Context Matters

Abstract

Signaling pathways initiated by inflammatory cytokines enable nuclear factor κB (NF-κB) to translocate to the nucleus so as to activate target genes transcriptionally. NF-κB--specifically the RelA subunit--has been associated with prosurvival responses mediated through the activation of antiapoptotic genes and NF-κB inhibition has been scrutinized for potential use in cancer therapy (see Preview by Miyamoto). NF-κB is also activated by cytotoxic stimuli; however, the effects of cytotoxic activators on NF-κB are incompletely understood. Noting reports of proapoptotic effects of NF-κB, Campbell et al. investigated the effects of NF-κB activation by ultraviolet light (UV-C) and DNA-damaging drugs used in chemotherapy. Treatment of U-2 OS human osteosarcoma cells with UV-C or with daunorubicin and doxorubicin (which inhibit topoisomerase II) stimulated DNA binding of a RelA-containing NF-κB heterodimer but inhibited activity of NF-κB-dependent gene reporters. In contrast, etoposide, which also inhibits topoisomerase II, stimulated NF-κB-dependent transcriptional activity. UV-C and daunorubicin decreased mRNA and protein levels from endogenous antiapoptotic genes regulated by NF-κB. Moreover, UV-C and daunorubicin inhibited NF-κB-dependent transcriptional activity elicited by tumor necrosis factor α. Experiments comparing wild-type mouse embryo fibroblasts with those from mice lacking RelA indicated that RelA was required for repression of Bcl-xL by UV-C and daunorubicin, as did experiments using RNA interference in U-2 OS cells. UV-C and daunorubicin increased RelA association with histone deacetylases and decreased histone H3 acetylation at the Bcl-xL promoter. Thus, the pro- or antisurvival effects of NF-κB appear to depend on how it is activated and (based on comparisons with previous research) may be critically dependent on cellular context. K. J. Campbell, S. Rocha, N. D. Perkins, Active repression of antiapoptotic gene expression by RelA(p65) NF-κB. Mol. Cell 13 , 853-865 (2004). [Online Journal] S. Miyamoto, RelA life and death decisions. Mol. Cell 13 , 763-764 (2004). [Online Journal]