Editors' ChoiceApoptosis

Of Arsenic and NF-κB

Science's STKE  28 Nov 2006:
Vol. 2006, Issue 363, pp. tw402
DOI: 10.1126/stke.3632006tw402

Arsenic (used in the therapy of some cancers) is carcinogenic at low doses but can be cytotoxic at higher concentrations. Song et al. investigated the mechanisms underlying arsenite cytotoxicity, focusing on the role of nuclear factor-κB (NF-κB), a family of proteins sequestered in the cytoplasm that translocates to the nucleus to regulate the transcription of target genes when activated by means of IκB kinase (IKK). Although NF-κB generally mediates antiapoptotic signals--in part through inhibition of c-Jun N-terminal kinase (JNK) signaling--under some conditions, NF-κB signaling is proapoptotic. Wild-type mouse embryo fibroblasts (MEFs) were more sensitive to the cytotoxic effects of arsenite than were MEFs lacking IKKβ or expressing an IKKβ dominant-negative. IKKβ–/– MEFs failed to show arsenite-dependent JNK phosphorylation, and inhibition of JNK signaling attenuated arsenite-mediated cell death. Arsenite stimulated NF-κB-dependent phosphorylation of MKK4, a kinase upstream of JNK that dominant-negative experiments implicated in arsenite-mediated JNK activation and cell death. Arsenite acted through IKKβ-NF-κB to increase the abundance of GADD45α (growth arrest and DNA damage-inducible gene); experiments with GADD45α overexpression and silencing indicated that GADD45α up-regulation was required for arsenite-induced phosphorylation of MKK4 and JNK. Analysis of MEFs from knockout mice implicated the NF-κB1 subunit (p50), which lacks a transactivation domain, in arsenite’s cytotoxic effects. Indeed, a combination of pharmacological analysis and immunoprecipitation in wild-type, IKKβ–/–, and p50–/– MEFs suggested that GADD45α up-regulation depended on p50-dependent inhibition of ubiquitination and proteasomal degradation. Thus, arsenite-mediated cytotoxicity appears to involve IKKβ-NF-κB-dependent activation of JNK signaling through a mechanism that depends on accumulation of GADD45α rather than the transcriptional activation of target genes.

L. Song, J. Li, D. Zhang, Z.-g. Liu, J. Ye, Q. Zhan, H.-M. Shen, M. Whiteman, C. Huang, IKKβ programs to turn on the GADD45-MKK4-JNK apoptotic cascade specifically via p50 NF-κB in arsenite response. J. Cell Biol. 175, 607-617 (2006). [Abstract] [Full Text]