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Divalent Metal‐Dependent Regulation of Hepcidin Expression by MTF‐1
Author(s) -
Balesaria Sara,
Bayele Henry,
Srai Kaila
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.894.1
Subject(s) - hepcidin , dmt1 , cadmium , zinc finger , zinc , chemistry , transcription factor , divalent , zinc finger transcription factor , transcription (linguistics) , repressor , regulator , messenger rna , peptide , microbiology and biotechnology , biochemistry , biology , transporter , inflammation , gene , immunology , linguistics , philosophy , organic chemistry
There appears to be cross‐talk between metal ions and their acquisition pathways. In particular, zinc and iron reciprocally inhibit each other's uptake. Hepcidin, a small acute phase and antimicrobial peptide, is the principle regulator of iron absorption. This peptide is induced by inflammation and infection, but is repressed by anaemia and hypoxia, suggesting a complex array of regulatory pathways underlying its expression. Here we further reveal that it also appears to be a sensor of other divalent metal ions, principally zinc and cadmium. Using 1.8kb of the human hepcidin promoter tagged with luciferase as a reporter, we show that hepcidin transcription can be significantly modulated by zinc and cadmium levels. This process is entirely dependent on functional metal response elements (MREs) that recruit the MRE‐binding transcription factor MTF‐1 to the promoter, as ascertained by site‐directed mutagenesis. Analysis of hepcidin expression both at the mRNA and protein levels in hepatoma cells suggests that its induction by zinc is rapid; paradoxically, cobalt and iron significantly decreased its mRNA levels. Taken together, these data show that hepcidin may be a pleiotropic sensor of divalent metals some of which are xenobiotic environmental toxins.