Linked Life Data

15367577

Source:http://linkedlifedata.com/resource/pubmed/id/15367577

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2005-1-17
pubmed:abstractText
The pregnane X receptor (PXR) is a key regulator on the expression of genes involved in the elimination of chemicals. As one of the most divergent members in the nuclear receptor family, PXR is activated in a highly species-dependent manner by certain chemicals. Pregnenolone 16alpha-carbonitrile (PCN), a glucocorticoid antagonist, efficaciously activates rodent but not human PXR. This study was undertaken to investigate the structural basis for PCN-mediated activation of rat PXR. A series of rat-human chimeric PXRs were prepared to gradually replace the ligand-binding domain of human PXR with the corresponding rat sequence at an increasing length of 20 residues. Cotransfection experiments established that region(306-326) acted as a transitional conjunction from none to full PCN responsive status. Site-directed mutagenesis study identified two residues (Phe-305 and Asp-318) that were critical in supporting PCN-mediated activation, and simultaneous substitution of both residues abolished the ability of rat PXR to transactivate the CYP3A23 promoter. In addition, substitutions on Phe-305, Asp-318, or both markedly reduced the basal transcriptional activity, and the reduction occurred with the CYP3A4 but not CYP3A23 promoter. Further study with CYP3A4 and CYP3A23 hybrid reporters demonstrated that the region harboring the distal PXR element in the CYP3A4 promoter mediated the repressive activity. PXR has been shown to interact with corepressors in the absence of ligand. The decreased responsiveness toward PCN and reduced basal transcriptional activity suggest that Phe-305 and Asp-318 are involved in both ligand-binding and corepressor interactions.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
312
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
571-82
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:15367577-Amino Acid Sequence, pubmed-meshheading:15367577-Amino Acid Substitution, pubmed-meshheading:15367577-Animals, pubmed-meshheading:15367577-Aryl Hydrocarbon Hydroxylases, pubmed-meshheading:15367577-Aspartic Acid, pubmed-meshheading:15367577-Blotting, Western, pubmed-meshheading:15367577-Humans, pubmed-meshheading:15367577-Ligands, pubmed-meshheading:15367577-Molecular Sequence Data, pubmed-meshheading:15367577-Mutagenesis, Site-Directed, pubmed-meshheading:15367577-Mutation, pubmed-meshheading:15367577-Phenylalanine, pubmed-meshheading:15367577-Plasmids, pubmed-meshheading:15367577-Pregnenolone Carbonitrile, pubmed-meshheading:15367577-Promoter Regions, Genetic, pubmed-meshheading:15367577-Rats, pubmed-meshheading:15367577-Receptors, Cytoplasmic and Nuclear, pubmed-meshheading:15367577-Receptors, Steroid, pubmed-meshheading:15367577-Transcriptional Activation, pubmed-meshheading:15367577-Transfection
pubmed:year
2005
pubmed:articleTitle
Simultaneous substitution of phenylalanine-305 and aspartate-318 of rat pregnane X receptor with the corresponding human residues abolishes the ability to transactivate the CYP3A23 promoter.
pubmed:affiliation
Department of Biomedical Sciences, University of Rhode Island, 41 Lower College Road, Kingston, RI 02881, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.