H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload

Ferreira, Chrystophe; Santambrogio, Paolo; Martin, M. E.; Andrieu, Valérie; Feldmann, Gérard; Hénin, Dominique; Beaumont, Carole

doi:10.1182/blood.v98.3.525

Cited by 84 publications

(52 citation statements)

References 34 publications

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“…2D). No IRP2 binding activity was detected, as previously observed in mouse tissues [15] or human placenta [16]. Since there is no change in placenta iron content and no modification in the IRE binding activity of the IRP, it is likely that the strong reduction in TfR1 mRNA results from transcriptional repression of the TfR1 gene, rather than from degradation of TfR1 mRNA.…”

Section: Hepcidin Induces Tfr1 Mrna Downregulation In Placentasupporting

confidence: 56%

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Transferrin receptor 1 mRNA is downregulated in placenta of hepcidin transgenic embryos

et al. 2004

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We have previously shown that hepcidin transgenic embryos are severely anemic and die around birth. Here, we report that embryonic hepcidin transgene expression decreases transferrin receptor 1 (TfR1) mRNA level in placenta, as shown by cDNA microarray analysis and quantitative RT-PCR, by a mechanism which is independent of placenta iron content and iron responsive element/iron regulatory protein (IRE/IRP) activity. On the contrary, iron injections into pregnant mothers result in increased placenta iron and ferritin content, and reduced IRE binding activity of IRP1 leading to decreased TfR1 mRNA level. Taken together, these results suggest that hepcidin action on placenta is mostly through transcriptional downregulation of the iron uptake machinery.

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Section: Hepcidin Induces Tfr1 Mrna Downregulation In Placentasupporting

confidence: 56%

“…IRE/IRP interactions were measured as previously described [15], by incubating a [ 32 P]-labeled IREHFt mRNA probe (3 · 10 4 cpm at 10 4 cpm/ng) transcribed in vitro from pIL2CAT with 5 lg of cytoplasmic extracts. After 15 min.…”

Section: Rna Gel Shift Assays Of Irp Activitymentioning

confidence: 99%

Transferrin receptor 1 mRNA is downregulated in placenta of hepcidin transgenic embryos

et al. 2004

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“…Therefore, a more relevant animal model to explore the relationship between ferritins and apoB is a mouse engineered to have altered levels of tissue ferritins without iron deposition in tissues. One such model is the ferritin H (ϩ/Ϫ) mouse (40), which has decreased levels of ferritin H and increased levels of ferritin L. We anticipate that this mouse model will help elucidate the intersection between the pathways used by ferritins and apoB.…”

Section: The Block In Apob Secretion Induced By Ferritin H or L Is Nomentioning

confidence: 99%

Ferritins Can Regulate the Secretion of Apolipoprotein B

Hevi

Chuck

2003

Journal of Biological Chemistry

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Apolipoprotein B is secreted with atherogenic lipids as lipoprotein particles from hepatocytes. Regulation of the secretion of apolipoprotein B is largely post-translational and reflects the balance between processes that leads to particle assembly or to intracellular degradation. Previously, we conducted a proteomic screen to find proteins that bind apolipoprotein B in rat liver microsomes. We identified ferritin heavy and light chains in this screen among other proteins and showed that the two ferritins bind apolipoprotein B directly in vitro. In hepatocytes and other cells, ferritin heavy and light chains form cytosolic cages that store iron. We now show that ferritin heavy or light chains post-translationally inhibit the secretion of apolipoprotein B without altering the export of other hepatic proteins including albumin, factor XIII, and apolipoprotein A-I. This inhibition of apolipoprotein B secretion is not due to diminished lipid synthesis and can be partially overcome by stimulating triglyceride synthesis. The block in apolipoprotein B secretion by ferritins leads to an increase in endoplasmic reticulum-associated degradation of the apolipoprotein. Thus, despite being cytosolic proteins without known chaperone activity, ferritins can specifically regulate the secretion of apolipoprotein B post-translationally. The metabolic pathways for iron storage and intercellular cholesterol and triglyceride transport could intersect. Apolipoprotein B (apoB)1 is the large (molecular mass greater than 500 kDa), hydrophobic protein that is secreted with cholesterol esters and triglycerides in very low density lipoprotein particles (1). Regulation of the secretion of apoB from hepatocytes occurs largely post-translationally (2). Newly synthesized apoB can be assembled with lipids into lipoprotein particles or degraded intracellularly (3, 4), and it is the balance assembly and degradation that determines secretion. Since cholesterol esters and triglycerides can only be secreted into the bloodstream with apoB, factors that regulate the secretion of this protein likewise impact plasma levels of these atherogenic lipids.In HepG2 cells, unassembled apoB can be targeted for endoplasmic reticulum-associated degradation (ERAD) via the ubiquitin-proteasome pathway (5-8). ApoB is marked with ubiquitin for degradation even before it is finished being translated (7, 9, 10) while the protein is still in the translocation channel (8, 11). Furthermore, factors that slow the translocation of apoB increase the number of ubiquitin-conjugated apoB molecules marked for degradation by proteasomes (8) suggesting that translocation is a point of regulation of secretion. Other factors also regulate secretion since some ubiquitin-conjugated apoB can be deubiquitinylated and secreted (11). In HepG2 cells, other non-ERAD routes for disposal exist but are not sensitive to agents that inhibit proteasomes (12-15).The intertwined processes of lipidation, folding, translocation, intracellular degradation, quality control, and regulation of the secret...

