I<scp>RON</scp> R<scp>EGULATORY</scp> P<scp>ROTEINS AND THE</scp> M<scp>OLECULAR</scp> C<scp>ONTROL OF</scp> M<scp>AMMALIAN</scp> I<scp>RON</scp> M<scp>ETABOLISM</scp>

Eisenstein, Richard S.

doi:10.1146/annurev.nutr.20.1.627

Cited by 609 publications

(243 citation statements)

References 218 publications

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“…Taken together, these data and considerations are in favor of the nitrite/H 2 O 2 /peroxidase pathway as the major IRP-1 nitrating pathway in physiologically activated macrophages. IRP-1 is a bifunctional metalloprotein in which the aconitase and IRE-binding activities are mutually exclusive, depending on the presence or absence of its [4Fe-4S] cluster (1). In the present study, we show that endogenous nitration of IRP-1 in activated macrophages boosted with PMA is associated with impairment of both IRP-1 functions.…”

Section: Endogenous Irp-1 Nitration In Activated Macrophagessupporting

confidence: 55%

“…In mammalian cells, iron regulatory proteins (IRP-1 and -2) 1 marshal iron trafficking, storage, and availability by modulating ferritin and transferrin receptor expression at a post-transcriptional level (1). They operate by interacting with one or several specific stem-loop RNA structures called iron-responsive elements (IREs), which are located in untranslated regions (UTR) of several mRNAs.…”

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confidence: 99%

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Endogenous Nitration of Iron Regulatory Protein-1 (IRP-1) in Nitric Oxide-producing Murine Macrophages

González

Drapier

Bouton

2004

Journal of Biological Chemistry

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Iron regulatory protein-1 (IRP-1) is a bifunctional [4Fe-4S] protein that functions as a cytosolic aconitase or as a trans-regulatory factor controlling iron homeostasis at a post-transcriptional level. Because IRP-1 is a sensitive target protein for nitric oxide (NO), we investigated whether this protein is nitrated in inflammatory macrophages and whether this post-transcriptional modification changes its activities. RAW 264.7 macrophages were first stimulated with interferon-␥ and lipopolysaccharide (IFN-␥/LPS) and then triggered by phorbol 12-myristate 13-acetate (PMA) in order to promote co-generation of NO In mammalian cells, iron regulatory proteins (IRP-1 and -2) 1 marshal iron trafficking, storage, and availability by modulating ferritin and transferrin receptor expression at a post-transcriptional level (1). They operate by interacting with one or several specific stem-loop RNA structures called iron-responsive elements (IREs), which are located in untranslated regions (UTR) of several mRNAs. At low intracellular iron concentration, IRPs bind to the IRE of ferritin mRNA at its 5Ј-UTR and block translation, whereas they stabilize transferrin receptor mRNA through direct interactions with several IRE motifs in the 3Ј-UTR. One critical discrepancy between the two IRPs is that only IRP-1 functions as a cytosolic aconitase when holding a [4Fe-4S] cluster, which masks the IRE-binding domain. In this case, holo-IRP-1 catalyzes the interconversion of citrate into isocitrate via the intermediate formation of cis-aconitate, as does its mitochondrial counterpart in the Krebs cycle (2).It is well documented that nitric oxide (NO ⅐ ) also stimulates the trans-regulatory activity of IRP-1 and consequently disturbs iron homeostasis in various cellular systems exposed to inflammatory conditions (3). More specifically, NO ⅐ converts IRP-1 from an aconitase to a trans-regulatory factor by directly targeting its [Fe-S] cluster leading to its complete disassembly (4 -6). In this way, the apoprotein generated by NO ⅐ , in a reducing environment, tightly binds to IRE(s) and exerts its iron-regulatory function (7,8). In the early 1990s, it was reported that simultaneous production of NO ⅐ and superoxide (O 2 . ) by activated macrophages led to intracellular formation of peroxynitrite (9). Since NO ⅐ can turn into a powerful oxidizing and nitrating agent such as peroxynitrite in vivo, its reactivity toward key enzymes of cellular metabolism has become an active area of investigation (10, 11). Regarding IRP-1, in vitro studies have demonstrated that peroxynitrite causes the direct inhibition of its aconitase activity by promoting complete disruption of the [4Fe-4S] cluster but, unlike NO ⅐ , without stimulating the IRE-binding activity of IRP-1 (5-6, 12). These data suggest that peroxynitrite might generate additional posttranslational modifications of IRP-1 in comparison with NO ⅐ . Interestingly, recent biochemical and resonance Raman studies have allowed the detection of tyrosine nitration on pure recombinant IRP-1 by sy...

