RRC ID 34857
Author Kanamori Y, Murakami M, Matsui T, Funaba M.
Title The regulation of hepcidin expression by serum treatment: requirements of the BMP response element and STAT- and AP-1-binding sites.
Journal Gene
Abstract Expression of hepcidin, a central regulator of systemic iron metabolism, is transcriptionally regulated by the bone morphogenetic protein (BMP) pathway. However, the factors other than the BMP pathway also participate in the regulation of hepcidin expression. In the present study, we show that serum treatment increased hepcidin expression and transcription without inducing the phosphorylation of Smad1/5/8 in primary hepatocytes, HepG2 cells or Hepa1-6 cells. Co-treatment with LDN-193189, an inhibitor of the BMP type I receptor, abrogated this hepcidin induction. Reporter assays using mutated reporters revealed the involvement of the BMP response element-1 (BMP-RE1) and signal transducers and activator of transcription (STAT)- and activator protein (AP)-1-binding sites in serum-induced hepcidin transcription in HepG2 cells. Serum treatment induced the expression of the AP-1 components c-fos and junB in primary hepatocytes and HepG2 cells. Forced expression of c-fos or junB enhanced the response of hepcidin transcription to serum treatment. By contrast, the expression of dominant negative (dn)-c-fos and dn-junB decreased hepcidin transcription. The present study reveals that serum contains factors stimulating hepcidin transcription. Basal BMP activity is essential for the serum-induced hepcidin transcription, although serum treatment does not stimulate the BMP pathway. The induction of c-fos and junB by serum treatment stimulates hepcidin transcription, through possibly cooperation with BMP-mediated signaling. Considering that AP-1 is induced by various stimuli, the present results suggest that hepcidin expression is regulated by more diverse factors than had been previously considered.
Volume 551(2)
Pages 119-26
Published 2014-11-10
DOI 10.1016/j.gene.2014.08.037
PII S0378-1119(14)00963-9
PMID 25151311
MeSH Animals Base Sequence Binding Sites / genetics Blotting, Western Bone Morphogenetic Proteins / genetics Cell Line, Tumor Culture Media / chemistry Culture Media / pharmacology Gene Expression Regulation / drug effects Gene Expression Regulation / genetics* Hep G2 Cells Hepatocytes / cytology Hepatocytes / drug effects Hepatocytes / metabolism* Hepcidins / genetics* Hepcidins / metabolism Humans Male Mutation Phosphorylation / drug effects Primary Cell Culture Proto-Oncogene Proteins c-fos / genetics Proto-Oncogene Proteins c-fos / metabolism Proto-Oncogene Proteins c-jun / genetics Proto-Oncogene Proteins c-jun / metabolism Pyrazoles / pharmacology Pyrimidines / pharmacology Rats, Sprague-Dawley Response Elements / genetics Reverse Transcriptase Polymerase Chain Reaction STAT Transcription Factors / metabolism Serum / chemistry* Transcription Factor AP-1 / metabolism
IF 2.984
Times Cited 14
DNA material Hamp1(-2018)-luc (RDB13383) dn-c-fos (delta133-159)/pcDNA (RDB13384).