Induction of iron regulatory protein 1 RNA-binding activity by nitric oxide is associated with a concomitant increase in the labile iron pool: implications for DNA damage.
Iron regulatory protein 1 (IRP1) is a bifunctional [4Fe-4S] protein that controls iron homeostasis. Switching off its function from an aconitase to an apo-IRP1 interacting with iron-responsive element-containing mRNAs depends on the reduced availability of iron in labile iron pool (LIP). Although the modulation of IRP1 by nitric oxide has been characterized, its impact on LIP remains unknown. Here, we show that inhibition of IRP1 aconitase activity and induction of its IRE-binding activity during exposure of L5178Y mouse lymphoma cells to NO are associated with an increase in LIP levels. Removal of NO resulted in a reverse regulation of IRP1 activities accompanied by a decrease of LIP. The increased iron burden in LIP caused by NO exacerbated hydrogen peroxide-induced genotoxicity in L5178Y cells. We demonstrate that the increase in LIP levels in response to chronic but not burst exposure of L5178Y cells to NO is associated with alterations in the expression of proteins involved in iron metabolism.
Lipinski
Pawel
P
Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, ul. Postepu 1, 05-552 Wolka Kosowska, Poland. P.Lipinski@ighz.pl
Starzynski
Rafal R
RR
Drapier
Jean-Claude
JC
Bouton
Cecile
C
Bartlomiejczyk
Teresa
T
Sochanowicz
Barbara
B
Smuda
Ewa
E
Gajkowska
Agnieszka
A
Kruszewski
Marcin
M
D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D005293:Ferritins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D009589:Nitrogen Oxides; D021122:Protein Subunits; D012313:RNA / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
D008565:Membrane Proteins; D009589:Nitrogen Oxides; D021122:Protein Subunits; D011990:Receptors, Transferrin; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D012313:RNA; D005293:Ferritins; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D035941:Iron Regulatory Protein 1