title: Prohepcidin binds to the HAMP promoter and autoregulates its own expression.
abstract: Hepcidin is the major regulatory peptide hormone of iron metabolism, encoded by the HAMP (hepcidin antimicrobial peptide) gene. Hepcidin is expressed mainly in hepatocytes, but is also found in the blood in both a mature and prohormone form. Although, the function of mature hepcidin and the regulation of the HAMP gene have been extensively studied, the intracellular localization and the fate of prohepcidin remains controversial. In the present study, we propose a novel role for prohepcidin in the regulation of its own transcription. Using indirect immunofluorescence and mCherry tagging, a portion of prohepcidin was detected in the nucleus of hepatocytes. Prohepcidin was found to specifically bind to the STAT3 (signal transducer and activator of transcription 3) site in the promoter of HAMP. Overexpression of prohepcidin in WRL68 cells decreased HAMP promoter activity, whereas decreasing the amount of prohepcidin caused increased promoter activity measured by a luciferase reporter-gene assay. Moreover, overexpression of the known prohepcidin-binding partner, α-1 antitrypsin caused increased HAMP promoter activity, suggesting that only the non-α-1 antitrypsin-bound prohepcidin affects the expression of its own gene. The results of the present study indicate that prohepcidin can bind to and transcriptionally regulate the expression of HAMP, suggesting a novel autoregulatory pathway of hepcidin gene expression in hepatocytes.
authors: Department of Forensic Medicine, University of Pécs, Szigeti str 12, H-7624 Pécs, Hungary.
authors: Edina
authors: E
authors: Pandur
authors: Katalin
authors: K
authors: Sipos
authors: László
authors: L
authors: Grama
authors: Judit
authors: J
authors: Nagy
authors: Viktor S
authors: VS
authors: Poór
authors: György
authors: G
authors: Sétáló
authors: Attila
authors: A
authors: Miseta
authors: Zsuzsanna
authors: Z
authors: Fekete
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D011498:Protein Precursors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000515:alpha 1-Antitrypsin