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Section: Endogenous Irp-1 Nitration In Activated Macrophagessupporting

confidence: 55%

mentioning

confidence: 99%

Endogenous Nitration of Iron Regulatory Protein-1 (IRP-1) in Nitric Oxide-producing Murine Macrophages

González

Drapier

Bouton

2004

Journal of Biological Chemistry

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“…Fe is an essential element involved in several biological processes ranging from electron transport to ATP production, heme and DNA synthesis (Eisenstein, 2000;Arredondo and Nunez, 2005). However, low tissue Fe isn't expected at tissues surrounding a tumor, as literature suggests that excessive Fe is associated with adverse effects resulted from oxidative stress induced (Reddy and Clark, 2004).…”

Section: Discussionmentioning

confidence: 99%

Serum Levels of Trace Elements in Patients with Prostate Cancer

Kaba¹,

Pirinççi²,

Yüksel³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Trace elements are major components of biological structures; however, excessive levels of these elements can be toxic. Materials and Methods: In the present study, serum levels of trace elements were measured in 30 patients with newly diagnosed as prostate cancer and 32 healthy volunteer by using furnace atomic absorption spectrophotometry. Results: It was found that there was an increase in serum levels of Co, Cu, Mg and Pb (p<0.05), whereas a decrease in serum levels of Fe, Mn, and Zn levels in patients with prostate cancer (p<0.05). Conclusions: These changes may be important in the pathogenesis of prostate cancers; however, further prospective studies are needed to identify relationships between prostate cancer and trace elements.

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“…C-ACO and M-ACO have been used as sensitive biomarkers for increased oxidative stress because their [4Fe-4S] clusters, which are required for enzymatic activity, are accessible to low molecular weight compounds including agents that disrupt Fe-S clusters such as O 2 À , NO, ONOO À , and OH (Drapier, 1997;Gardner, 1997;Eisenstein, 2000). In the case of C-ACO, interest has focused on the role of such agents in promoting loss of the Fe-S cluster and possible conversion of the protein to iron regulatory protein 1 (IRP1), which post-transcriptionally regulates the synthesis of proteins required for the maintenance of iron homeostasis.…”

Section: Discussionmentioning

confidence: 99%

CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

et al. 2004

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Mice deficient in CuZn superoxide dismutase (CuZn-SOD) showed no overt abnormalities during development and early adulthood, but had a reduced lifespan and increased incidence of neoplastic changes in the liver. Greater than 70% of Sod1À/À mice developed liver nodules that were either nodular hyperplasia or hepatocellular carcinoma (HCC). Cross-sectional studies with livers collected from Sod1À/À and age-matched þ / þ controls revealed extensive oxidative damage in the cytoplasm and, to a lesser extent, in the nucleus and mitochondria from as early as 3 months of age. A marked reduction in cytosolic aconitase, increased levels of 8-oxo dG and F2-isoprostanes, and a moderate reduction in glutathione peroxidase activities and porin levels were observed in all age groups of Sod1À/À mice examined. There were also age-related reductions in Mn superoxide dismutase activities and carbonic anhydrase III. Parallel to the biochemical changes, there were progressive increases in the DNA repair enzyme APEX1, the cell cycle control proteins cyclin D1 and D3, and the hepatocyte growth factor receptor Met. Increased cell proliferation in the presence of persistent oxidative damage to macromolecules likely contributes to hepatocarcinogenesis later in life.

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IRON REGULATORY PROTEINS AND THE MOLECULAR CONTROL OF MAMMALIAN IRON METABOLISM

Cited by 609 publications

References 218 publications

Endogenous Nitration of Iron Regulatory Protein-1 (IRP-1) in Nitric Oxide-producing Murine Macrophages

Endogenous Nitration of Iron Regulatory Protein-1 (IRP-1) in Nitric Oxide-producing Murine Macrophages

Serum Levels of Trace Elements in Patients with Prostate Cancer

CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

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