Wang, R.-H. et al. A role of SMAD4 in iron metabolism through positive regulation of hepcidin expression. Cell Metab. 2, 399-409

Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Cell Metabolism (Impact Factor: 17.57). 01/2006; 2(6):399-409. DOI: 10.1016/j.cmet.2005.10.010
Source: PubMed


Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-beta, BMP, or IL-6. Our study uncovers a novel role of TGF-beta/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis.

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Available from: Yin Zheng, Mar 28, 2014
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    • "In particular, post-translational modification of Histone H3, one of the core proteins of the nucleosome, regulates transcription and chromatin condensation [48]. Transfection of Smad4 into Smad4-null hepatocytes increases binding of Histone 3 acetylated at lysine 9 (H3K9) to the Hepcidin promoter [4]. Histone acetylation also appears to affect Stat3 binding to the Hepcidin promoter. "
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    ABSTRACT: Hepcidin, a peptide hormone produced in the liver, decreases intestinal iron absorption and macrophage iron release via effects on ferroportin. Bone morphogenic protein and Stat3 signaling regulate Hepcidin's transcription. Hepcidin is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. To generate a tool for identifying small molecules that modulate Hepcidin expression, we stably transfected human hepatocytes (HepG2) cells with a reporter construct containing 2.7 kb of the human Hepcidin promoter upstream of a firefly reporter gene. We used high throughput methods to screen 10,169 chemicals in duplicate for their effect on Hepcidin expression and cell viability. Regulators were identified as chemicals that caused a change > 3 standard deviations above or > 1 standard deviation below the mean of the other chemicals (z-score > 3 or < 1), while not adversely affecting cell viability, quantified by fluorescence assay. Following validation assays, we identified 16 chemicals in a broad range of functional classes that promote Hepcidin expression. All of the chemicals identified increased expression of bone morphogenic protein-dependent and/or Stat3-dependent genes, however none of them strongly increased phosphorylation of Smad1,5,8 or Stat3.
    Blood Cells Molecules and Diseases 12/2014; 53(4). DOI:10.1016/j.bcmd.2014.06.002 · 2.65 Impact Factor
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    • "This theory requires further epidemiological studies and clinical trials for demonstration. Reportedly, cancer may hijack cytokine systems (e.g., SMAD4) via mutation to collect iron for proliferation (Wang et al., 2005). Notably, there is an opposing report that iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans (Noto et al., 2013). "
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    ABSTRACT: Iron is the most abundant metal in the human body and mainly works as a cofactor for proteins such as hemoglobin and various enzymes. No independent life forms on earth can survive without iron. However, excess iron is intimately associated with carcinogenesis by increasing oxidative stress via its catalytic activity to generate hydroxyl radicals. Biomolecules with redox-active sulfhydryl function(s) (thiol compounds) are necessary for the maintenance of mildly reductive cellular environments to counteract oxidative stress, and for the execution of redox reactions for metabolism and detoxification. Involvement of glutathione S-transferase and thioredoxin has long attracted the attention of cancer researchers. Here, I update recent findings on the involvement of iron and thiol compounds during carcinogenesis and in cancer cells. It is now recognized that the cystine/glutamate transporter (antiporter) is intimately associated with ferroptosis, an iron-dependent, non-apoptotic form of cell death, observed in cancer cells, and also with cancer stem cells; the former with transporter blockage but the latter with its stabilization. Excess iron in the presence of oxygen appears the most common known mutagen. Ironically, the persistent activation of antioxidant systems via genetic alterations in Nrf2 and Keap1 also contributes to carcinogenesis. Therefore, it is difficult to conclude the role of iron and thiol compounds as friends or foes, which depends on the quantity/distribution and induction/flexibility, respectively. Avoiding further mutation would be the most helpful strategy for cancer prevention, and myriad of efforts are being made to sort out the weaknesses of cancer cells.
    Frontiers in Pharmacology 08/2014; 5:200. DOI:10.3389/fphar.2014.00200 · 3.80 Impact Factor
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    • "Hepcidin is controlled homeostatically primarily via the bone morphogenetic protein (BMP) pathway. BMPs signal through the phosphorylation of SMAD transcription factors, which bind to a well-studied site on the hepcidin promoter and increase hepcidin transcription (Wang et al., 2005). Inflammation and infection also induce interleukin (IL)-6 or IL-22, which can upregulate hepcidin through the phosphorylation of STAT3 (Nemeth et al., 2003; Armitage et al., 2011). "
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    ABSTRACT: Malaria and iron have a complex but important relationship. Plasmodium proliferation requires iron, both during the clinically silent liver stage of growth and in the disease-associated phase of erythrocyte infection. Precisely how the protozoan acquires its iron from its mammalian host remains unclear, but iron chelators can inhibit pathogen growth in vitro and in animal models. In humans, iron deficiency appears to protect against severe malaria, while iron supplementation increases risks of infection and disease. Malaria itself causes profound disturbances in physiological iron distribution and utilization, through mechanisms that include hemolysis, release of heme, dyserythropoiesis, anemia, deposition of iron in macrophages, and inhibition of dietary iron absorption. These effects have significant consequences. Malarial anemia is a major global health problem, especially in children, that remains incompletely understood and is not straightforward to treat. Furthermore, the changes in iron metabolism during a malaria infection may modulate susceptibility to co-infections. The release of heme and accumulation of iron in granulocytes may explain increased vulnerability to non-typhoidal Salmonella during malaria. The redistribution of iron away from hepatocytes and into macrophages may confer host resistance to superinfection, whereby blood-stage parasitemia prevents the development of a second liver-stage Plasmodium infection in the same organism. Key to understanding the pathophysiology of iron metabolism in malaria is the activity of the iron regulatory hormone hepcidin. Hepcidin is upregulated during blood-stage parasitemia and likely mediates much of the iron redistribution that accompanies disease. Understanding the regulation and role of hepcidin may offer new opportunities to combat malaria and formulate better approaches to treat anemia in the developing world.
    Frontiers in Pharmacology 05/2014; 5:125. DOI:10.3389/fphar.2014.00125 · 3.80 Impact Factor
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