Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two genes, MDR1 and MDR3, constitute the human P-glycoprotein gene family. To examine the evolutionary relationship between the three known classes of mammalian P-glycoprotein genes, we have cloned the MDR3 gene and compared its structure with that of the human MDR1 and the mouse mdr1 (mdr1b) genes analyzed by other groups. The MDR3 gene contains 28 exons and 27 of these contain coding sequences for the two homologous halves of the protein that correlate with functional domains. This structure is virtually identical to that of the human MDR1 gene and the mouse mdr1 (mdr1b) gene, indicating that the exon/intron structure was fixed before the duplication events that generated different classes of P-glycoproteins, but after the P-glycoproteins diverged from related genes, like the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which has an entirely different exon/intron structure. The four alternatively spliced transcripts of the MDR3 gene arise from alternative splicing of exons 23 and 26. Our analysis of DNA clones covering about 120 kilobases (kb) of the human MDR locus, including the entire MDR3 gene (74 kb) and the intergenic region between both genes (34 kb), combined with pulsed-field gel electrophoresis data shows that the human MDR locus covers about 230 kb. In contrast to the mouse mdr genes, both human genes are transcribed in the same direction (MDR3 located downstream of MDR1). The CpG-rich sequences marking the 5' ends of both genes are hypomethylated to different extents in different cell lines. Hypomethylation roughly correlates with transcriptional activity.
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PMID:Structure of the human MDR3 gene and physical mapping of the human MDR locus. 200 63

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.
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PMID:The alternatively spliced murine pregnane X receptor isoform, mPXR(delta171-211) exhibits a repressive action. 2006 Sep 28