Of Arsenic and NF-κB

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Science  08 Dec 2006:
Vol. 314, Issue 5805, pp. 1517
DOI: 10.1126/science.314.5805.1517c

Arsenic is carcinogenic at low doses and cytotoxic at higher concentrations. Song et al. investigated the mechanisms underlying arsenite cytotoxicity, focusing on nuclear factor κB (NF-κB), which regulates the transcription of target genes when activated by means of IκB kinase (IKK). Although NF-κB generally mediates antiapoptotic signals-in part through inhibiting c-Jun N-terminal kinase (JNK) signaling-under some conditions, NF-κB signaling is proapoptotic. Wild-type mouse fibroblasts were more sensitive to the cytotoxic effects of arsenite than were cells lacking the β subunit of IKK. IKKβ−/− cells failed to show arsenite-dependent JNK phosphorylation, and inhibiting JNK signaling attenuated arsenitemediated cell death. Arsenite acted through IKKβ-NF-κB to increase the abundance of growth arrest and DNA damage-inducible (GADD) 45α, whose up-regulation was required for arseniteinduced phosphorylation of JNK. Analysis of fibroblasts from knockout mice implicated the NF-κB1 subunit (p50) in arsenite's cytotoxic effects, and further analysis suggested that GADD45α up-regulation depended on p50-dependent inhibition of ubiquitination and proteasomal degradation. Thus, arsenite-mediated cytotoxicity appears to involve IKKβ-NF-κBdependent activation of JNK signaling through a mechanism that depends on the accumulation of GADD45α rather than transcriptional activation. — EMA

J. Cell Biol. 175, 607 (2006).

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