Jerry Kaplan

..It is hypothesized that the biochemical feature common to these ataxias is increased oxidant damage either through increased oxidants or decreased anti-oxidants...

..Two reports in the current issue of Molecular Cell suggest an unexpected candidate for the Tf-independent system...

..Genetic disorders of iron overload of iron-linked anemia can be explained by changes in the level of hepcidin or ferroportin and of the ability of ferroportin to be internalized by hepcidin...

..In this review, we describe how the budding yeast Saccharomyces cerevisiae utilizes multiple mechanisms to optimize iron usage under iron limiting conditions...

..These observations indicate that there are probably multiple pathways for protein sorting/MVB vesicle formation in human cells and that HIV-1 does not utilize an ESCRT-II-dependent pathway to leave the cell...

..These mutations are within the second hydrophobic domain of the transporters and show the essential nature of this domain in the specificity of metal transport...

..Depletion of proteins involved in multivesicular body trafficking (Endosome Sorting Complex Required for Transport proteins), by small-interfering RNA, reduces the trafficking of Fpn-green fluorescent to the lysosome...

..These results show that the Fra-Grx complex is an intermediate between the production of mitochondrial Fe-S clusters and transcription of the iron regulon...

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..These results suggest that mitochondria-induced oxidant damage is responsible for activating Ccc1 and that Fra1 and Tsa1 can reduce oxidant damage...

..Iron affects the sulfhydryl status of Yap5, which is indicative of the generation of intramolecular disulfide bonds. These results show that Yap5 is an iron-sensing transcription factor and that iron regulates transcriptional activation...

..Deletion of TSA1, which encodes a peroxiredoxin, exacerbated iron toxicity in Δccc1 cells under both aerobic and anaerobic conditions, suggesting a unique role for Tsa1 in iron toxicity...

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..We demonstrate that Fpn can transport zinc and can protect zinc sensitive cells from high zinc toxicity...

..The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses...

..Regulation of transcription by Fe-S biosynthesis represents a mechanism by which cellular iron acquisition is integrated with mitochondrial iron metabolism...

..The affinity of hepcidin for the HBD permits a rapid, sensitive assay of hepcidin from all species and yields insights into the evolution of hepcidin...

..These results suggest that deletion of mitochondrial proteins can alter vacuolar metal homeostasis. The data also indicate that increased expression of the AFT1-regulated gene(s) can disrupt copper homeostasis...

..We conclude that the Yap5-mediated induction of TYW1 provides protection from high iron toxicity by the consumption of free cytosolic iron through the formation of protein-bound iron-sulfur clusters...

..We hypothesize that transcription of the siderophore transporter ARN1 permits yeast to accumulate iron in the absence of oxygen and to deny iron to competing organisms...

..Our data indicate that Pkr1p functions together with the other V-ATPase assembly factors in the ER to efficiently assemble the V-ATPase membrane sector...

..These results suggest that the high iron transcriptional response, as well as the low iron transcriptional response, senses iron-sulfur clusters...

..These data provide strong evidence for a role for Mon1a in anterograde trafficking through the secretory apparatus...

..Secretion of ferritin chains provides a mechanism that limits ferritin nanocage assembly and ferritin-mediated iron sequestration in the absence of the translational inhibition of ferritin synthesis...

..Thus, ferritin degradation can occur through two different mechanisms...

..These results suggest that substrate selection involves co-operativity between transmembrane domains...

..These results suggest that mitochondrial iron accumulation is tightly regulated and that controlling mitoferrin levels within the mitochondrial membrane provides a mechanism to regulate mitochondrial iron levels...

..These results provide a molecular explanation for the dominant inheritance of hepcidin resistant iron overload disease...

..Our results show that the activity of mitoferrin1 is required to manage an increase in heme synthesis. The data also show that alterations in heme synthesis within hepatocytes can lead to protoporphyria and hepatotoxicity...

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..Finally, we provide evidence that under heme-depleted conditions, yeast are able to regulate mitochondrial iron uptake and do not accumulate pathologic iron concentrations, as is seen when iron-sulfur cluster synthesis is disrupted...

