|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
5
|
|
pubmed:dateCreated |
2007-4-20
|
|
pubmed:abstractText |
We have previously shown that cadmium, a metal that alters cellular redox status, induces CYP2A5 expression in nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2+/+) mice but not in the knockout (Nrf2-/-) mice. In the present studies, the potential role of Nrf2 in cadmium-mediated regulation of Cyp2a5 gene was investigated in mouse primary hepatocytes. Cadmium chloride (CdCl2) caused a time-dependent induction of the CYP2A5 at mRNA, protein, and activity levels, with a substantial increase observed within 3 h of exposure. Immunoblotting showed cadmium-dependent nuclear accumulation of Nrf2 within 1 h of exposure. Cotransfection of mouse primary hepatocytes with Cyp2a5 promoter-luciferase reporter plasmids and Nrf2 expression plasmid resulted in a 3-fold activation of Cyp2a5 promoter-mediated transcription relative to the control. Deletion analysis of the promoter localized the Nrf2 responsive region to an area from -2656 to -2339 base pair. Computer-based sequence analysis identified two putative stress response elements (StRE) within the region at positions -2514 to -2505 and -2386 to -2377. Chromatin immunoprecipitation and electrophoretic mobility shift assays showed that interaction of the more proximal StRE with Nrf2 was stimulated by CdCl2. Finally, site-directed mutagenesis of the proximal StRE in Cyp2a5 promoter-luciferase reporter plasmids abolished Nrf2-mediated induction. Collectively, the results indicate that Nrf2 activates Cyp2a5 transcription by directly binding to the StRE in the 5'-flanking region of the gene. This acknowledges Cyp2a5 as the first phase I xenobiotic-metabolizing gene identified under the control of the StRE-Nrf2 pathway with a potential role in adaptive response to cellular stress.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Aryl Hydrocarbon Hydroxylases,
http://linkedlifedata.com/resource/pubmed/chemical/Cadmium Chloride,
http://linkedlifedata.com/resource/pubmed/chemical/Heme Oxygenase-1,
http://linkedlifedata.com/resource/pubmed/chemical/Hmox1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mixed Function Oxygenases,
http://linkedlifedata.com/resource/pubmed/chemical/NF-E2-Related Factor 2,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/coumarin 7-hydroxylase
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
May
|
|
pubmed:issn |
0090-9556
|
|
pubmed:author |
|
|
pubmed:issnType |
Print
|
|
pubmed:volume |
35
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
787-94
|
|
pubmed:meshHeading |
pubmed-meshheading:17303623-Animals,
pubmed-meshheading:17303623-Aryl Hydrocarbon Hydroxylases,
pubmed-meshheading:17303623-Base Sequence,
pubmed-meshheading:17303623-Binding Sites,
pubmed-meshheading:17303623-Blotting, Western,
pubmed-meshheading:17303623-Cadmium Chloride,
pubmed-meshheading:17303623-Cells, Cultured,
pubmed-meshheading:17303623-Chromatin Immunoprecipitation,
pubmed-meshheading:17303623-Electrophoretic Mobility Shift Assay,
pubmed-meshheading:17303623-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:17303623-Heme Oxygenase-1,
pubmed-meshheading:17303623-Hepatocytes,
pubmed-meshheading:17303623-Male,
pubmed-meshheading:17303623-Membrane Proteins,
pubmed-meshheading:17303623-Mice,
pubmed-meshheading:17303623-Mice, Inbred DBA,
pubmed-meshheading:17303623-Mixed Function Oxygenases,
pubmed-meshheading:17303623-Molecular Sequence Data,
pubmed-meshheading:17303623-Mutagenesis, Site-Directed,
pubmed-meshheading:17303623-Mutation,
pubmed-meshheading:17303623-NF-E2-Related Factor 2,
pubmed-meshheading:17303623-Protein Binding,
pubmed-meshheading:17303623-RNA, Messenger,
pubmed-meshheading:17303623-Response Elements,
pubmed-meshheading:17303623-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:17303623-Time Factors,
pubmed-meshheading:17303623-Transcription Initiation Site
|
|
pubmed:year |
2007
|
|
pubmed:articleTitle |
Regulation of CYP2A5 gene by the transcription factor nuclear factor (erythroid-derived 2)-like 2.
|
|
pubmed:affiliation |
National Research Centre for Environmental Toxicology, University of Queensland, Brisbane, QLD, Australia. a.abubakar@uq.edu.au
|
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|
