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      Inhibition of NF-kappa B by S-nitrosylation.

      Biochemistry
      Active Transport, Cell Nucleus, drug effects, Animals, Cell Line, Cysteine, analogs & derivatives, metabolism, pharmacology, Cytokines, DNA, antagonists & inhibitors, DNA-Binding Proteins, Down-Regulation, Enzyme Inhibitors, Humans, I-kappa B Proteins, Mercaptoethanol, Mice, NF-kappa B, genetics, isolation & purification, physiology, NF-kappa B p50 Subunit, Nitric Oxide Synthase, Nitrosation, Nitroso Compounds, Protein Binding, S-Nitrosothiols, Transcription, Genetic, Transfection

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          Abstract

          It is not clear if redox regulation of transcription is the consequence of direct redox-related modifications of transcription factors, or if it occurs at some other redox-sensitive step. One obstacle has been the inability to demonstrate redox-related modifications of transcription factors in vivo. The redox-sensitive transcriptional activator NF-kappaB (p50-p65) is a case in point. Its activity in vitro can be inhibited by S-nitrosylation of a critical thiol in the DNA-interacting p50 subunit, but modulation of NF-kappaB activity by nitric oxide synthase (NOS) has been attributed to other mechanisms. Herein we show that cellular NF-kappaB activity is in fact regulated by S-nitrosylation. We observed that both S-nitrosocysteine and cytokine-activated NOS2 inhibited NF-kappaB in human respiratory cells or murine macrophages. This inhibition was reversed by addition of the denitrosylating agent dithiothreitol to cellular extracts, whereas NO bioactivity did not affect the TNFalpha-induced degradation of IkappaBalpha or the nuclear translocation of p65. Recapitulation of these conditions in vitro resulted in S-nitrosylation of recombinant p50, thereby inhibiting its binding to DNA, and this effect was reversed by dithiothreitol. Further, an increase in S-nitrosylated p50 was detected in cells, and the level was modulated by TNFalpha. Taken together, these data suggest that S-nitrosylation of p50 is a physiological mechanism of NF-kappaB regulation.

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