Signaling from toxic metals to NF-kappaB and beyond: not just a matter of reactive oxygen species.

Abstract

The nuclear factor kappa B (NF-kappaB) family of transcription factors controls expression of a number of early response genes associated with inflammatory responses, cell growth, cell cycle progression, and neoplastic transformation. These genes include a multitude of cytokines, chemokines, adhesion molecules, immune receptors, stress proteins, apoptotic or anti-apoptotic regulators, and several oncogenes. Accumulating evidence indicates that a variety of toxic metals are able to affect the activation or activity of NF-kappaB, but the molecular mechanisms involved in this process remain largely unknown. The signaling pathways mediating cytokine- or microorganism-induced NF-kappaB activation have been well established recently. Whether the same signaling systems are involved in metal-induced NF-kappaB activation, however, is unclear. In the present review, we have attempted to evaluate and update the possible mechanisms of metal signals on the activation and function of NF-kappaB.

Crystal Structure of Human Pirin

“…Pirin is newly identified in this study to be a metal-binding protein, and, interestingly, the metal-binding residues of Pirins are highly conserved across mammals, plants, fungi, and prokaryotic organisms. Pirin acts as a cofactor for the transcription factor NFI, the regulatory mechanism of which is generally believed to require the assistance of a metal ion (30). Our structural data support the hypothesis that the bound iron of Pirin may participate in this transcriptional regulation by enhancing and stabilizing the formation of the p50⅐Bcl-3⅐DNA complex.…”

“…Our structural data support the hypothesis that the bound iron of Pirin may participate in this transcriptional regulation by enhancing and stabilizing the formation of the p50⅐Bcl-3⅐DNA complex. Metals have been implicated directly or indirectly in the NF-B family of transcription factors that control expression of a number of early response genes associated with inflammatory responses, cell growth, cell cycle progression, and neoplastic transformation (30). However, most metal-dependent transcription factors are DNA-binding proteins that bind to specific sequences when the metal binds to the protein.…”

Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance

“…High levels of oxidized GSH were found to hinder activity of ubiquitinconjugating enzymes, and accordingly, block proteolysis of IkBa following treatment with H 2 O 2 (Obin et al, 1998;Jaspers et al, 2001). Further, comparative analysis between the structure of the kinase domains of IKKs and related kinases indicated that, in contrast to what was suggested in other reports (discussed above), oxidation of Cys-179 in either IKKa or IKKb would lead to the inhibition, rather than activation, of kinase activity (Chen and Shi, 2002;Michiels et al, 2002;Gloire et al, 2006). This residue is oxidized, for instance, upon treatment with arsenite (Kapahi et al, 2000), and this oxidation has been implicated in ROS-mediated inactivation of IKKb function in alveolar epithelial cells (Korn et al, 2001;Gloire et al, 2006).…”

The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: a potential mechanism for thrombosis in eosinophilic inflammatory states

“…Both of the IB kinases (␣ and ␤) that phosphorylate the NF-B-inhibitory IB-␣ to cause its ubiquination and subsequent degradation have redox-sensitive cysteines whose oxidation state regulates their activities. [35][36][37] In addition, both p50 and c-Rel have a cysteine, Cys62, that forms a covalent conjugate with the NF-B inhibitor, andrographolide, 27 suggesting that redox modification of this amino acid influences NF-B activation. These as well as various redox-sensitive kinase cascades 38 are candidates for further investigation of NF-B activation by HOSCN.…”