| Interaction of hepatocyte nuclear factors in transcriptional regulation of tissue specific hormonal expression of human multidrug resistance-associated protein 2 (abcc2). | |
| | |
MedLine Citation:
|
PMID: 19010343 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Multidrug resistance-associated protein 2 (MRP2) (ABCC2) is an ATP-binding cassette membrane protein located primarily on apical surface of hepatocytes that mediates transport of conjugated xenobiotics and endogenous compounds into bile. MRP2 is highly expressed in hepatocytes, and at lower levels in small intestines, stomach and kidney. Previous reports have characterized mammalian MRP2 promoters, but none have established the molecular mechanism(s) involved in liver enriched expression. This study aims to investigate the mechanism of hepatic MRP2 regulation. A 2130 bp of MRP2 promoter was cloned from PAC-1 clone P108G1-7, to identify putative liver specific/hormone responsive functional DNA binding sites. Using deletion analysis, site specific mutagenesis and co-transfection studies, liver specific expression was determined. MRP2 promoter-LUC constructs were highly expressed in liver cell lines compared to non-liver cells. The region extending from -3 to+458 bp of MRP2 promoter starting from AUG contained the potential binding sites for CAATT box enhancer binding protein (C/EBP), hepatocytes nuclear factor 1, 3 and 4 (HNF1, HNF3, and HNF4. Only HNF1 and HNF4 co-transfection with MRP2 luciferase increased expression. Site specific mutational analysis of HNF1 binding site indicated an important role for HNF1alpha. HNF4alpha induction of MRP2 was independent of HNF1 binding site. C/EBP, HNF3, and HNF6 inhibited HNF1alpha while HNF4alpha induced MRP2 luciferase expression and glucocorticoids stimulated MRP2 expression. This study emphasizes the complex regulation of MRP2 with HNF1alpha and HNF4alpha playing a central role. The coordinated regulation of xenobiotic transporters and oxidative conjugation may determine the adaptive responses to cellular detoxification processes. |
| | |
Authors:
|
Ishtiaq Qadri; Ling-Jia Hu; Mieko Iwahashi; Subhi Al-Zuabi; Linda C Quattrochi; Francis R Simon |
Related Documents
:
|
10947163 - Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter... 10930443 - In vivo alterations of ifn regulatory factor-1 and pias1 protein levels in cystic fibro... 16956603 - Fibroblast growth factor 10 is required for survival and proliferation but not differen... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-10-29 |
Journal Detail:
|
Title: Toxicology and applied pharmacology Volume: 234 ISSN: 1096-0333 ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 2009 Feb |
Date Detail:
|
Created Date: 2009-02-02 Completed Date: 2009-02-12 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: United States |
Other Details:
|
Languages: eng Pagination: 281-92 Citation Subset: IM |
Affiliation:
|
NUST Center of Virology and Immunology, National University of Science and Technology, Tamizudin Road, Rawalpindi, Pakistan. dg-ncvi@nust.edu.pk |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
5' Flanking Region ATP-Binding Cassette Transporters / genetics, metabolism* Animals Base Sequence CCAAT-Enhancer-Binding Proteins / metabolism CHO Cells Cloning, Molecular Cricetinae Cricetulus Dexamethasone / pharmacology* Genes, Reporter Glucocorticoids / pharmacology* Hela Cells Hepatocyte Nuclear Factor 1-alpha / metabolism Hepatocyte Nuclear Factor 4 / metabolism Hepatocyte Nuclear Factor 6 / metabolism Hepatocyte Nuclear Factors / genetics, metabolism* Hepatocytes / drug effects*, metabolism Humans Molecular Sequence Data Multidrug Resistance-Associated Proteins / genetics, metabolism* Mutagenesis, Site-Directed Promoter Regions, Genetic / drug effects* Rats Transcription, Genetic / drug effects* Transfection |
| Grant Support | |
ID/Acronym/Agency:
|
DK-15851/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/ATP-Binding Cassette Transporters; 0/Abcc2 protein, rat; 0/CCAAT-Enhancer-Binding Proteins; 0/Glucocorticoids; 0/Hepatocyte Nuclear Factor 1-alpha; 0/Hepatocyte Nuclear Factor 4; 0/Hepatocyte Nuclear Factor 6; 0/Hepatocyte Nuclear Factors; 0/Multidrug Resistance-Associated Proteins; 0/multidrug resistance-associated protein 2; 50-02-2/Dexamethasone |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Three conazoles increase hepatic microsomal retinoic acid metabolism and decrease mouse hepatic reti...
Next Document: Asymmetrical perception of motion smear in infantile nystagmus.