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“…The importance of ferritin is supported by its ubiquitous expression, highly conserved protein structure (6,7), and embryonic lethality in ferritin H knockout mice (8). The H subunit has ferroxidase activity, which is involved in the oxidation and incorporation of ferrous iron into the ferritin shell, whereas the L subunit plays a role in the formation of the iron core (6,7).…”

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PIAS3 Interacts with ATF1 and Regulates the Human Ferritin H Gene through an Antioxidant-responsive Element

Iwasaki

Hailemariam²,

Tsuji

2007

Journal of Biological Chemistry

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Gene transcription is coordinately regulated by the balance between activation and repression mechanisms in response to various external stimuli. Ferritin, composed of H and L subunits, is the major intracellular iron storage protein involved in iron homeostasis. We previously identified an enhancer, termed antioxidant-responsive element (ARE), in the human ferritin H gene and its respective transcriptional activators including Nrf2 and JunD. Here we found that ATF1 (activating transcription factor 1) is a transcriptional repressor of the ferritin H ARE. Subsequent yeast two-hybrid screening identified PIAS3 (protein inhibitor of activated STAT3) as an ATF1-binding protein.Further investigation of the human ferritin H ARE regulation showed that 1) PIAS3 reversed ATF1-mediated repression of the ferritin H ARE; 2) ATF1 was sumoylated, but PIAS3, a SUMO E3 ligase, did not appear to play a major role in SUMO1-mediated ATF1 sumoylation or ATF1 transcription activating function; 3) PIAS3 decreased ATF1 binding to the ARE; and 4) ATF1 knockdown with siRNA increased ferritin H expression, whereas PIAS3 knockdown decreased basal expression and oxidative stress-mediated induction of ferritin H. These results suggest that PIAS3 antagonizes the repressor function of ATF1, at least in part by blocking its DNA binding, and ultimately activates the ARE. Collectively our results suggest that PIAS3 is a new regulator of ATF1 that regulates the ARE-mediated transcription of the ferritin H gene.Iron is a vital element that participates in numerous metabolic functions in all organisms; however, excess iron is harmful because it catalyzes formation of hydroxyl radicals by reacting with hydrogen peroxide in the Fenton chemistry (1). Hydroxyl radicals as well as other reactive oxygen species potentially damage cellular components such as proteins, membrane lipids, and nucleic acids, which have been implicated in the etiology of many human diseases and disorders including neurodegenerative disease, cancer, and aging (2-4). Therefore, cells must tightly control cellular iron levels under various physiological conditions by storing excess iron in a nontoxic but bioavailable form.Ferritin is the major intracellular iron-binding protein comprised of 24 subunits of the heavy (H) and light (L) chains (5). The importance of ferritin is supported by its ubiquitous expression, highly conserved protein structure (6, 7), and embryonic lethality in ferritin H knockout mice (8). The H subunit has ferroxidase activity, which is involved in the oxidation and incorporation of ferrous iron into the ferritin shell, whereas the L subunit plays a role in the formation of the iron core (6, 7). Post-transcriptional regulation of ferritin and the transferrin receptor by iron was elegantly characterized by experiments that showed iron-regulated interactions between trans-acting iron regulatory proteins and iron-responsive elements in these mRNAs (9 -11). Ferritin expression is also regulated at the transcriptional level in an iron-independent manner during in...

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H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload

Cited by 84 publications

References 34 publications

Transferrin receptor 1 mRNA is downregulated in placenta of hepcidin transgenic embryos

Transferrin receptor 1 mRNA is downregulated in placenta of hepcidin transgenic embryos

Ferritins Can Regulate the Secretion of Apolipoprotein B

PIAS3 Interacts with ATF1 and Regulates the Human Ferritin H Gene through an Antioxidant-responsive Element

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