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Science 8 December 2006:
Vol. 314. no. 5805, p. 1517
DOI: 10.1126/science.314.5805.1517c
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Editors' Choice: Highlights of the recent literature

Arsenic is carcinogenic at low doses and cytotoxic at higher concentrations. Song et al. investigated the mechanisms underlying arsenite cytotoxicity, focusing on nuclear factor kappaB (NF-kappaB), which regulates the transcription of target genes when activated by means of IkappaB kinase (IKK). Although NF-kappaB generally mediates antiapoptotic signals-in part through inhibiting c-Jun N-terminal kinase (JNK) signaling-under some conditions, NF-kappaB signaling is proapoptotic. Wild-type mouse fibroblasts were more sensitive to the cytotoxic effects of arsenite than were cells lacking the beta subunit of IKK. IKKbeta-/- cells failed to show arsenite-dependent JNK phosphorylation, and inhibiting JNK signaling attenuated arsenitemediated cell death. Arsenite acted through IKKbeta-NF-kappaB to increase the abundance of growth arrest and DNA damage-inducible (GADD) 45alpha, whose up-regulation was required for arseniteinduced phosphorylation of JNK. Analysis of fibroblasts from knockout mice implicated the NF-kappaB1 subunit (p50) in arsenite's cytotoxic effects, and further analysis suggested that GADD45alpha up-regulation depended on p50-dependent inhibition of ubiquitination and proteasomal degradation. Thus, arsenite-mediated cytotoxicity appears to involve IKKbeta-NF-kappaBdependent activation of JNK signaling through a mechanism that depends on the accumulation of GADD45alpha rather than transcriptional activation. -- EMA

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




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Science. ISSN 0036-8075 (print), 1095-9203 (online)