Role of a TPA-responsive element in hepcidin transcription induced by the bone morphogenetic protein pathway.
Systemic iron balance is governed by the liver-derived peptide hormone hepcidin. The transcription of hepcidin is primarily regulated by the bone morphogenetic protein (BMP) and inflammatory cytokine pathways through the BMP-response element (BMP-RE) and STAT-binding site, respectively. In addition to these elements, we previously identified a TPA-responsive element (TRE) in the hepcidin promoter and showed that it mediated the transcriptional activation of hepcidin through activator protein (AP)-1 induced by serum. In the present study, we examined the role of TRE in the BMP-induced transcription of hepcidin in HepG2 liver cells. The serum treatment increased the basal transcription of hepcidin; however, responsiveness to the expression of ALK3(QD), a constitutively active BMP type I receptor, was unaffected. Consistent with these results, mutations in TRE in the hepcidin promoter decreased basal transcription, whereas responsiveness to the expression of ALK3(QD) remained unchanged. HepG2 cells significantly expressed AP-1 components in the basal state, whereas BMP did not up-regulate the expression of these components. The expression of c-fos enhanced the basal transcription of hepcidin as well as ALK3(QD)-mediated hepcidin transcription, whereas that of dominant-negative c-fos decreased hepcidin transcription. The results of the present study suggested that the cis-elements of the hepcidin promoter, BMP-RE and TRE, individually transmitted BMP-mediated and AP-1-mediated signals, respectively, whereas transcription was synergistically increased by the stimulation of BMP-RE and TRE.
Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
Yohei
Y
Kanamori
Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan.
Masaru
M
Murakami
Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
Tohru
T
Matsui
Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address: mfunaba@kais.kyoto-u.ac.jp.
Masayuki
M
Funaba
D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D056945:Hep G2 Cells; D064451:Hepcidins / Q000235:genetics*; D006801:Humans; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014158:Transcription, Genetic
D019485:Bone Morphogenetic Proteins; D064451:Hepcidins; D013755:Tetradecanoylphorbol Acetate
AP-1; BMP; Hepcidin; TPA-Responsive element