Regulation of Hepcidin and Iron-Overload Disease

Lee, Pauline L.; Beutler, Ernest

doi:10.1146/annurev.pathol.4.110807.092205

Cited by 160 publications

(153 citation statements)

References 133 publications

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“…However, because protein-level inhibition of ferroportin is linked to high mRNA expression of hepcidin (36), and hepcidin is expressed in breast cells (Fig. 1 and fig.…”

Section: Resultsmentioning

confidence: 99%

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

Pinnix¹,

Miller²,

Wang³

et al. 2010

Science Translational Medicine

245

278

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Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. Ferroportin is the only known mechanism for export of intracellular non–heme-associated iron; its stability is regulated by the hormone hepcidin. Although ferroportin profoundly affects concentrations of intracellular iron in tissues important for systemic iron absorption and trafficking, ferroportin concentrations in breast cancer and their influence on growth and prognosis have not been examined. We demonstrate here that both ferroportin and hepcidin are expressed in cultured human breast epithelial cells and that hepcidin regulates ferroportin in these cells. Further, ferroportin protein is substantially reduced in breast cancer cells compared to nonmalignant breast epithelial cells; ferroportin protein abundance correlates with metabolically available iron. Ferroportin protein is also present in normal human mammary tissue and markedly decreased in breast cancer tissue, with the highest degree of anaplasia associated with lowest ferroportin expression. Transfection of breast cancer cells with ferroportin significantly reduces their growth after orthotopic implantation in the mouse mammary fat pad. Gene expression profiles in breast cancers from >800 women reveal that decreased ferroportin gene expression is associated with a significant reduction in metastasis-free and disease-specific survival that is independent of other breast cancer risk factors. High ferroportin and low hepcidin gene expression identifies an extremely favorable cohort of breast cancer patients who have a 10-year survival of >90%. Ferroportin is a pivotal protein in breast biology and a strong and independent predictor of prognosis in breast cancer.

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“…However, because protein-level inhibition of ferroportin is linked to high mRNA expression of hepcidin (36), and hepcidin is expressed in breast cells (Fig. 1 and fig.…”

Section: Resultsmentioning

confidence: 99%

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

Pinnix¹,

Miller²,

Wang³

et al. 2010

Science Translational Medicine

245

278

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“…Regulation of Fpn at the translational and posttranslational level is well described, 23 but little is known about transcriptional regulation of Fpn. Previous studies have shown that FPN1 mRNA is increased in vivo in response to iron deficiency anemia and hereditary hemochromatosis 24,25 but is unaffected by dietary iron loading.…”

Section: Discussionmentioning

confidence: 99%

Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux

Troadec¹,

Ward²,

Lo³

et al. 2010

Blood

120

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IntroductionFerroportin (Fpn) is the only known mammalian iron exporter and plays an essential role in the entry of iron into plasma (for review, see Wessling-Resnick 1 and Wrighting and Andrews 2 ). Fpn is most highly expressed in cells that play a major role in iron acquisition: duodenal enterocytes, macrophages, hepatocytes and syncytial trophoblasts. Fpn, however, can be expressed on a wide variety of other cell types in response to heme 3,4 or iron. [5][6][7] Iron can regulate Fpn expression through transcriptional and translational mechanisms. Ferroportin1 (FPN1), the gene that encodes Fpn, contains a 5Ј iron-responsive element (IRE), which places its translation under the control of iron regulatory proteins. It is thought that the increased expression of Fpn by iron is a response to cellular iron load, as increased cytosolic iron would lead to increased iron export.FPN1 mRNA levels are also increased when cells are exposed to transition metals such as zinc, manganese, cadmium, copper, and other transition metals. 6 In both J774 cells and Caco cells, the increase in Fpn expression resulted in increased iron export. What is unclear, however, is the physiologic function of transition metal-induced expression of Fpn. Iron export in response to increased transition metals may protect cells from transition metal toxicity, perhaps by reducing the potential for iron-induced Fenton chemistry. Alternatively, Fpn might export other metals in addition to iron and thus increased expression of Fpn would directly protect cells from metal toxicity.In this study, we identify at least 1 mechanism by which transition metals induce Fpn expression. We show that zinc and cadmium can activate FPN1 transcription through the Metal Transcription Factor-1 (MTF-1). We also demonstrate that Fpn transports zinc and can protect cells from zinc toxicity. MethodsVector pcDNA3.1-mouse-MTF1-Flag was a gift from Dr G. K. Andrews. 8 We produced a chimera pcDNA3.1-mouse/human-MTF1-Flag by switching the mouse fragment with the human corresponding fragment between KpnI/FseI sites of mouse MTF1-Flag. To express an shRNA against mouse MTF-1, we inserted a double strand oligonucleotide targeting the gtacttcgccaccgctgta sequence of mouse MTF-1 into BamHI and EcoRI sites of pSIREN-DNR-DSRed (Clontech) according to manufacturer's instructions. The mouse/human chimera MTF-1 is resistant to shRNA against mouse MTF-1. The pGL3-control vector (Promega) was modified to perform the luciferase assay. The SV40 promoter was removed by HindIII/NheI digestion and the mouse Fpn promoter (starting at Ϫ2378, Ϫ1154, and Ϫ623 from the TATAA box) was amplified by polymerase chain reaction (PCR) and inserted using same restriction sites. The 5ЈIRE in the FPN1 promoter was deleted by BamHI/SamI digestion as described. 9 The putative metal-responsive elements (MREs) in the Fpn promoter in pGL3 were mutagenized by PCR to produce TCCAGCA*GA*AT*CT*CG and TGGAAGAA*TT*CG*AG (the consensus sequence is underlined, *mutagenized base). Fpn-green fluorescent protein (GFP) was car...

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“…Hereditary hemochromatoses are a group of genetic disorders that are characterized by body iron overload due to excessive absorption of dietary iron and resulting organ deposition and subsequent injury [21]. Hepcidin dysregulation (deficiency or resistance) is a common feature among these diseases and can be used to screen for HH in patients with increased ferritin concentrations [22]. Also, it can be used to determine phlebotomy intervals as hepcidin concentrations often return to normal after phlebotomy treatments [23].…”

Section: Inherited Disorders Of Iron Metabolismmentioning

confidence: 99%

Peering into the future: Hepcidin testing

2013

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Hepcidin, a small 25 amino acid peptide, has been well established as the iron regulatory hormone. Its expression is upregulated in response to iron and inflammatory cytokines, and downregulated in anemic or hypoxic states. Hepcidin decreases iron export into the plasma by binding to and inducing the degradation of ferroportin, an iron channel located on macrophages and the basolateral surface of enterocytes. This leads to decreased absorption of parental iron by the enterocytes, reduced recycling of erythrocyte iron by macrophages, and increased iron stores in the hepatocytes. Although hepcidin assays are not currently approved for clinical use in the United States, there is much interest in the potential use of this biomarker for management of iron related medical conditions. This review briefly summarizes the current hepcidin test platforms under investigation and the challenges associated with development of a clinical assay for this biomarker. In addition, selected potential future applications hepcidin testing in the clinical setting are addressed. Am. J.

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Regulation of Hepcidin and Iron-Overload Disease

Cited by 160 publications

References 133 publications

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux

Peering into the future: Hepcidin testing

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