..These results identify a hepcidin-independent regulation of Fpn that can result in alterations in iron homeostasis...

..Regulation of ferroportin is critical for iron homeostasis as alterations in ferroportin may result in either iron deficiency or iron overload. This article is part of a Special Issue entitled: Cell Biology of Metals...

..We further show that overexpression of the Chs1/Lyst protein gives rise to a faster rate of lysosome fission. These results indicate that Chs1/Lyst regulates lysosome size by affecting fission...

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..Hepcidin expression induced by B burgdorferi was mediated primarily by activation of Toll-like receptor 2...

..These results indicate that ferritin degradation occurs by 2 routes: a DFO-induced entry of ferritin into lysosomes and a cytosolic route in which iron is extracted from ferritin before degradation by the proteasome...

..Together, these data suggest that Bph1p associates with a membrane and is involved in protein sorting and cell wall formation...

..Membrane-associated Vta1p co-purified with Vps60p, suggesting that Vta1p is a class E Vps protein that interacts with Vps60p on a prevacuolar compartment...

..in this issue of Developmental Cell show that ferritin, through its binding to the cell surface Scara5 receptor, can also deliver iron to cells, permitting kidney organogenesis...

..This gene contains two introns, has homologues in other Saccharomyces strains, and shows weak homology to a component of the vacuolar H+-ATPase found in organisms as diverse as insect and cow...

..The requirement for a ferroxidase to maintain iron transport activity represents a new mechanism of regulating cellular iron export, a new function for Cp and an explanation for brain iron overload in patients with aceruloplasminemia...

..These results suggest that high levels of citrate may promote iron-mediated tissue damage...

..This review will discuss the advances made in understanding the clinical aspects of the syndrome and the function of CHS1/LYST/Beige...

..Ferroportin degradation can occur by hepcidin-dependent and hepcidin-independent internalization. Ferroportin expression is regulated transcriptionally and posttranslationally...

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..Cells expressing PDR1(R821H) also showed increased resistance to copper and manganese because of increased metal export. These results suggest that expression of PDR1-regulated genes affects both efflux and storage of transition metals...

..These results demonstrate that recombinant HJV may be a useful therapeutic agent for treatment of the anemia of chronic disease, a disorder resulting from high levels of hepcidin expression...

..These results support the hypothesis that the dominant inheritance of Fpn-iron overload disease is due to the dominant-negative effects of mutant Fpn proteins...

..Two recent papers (Oliveira et al., 2009; Vecchi et al., 2009) show that the UPR modulates transcription of the hormone hepcidin, which controls plasma iron levels and perhaps innate immunity...

..These studies define a protein network required for human MVB biogenesis and indicate that the entire network participates in the release of HIV and probably many other viruses...

..Expression of wild-type ferroportin or hepcidin-resistant ferroportin (N144H) does not affect erythropoiesis. Zebrafish provides a facile way of identifying which ferroportin mutants may lead to macrophage iron loading...

..Discoveries of iron transporters and insights into their regulation have provided important information about iron metabolism and genetic iron disorders...

..Both mice had an increase in serum ferritin but a decrease in serum transferrin saturation. In conclusion, serum hepcidin regulation in C3H/HeJ mice does not appear to be solely dependent upon TLR4 or IL-6...

..These results demonstrate a direct role of Yfh1p in the formation of Fe-S clusters and indicate that mitochondrial iron export requires Fe-S cluster biosynthesis...

..The presence of the BEACH and WD40 domains defines a family of genes that encode extremely large proteins...

..Ferric iron (Fe(3+)) transport systems are highly specific for iron, and in vertebrates are used to target iron transport to specific tissues...

..The identification of CHS1/Beige has defined a family of genes containing a common BEACH motif. The function of these proteins in vesicular trafficking remains unknown...

..In this issue of Molecular Cell, Sanvisens et al. (2011) report a new mechanism for regulation of yeast ribonucleotide reductase activity that occurs during iron deprivation...

..This substrate preference switch is mediated by the membrane protein stomatin and is an evolutionary adaptation to vitamin C deficiency...

..Results from studies on S. cerevisiae have been used to understand metal transport in other species of yeast as well as in higher eukaryotes...

