The regulation of hepcidin expression by serum treatment: Requirements of the BMP response element and STAT- and AP-1-binding sites
The regulation of hepcidin expression by serum treatment: Requirements of the BMP response element and STAT- and AP-1-binding sites
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DOI：
10.1016/j.gene.2014.08.037
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发表时间：
2014-11-10
期刊：
影响因子：
3.5
通讯作者：
Funaba, Masayuki
中科院分区：
文献类型：
--
作者：
Kanamori, Yohei;Murakami, Masaru;Funaba, Masayuki
作为全身铁代谢的中枢调节因子，海普西丁的表达受骨形态发生蛋白(BMP)途径的转录调控。然而，BMP途径以外的其他因素也参与了海普西丁的表达调控。在本研究中，我们发现，血清处理增加了原代肝细胞、HepG2细胞或Hepa1-6细胞中Hepsidin的表达和转录，而不诱导Smad1/5/8的磷酸化。用骨形态发生蛋白I型受体的抑制剂LDN-193189共同处理，可取消这种海普西丁的诱导。利用突变记者的记者分析发现，在血清诱导的HepG2细胞中，BMP反应元件-1(BMP-Re1)、信号转导和转录激活因子(STAT)和激活蛋白(AP)-1结合位点参与其中。血清处理可诱导原代肝细胞和HepG2细胞表达AP-1组分c-fos和JunB。C-fos或JunB的强制表达增强了海普西丁转录对血清处理的反应。相反，显性负性(DN)-c-fos和dN-JunB的表达降低了海普西丁的转录。目前的研究表明，血清中含有刺激海普西丁转录的因子。基础骨形态发生蛋白活性对于血清诱导的海普西丁转录是必不可少的，尽管血清处理不刺激骨形态发生蛋白途径。血清处理对c-fos和JunB的诱导可能通过与BMP介导的信号转导协同作用来刺激海普西丁的转录。考虑到AP-1是由各种刺激诱导的，本研究结果表明，海普西丁的表达受到比先前认为的更多不同因素的调控。(C)2014爱思唯尔B.V.保留所有权利。
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. (C) 2014 Elsevier B.V. All rights reserved.