Untitled Document

Research

Richard S. Eisenstein

Ph.D., University of Wisconsin-Madison
Professor, Department of Nutritional Sciences
eisenste@nutrisci.wisc.edu
http://www.nutrisci.wisc.edu/FACULTYPAGES/f_eisenstein.html

Molecular Control of Vertebrate Iron Homeostasis

Our research is aimed at elucidating the mechanisms by which mammalian iron homeostasis is maintained in response to specific physiological and pathological situations. Iron is crucial to cell viability because it is a component of proteins that function in a number of physiological processes including respiration and cell division. However, excess iron can be toxic because it participates in the production of potentially lethal oxidizing agents. Mammals use a number of specific proteins to promote the specific and safe transport, uptake and storage of iron.

Cellular iron homeostasis is regulated through changes in synthesis of proteins involved in the uptake, storage, and utilization of this essential mineral. Synthesis of these proteins is regulated by cytosolic RNA binding proteins, the iron regulatory proteins (IRPs). Under low iron conditions IRPs bind structures in mRNAs specific for these and other proteins thereby regulating the translation or stability of the affected mRNA. In this manner iron and other factors that regulate IRP activity alter the uptake and metabolic fate of iron. IRPs are considered to be central regulators of iron metabolism.

Our studies fall into three areas. First, a major thrust of our research involves understanding how hormones and growth factors modulate iron metabolism through activation of signaling cascades that affect the phosphorylation state of IRP1 or IRP2 and alter the set-point at which IRP1 responds to iron. We have shown that the activity of both IRPs is regulated by changes in their phosphorylation status through the action of protein kinases. We are examining how phosphorylation affects the assembly or disassembly of its Fe-S cluster, a structure which primarily determines IRP1 binding to mRNAs. Second, there are up to 8 mRNA targets for IRPs and we are investigating how structural differences allow IRPs to selectively affect the utilization of these mRNAs. Included in this approach are studies aimed at determining the physiological effects of IRP-mediated changes in mitochondrial aconitase abundance. Third, we are developing transgenic animal models for studying the functions of IRP in modulating the expression of specific mRNAs including L-ferritin and mitochondrial aconitase.

Representative Publications
dos Santos, C.O., Dore, L.C., Valentine, E., Shelat, S.G., Hardison, R.C., Ghosh, M., Wang, W., Eisenstein, R.S., Costa, F.F., & Weiss, M.J. (2008). An iron responsive element-like stem-loop regulates alpha-hemoglobin-stabilizing protein mRNA. J. Biol. Chem., 283(40), 26956-64.

Stehling, O., Netz, D.J., Niggemeyer, B., R�sser, R., Eisenstein, R.S., Puccio, H., Pierik, A.J., & Lill, R. (2008). Human Nbp35 is essential for both cytosolic iron-sulfur protein assembly and iron homeostasis. Mol. Cell. Biol., 28(17), 5517-28.

Zhang, A.S., Anderson, S.A., Meyers, K.R., Hernandez, C., Eisenstein, R.S., & Enns, C.A. (2007). Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J. Biol. Chem., 282(17), 12547-56.

Wallander, M.L., Leibold, E.A., & Eisenstein, R.S. (2006). Molecular control of vertebrate iron homeostasis by iron regulatory proteins. Biochim. Biophys. Acta., 1763(7), 668-89.

Pondarr�, C., Antiochos, B., Campagna, D.R., Clarke, S.L., Greer, E.L., Deck, K.M., McDonald, A., Han, A-P., Medlock, A., Kutok, J.L., Anderson, S.A., Eisenstein, R.S., & Fleming M.D. (2006). The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulphur cluster biogenesis. Human Mol. Genet., 15, 953-964.

Clarke, S., Anderson, S., Pondarre, C., Vasanthakumar, A., Deck, K., Koh, C., Pitula, J., Epstein, C.J., Fleming, M.F., & Eisenstein, R.S. (2006). Iron-responsive degradation of iron regulatory protein 1 does not require the Fe-S cluster. EMBO Journal, 25, 544-553.

Rincker, M.J., Clarke, S.L., Eisenstein, R.S., Link, J.E., & Hill, G.M. (2005). Effects of iron supplementation on binding activity of iron regulatory proteins and the subsequent effect on growth performance and indices of hematological and mineral status of young pigs. J. Anim. Sci., 83(9), 2137-45.

Elchuri, S., Oberley, T.D., Qi, W., Eisenstein, R.S., Jackson, Roberts L., Van Remmen, H., Epstein, C.J., & Huang, T.T. (2005). CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene, 24(3), 367-80.

Pitula, J.S., Deck, K.M., Clarke, S.L., Anderson, S.A., Vasanthakumar, A., & Eisenstein, R.S. (2004). Selective inhibition of the citrate-to-isocitrate reaction of cytosolic aconitase by phosphomimetic mutation of serine-711. Proc. Natl. Acad. Sci. USA, 101, 10907-12.

Bradley, J., Leibold, E.A., Harris, Z.L., Wobken, J.D., Clarke, S., Zumbrennen, K.B., Eisenstein, R.S., & Georgieff, M.K. (2004). Influence of gestational age and fetal iron status on IRP activity and iron transporter protein expression in third-trimester human placenta. Am. J. Physiol. Regul. Integr. Comp. Physiol., 287(4), R894-901.

Eisenstein, R., & Ross, K.L. (2003). Novel roles for iron regulatory proteins in the adaptive response to iron deficiency. J. Nutr., 133(5), 1510S-1516S.

Brown, N.M., Kennedy, M.C., Antholine, W.E., Eisenstein, R.S., & Walden, W.E. (2002). Detection of a [3Fe-4S] cluster intermediate of cytosolic aconitase in yeast expressing IRP 1: Insights into the mechanism of Fe-S cluster cycling. J. Biol. Chem., 277, 7246-7254.

Roy, C.N., Blemings, K.P., Deck, K.M., Eisenstein, R.S., & Enns, C.A. (2002). Increased IRP activity in HFE-expressing cells implies reduction in the labile iron pool. J. Cell. Physiol., 190, 218-226.

Ross, K.L., & Eisenstein, R.S. (2002). Iron deficiency decreases m-aconitase abundance and citrate concentration without affecting TCA cycle capacity in rat liver. J. Nutr., 132, 643-651.

Eisenstein, R.S. (2000). Molecular control of mammalian iron metabolism. Ann. Rev. Nutr., 20, 627.

Theil, E.C., & Eisenstein, R.S. (2000). Combinatorial mRNA regulation: Iron regulatory proteins and iso-iron-responsive elements (Iso-IREs). J. Biol. Chem., 275, 40659-40662.

Chen, O.S., Blemings, K.P., Schalinske, K.L., & Eisenstein, R.S. (1998). Dietary Fe intake rapidly influences IRP, ferritin subunits and mitochondrial aconitase in rat liver. J. Nutr., 128, 525-35.

Schalinske, K.L., Chen, O.S., & Eisenstein, R.S. (1998). Iron differentially stimulates translation of mitochondrial aconitase and ferritin mRNAs in mammalian cells. J. Biol. Chem., 273, 3740-3746.

Brown, N.M., Anderson, S.A., Steffen, D.W., Carpenter, T.B., Kennedy, M.C., Walden, W.E., & Eisenstein, R.S. (1998). Novel role of phosphorylation in Fe-S cluster stability revealed by phosphomimetic mutations at Ser-138 of iron regulatory protein 1. Proc. Natl. Acad. Sci. U.S.A., 95, 15235-15240.

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