..These results suggest that the Beige protein interacts with at least two different partners and that the Beige protein affects cellular events, such as nuclear PtdIns(4,5)P2 localization, in addition to lysosome size...

..The posttranslational regulation of ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the cell surface...

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..The behavior of mutant Fpn in cell culture and the ability of mutant Fpn to act as a dominant negative explain the dominant inheritance of the disease as well as the different patient phenotypes...

..These mice were viable and did not develop anomalies of motor coordination, iron metabolism or response to iron loading. Repeats were meiotically and mitotically stable...

..Our data show that mfrn functions as the principal mitochondrial iron importer essential for haem biosynthesis in vertebrate erythroblasts...

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..Thus, the trafficking of heme, and not just elemental iron, facilitates erythropoiesis and systemic iron balance...

..These results show the conservation of function of copper-containing proteins in eukaryotic iron metabolism...

..Mon1a is also important for trafficking of cell-surface and secreted molecules unrelated to iron metabolism, suggesting that it has a fundamental role in the mammalian secretory apparatus...

..Thus, the severe symptoms exhibited by CHS patients may also include defects in the ability of cells to repair plasma membrane lesions...

..In summary, FAN mediates activation of N-SMase as well as regulation of lysosome size by signaling pathways that operate independent from activation/membrane recruitment of PKC...

..We have uncovered a fundamental aspect of seed biology that will ultimately aid the development of nutrient-rich seed, benefiting both human health and agricultural productivity...

..These studies demonstrate sophisticated systems that limit iron uptake under conditions of abundance and lead to metabolic remodeling when iron is limited...

..These findings uncover a connection between haem biosynthesis and Fe-S clusters, indicating that haemoglobin production in the differentiating red cell is regulated through Fe-S cluster assembly...

..G71D and K83R, substitutions previously described in humans, did not affect hepcidin activity. Apart from the essential nature of the N-terminus, hepcidin structure appears permissive for mutations...

..We suggest that FpnG80S represents a class of Fpn mutants whose behavior in vitro does not explain the patients' phenotype...

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..These results demonstrate that mutations in Fpn resulting in protein mislocalization act in a dominant-negative fashion to cause disease, and the Fpn(ffe) mouse represents the first mouse model of ferroportin disease...

..Our studies will provide information on how alterations in ferroportin result in disease and create new opportunities to manage and diagnose human diseases due to altered iron metabolism. ..

..We propose to determine the mechanism by which the absence of heme affects iron transport. ..

..The overall goal of the Bioiron (2005) World Congress is the international dissemination of important new research results to investigators working in the field of iron metabolism. ..

..They will determine if defective heme biosynthesis results, as it does in reticulocytes, in excessive iron deposition in mitochondria. These studies will help define the regulation of mitochondrial iron metabolism. ..

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..These studies will probe the mechanism that underlines the regulation of iron export by hepcidin and will define the roles of hepcidin and Fpn in iron physiology. ..

..Our studies on macrophage functions will provide information that may be used to manage and diagnose human diseases that affect vesicular trafficking and lung homeostasis. ..

..We also propose to identify mechanisms that regulate iron storage. Our studies will provide information that may be used to manage and diagnose human diseases to altered iron metabolism. ..

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..The overall goal of the BioIron 2007 World Congress is the international dissemination of important new research results to investigators working in the field of iron metabolism. ..

..We request funding for 25 fellowships per year. This number is based on the past number of applicants and on further training for highly meritorious applicants. ..

..Our studies will clarify the mechanisms that regulate cellular iron content and the role of iron in normal and pathological processes. ..

..These studies will yield insight into the normal mechanisms of macrophage activities and into derangements which may compromise lung function...

..This latter study will yield insights into the mechanism of pulmonary hemosiderosis. The studies will increase our understanding of the mechanisms of alveolar macrophage membrane dynamics and the role of macrophages in lung disease...

..These studies will yield information on the mechanisms of tissue iron overload and the role of iron in normal and pathological processes...

..These studies will probe the mechanism that underlines the regulation of iron export by hepcidin and will define the roles of hepcidin and Fpn in iron physiology. ..