©2003 by MEDIMOND S.r.l. 55 D627R9003 Iron Regulatory Proteins and Oxidative Stress K. Pantopoulos Lady Davis Institute for Medical Research and Department of Medicine, McGill University, Montreal, Quebec, Canada Summary Iron regulatory proteins, IRP1 and IRP2 are post-transcriptional regu- lators of iron metabolism. In iron starved cells, they bind to iron re- sponsive elements (IREs) within mRNAs and thereby control their translation or stability. The IRE/IRP system accounts for the coordi- nated reciprocal regulation in the expression of the transferrin receptor and ferritin, which are involved in cellular iron uptake and storage, respectively. The activities of IRP1 and IRP2 are regulated by distinct post-translational mechanisms in response to iron levels. Thus, in iron- replete cells, IRP1 assembles a cubane iron-sulfur cluster, which pre- vents IRE-binding, while IRP2 undergoes proteasomal degradation. IRP1 and IRP2 also respond, albeit differentially, to iron-independent signals, such H 2 O 2 , hypoxia or nitric oxide. These findings provide regulatory links between iron metabolism and oxidative stress. The IRE/IRP Regulatory System Iron is an essential cellular constituent but also potentially toxic. When present in excess, it engages in Fenton/Haber-Weiss reactions, catalyzing the generation of aggressive radicals, which readily attack and damage cellular macromolecules (1). Therefore, elegant mecha- nisms have evolved to regulate iron homeostasis. Mammalian cells re- spond to iron starvation by stimulating the expression of the transferrin receptor (TfR), which mediates iron uptake, and by repressing the syn- thesis of ferritin, which is utilized for iron storage (2, 3). This coordi- nated regulation is accomplished by binding of two iron regulatory proteins, IRP1 and IRP2 to iron responsive elements (IREs), struc-