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 Richard S. Eisenstein, Ph.D.
2004-08 J.H. & E.M. Billings-Bascom Professorship in Nutrition
1999 J.H. & E.M. Billings-Bascom Professorship in Nutrition
1998 Mead Johnson Award, American Institute of Nutrition
Eisenstein Lab Homepage
Emphasis Groups:
Biochemical & Molecular Nutrition
Human Nutrition
Principal Research Interest:
Research Summary:
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 participated 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 modulated through changes in synthesis of proteins
involved in the uptake (transferrin receptor, TfR), storage (H- and L-ferritin),
and utilization (erythroid 5-aminolevulinate synthase, eALAS) 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 stem-loop
structures (IREs) in TfR, ferritin, eALAS and other mRNAs 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. We have shown that the activity of both IRPs is regulated by changes
in their phosphorylation status through the action of protein kinase C (PKC)
or other protein kinases. We are examining how phosphorylation affects a number
of aspects of IRP function. For example, with IRP1 we are investigating how
phosphorylation affects the assembly or disassembly of its Fe-S cluster in the
protein. The presence of absence of the Fe-S cluster is the primary mechanism
for regulating whether or not IRP1 binds to mRNAs. We believe that phosphorylation
enhances the susceptibility of the Fe-S cluster of IRP1 to physiological destabilizing
agents such as superoxide anion and nitric oxide. Taken together, it is apparent
that phosphorylation of IRP1 provides a mechanism through which extracellular
agents modulate cellular iron metabolism by altering the set-point at which
IRP1 responds to iron.
Second, there are up to 8 mRNA targets for IRPs and we are investigating how
differences in RNA and protein structure 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 IRE-containing mRNAs including L-ferritin and mitochondrial aconitase.
Representative Publications
Pondarré, 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., and 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. and Eisenstein, R.S. (2006) Iron-responsive degradation of iron regulatory protein 1 does not require the Fe-S cluster. EMBO Journal. 25:544-553
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 U S A. 101:10907-12. [Abstract]
Eisenstein, R.S. and Ross, K.L (2003) Novel roles of iron regulatory proteins
in the adaptive response to iron deficiency. J. Nutr. 2003 May;133(5 Suppl 1):1510S-6S
[Abstract]
Brown, N.M., Kennedy, M.C., Antholine, W.E., Eisenstein, R.S. and Walden, W.E.
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. [Abstract]
Ross, K.L. and 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.[Abstract]
Eisenstein, R.S. (2000) Molecular Control of Mammalian Iron Metabolism.Ann.
Rev. Nutr. 20:627.[Abstract]
Schalinske, K.L., Chen, O.S. and Eisenstein, R.S. (1998) Iron Differentially
Stimulates Translation of Mitochondrial Aconitase and Ferritin mRNAs in Mammalian
Cells. J. Biol. Chem. 273:3740-3746. [Abstract]
N.M. Brown , S.A. Anderson, D.W. Steffen, T.B. Carpenter, M.C. Kennedy, W.E.
Walden, R.S. Eisenstein (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 [Abstract]
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