Lipinski Pawel, Starzynski Rafal R, Drapier Jean-Claude, Bouton Cecile, Bartlomiejczyk Teresa, Sochanowicz Barbara, Smuda Ewa, Gajkowska Agnieszka, Kruszewski Marcin
Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, ul. Postepu 1, 05-552 Wolka Kosowska, Poland.
Biochem Biophys Res Commun. 2005 Feb 4;327(1):349-55. doi: 10.1016/j.bbrc.2004.12.012.
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.
铁调节蛋白1（IRP1）是一种双功能的[4Fe-4S]蛋白，可控制铁稳态。将其功能从乌头酸酶转换为与含铁反应元件的mRNA相互作用的脱辅基IRP1，取决于不稳定铁池（LIP）中铁的可用性降低。尽管一氧化氮对IRP1的调节作用已得到表征，但其对LIP的影响仍不清楚。在这里，我们表明，在L5178Y小鼠淋巴瘤细胞暴露于NO期间，IRP1乌头酸酶活性的抑制及其IRE结合活性的诱导与LIP水平的增加有关。去除NO导致IRP1活性的反向调节，同时LIP减少。NO引起的LIP中铁负担增加加剧了过氧化氢诱导的L5178Y细胞遗传毒性。我们证明，L5178Y细胞长期而非突然暴露于NO后LIP水平的增加与铁代谢相关蛋白表达的改变有关。
