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Heme acts through the Bach1b/Nrf2a-MafK pathway to regulate exocrine peptidase precursor genes in porphyric zebrafish.
- Source :
-
Disease models & mechanisms [Dis Model Mech] 2014 Jul; Vol. 7 (7), pp. 837-45. Date of Electronic Publication: 2014 Mar 20. - Publication Year :
- 2014
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Abstract
- Using a zebrafish model of hepatoerythropoietic porphyria (HEP), we identify a previously unknown mechanism underlying heme-mediated regulation of exocrine zymogens. Zebrafish bach1b, nrf2a and mafK are all expressed in the zebrafish exocrine pancreas. Overexpression of bach1b or knockdown of nrf2a result in the downregulation of the expression of the exocrine zymogens, whereas overexpression of nrf2a or knockdown of bach1b cause their upregulation. In vitro luciferase assays demonstrate that heme activates the zymogens in a dosage-dependent manner and that the zymogen promoter activities require the integral Maf recognition element (MARE) motif. The Bach1b-MafK heterodimer represses the zymogen promoters, whereas the Nrf2a-MafK heterodimer activates them. Furthermore, chromatin immunoprecipitation (ChIP) assays show that MafK binds to the MARE sites in the 5' regulatory regions of the zymogens. Taken together, these data indicate that heme stimulates the exchange of Bach1b for Nrf2a at MafK-occupied MARE sites and that, particularly in heme-deficient porphyria, the repressive Bach1b-MafK heterodimer dominates, which can be exchanged for the activating Nrf2a-MafK heterodimer upon treatment with hemin. These results provide novel insights into the regulation of exocrine function, as well as the pathogenesis of porphyria, and should be useful for designing new therapies for both types of disease.<br /> (© 2014. Published by The Company of Biologists Ltd.)
- Subjects :
- Amino Acid Motifs
Amino Acid Sequence
Animals
Chromatin Immunoprecipitation
Enzyme Precursors metabolism
Gene Expression Regulation drug effects
Gene Knockdown Techniques
Heme pharmacology
In Situ Hybridization
Mice
Models, Biological
Molecular Sequence Data
NIH 3T3 Cells
Nucleotide Motifs genetics
Pancreas, Exocrine drug effects
Pancreas, Exocrine enzymology
Porphyrias, Hepatic enzymology
Promoter Regions, Genetic genetics
Protein Multimerization
RNA, Messenger genetics
RNA, Messenger metabolism
Zebrafish Proteins chemistry
Zebrafish Proteins genetics
Enzyme Precursors genetics
Heme metabolism
Peptide Hydrolases genetics
Porphyrias, Hepatic genetics
Signal Transduction drug effects
Signal Transduction genetics
Zebrafish genetics
Zebrafish Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1754-8411
- Volume :
- 7
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Disease models & mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- 24652768
- Full Text :
- https://doi.org/10.1242/dmm.014951