially bind the obligatory heterodimer partner retinoid X receptor. Furthermore, mPXR(431) and mPXR(Delta171-211) proteins could heterodimerize. These studies demonstrate that the variant mouse PXR isoform, mPXR(Delta171-211), has a distinct repressive function from mPXR(431) in regulating genes encoding important drug metabolizing enzymes and transport proteins.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1878-5875
pubmed:author
pubmed:copyrightInfo
2010 Elsevier Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
672-82
pubmed:meshHeading
pubmed-meshheading:20060928-Alternative Splicing, pubmed-meshheading:20060928-Amino Acid Sequence, pubmed-meshheading:20060928-Animals, pubmed-meshheading:20060928-Cell Line, pubmed-meshheading:20060928-Cercopithecus aethiops, pubmed-meshheading:20060928-Cytochrome P-450 CYP3A, pubmed-meshheading:20060928-DNA-Binding Proteins, pubmed-meshheading:20060928-Down-Regulation, pubmed-meshheading:20060928-Histone Deacetylase Inhibitors, pubmed-meshheading:20060928-Humans, pubmed-meshheading:20060928-Male, pubmed-meshheading:20060928-Mice, pubmed-meshheading:20060928-Organ Specificity, pubmed-meshheading:20060928-P-Glycoprotein, pubmed-meshheading:20060928-Protein Interaction Domains and Motifs, pubmed-meshheading:20060928-Protein Isoforms, pubmed-meshheading:20060928-Protein Multimerization, pubmed-meshheading:20060928-Receptors, Steroid, pubmed-meshheading:20060928-Recombinant Fusion Proteins, pubmed-meshheading:20060928-Regulatory Elements, Transcriptional, pubmed-meshheading:20060928-Retinoid X Receptors, pubmed-meshheading:20060928-Sequence Alignment, pubmed-meshheading:20060928-Sequence Deletion
pubmed:year
2010
pubmed:articleTitle
The alternatively spliced murine pregnane X receptor isoform, mPXR(delta171-211) exhibits a repressive action.
pubmed:affiliation
Cancer Pharmacology Unit, ANZAC Research Institute, Hospital Road, Concord RG Hospital, NSW 2139, Australia. mmatic@med.usyd.edu.au
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't