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The Rel/NF-kappaB transcription factors are key regulators of programmed cell death (PCD). Their activity has significant physiological relevance for normal development and homeostasis in various tissues and important pathological consequences are associated with aberrant NF-kappaB activity, including hepatocyte apoptosis, neurodegeneration, and cancer. While NF-kappaB is best characterized for its protective activity in response to proapoptotic stimuli, its role in suppressing programmed necrosis has come to light more recently. NF-kappaB most commonly antagonizes PCD by activating the expression of antiapoptotic proteins and antioxidant molecules, but it can also promote PCD under certain conditions and in certain cell types. It is therefore important to understand the pathways that control NF-kappaB activation in different settings and the mechanisms that regulate its anti- vs pro-death activities. Here, we review the role of NF-kappaB in apoptotic and necrotic PCD, the mechanisms involved, and how its activity in the cell death response impacts cancer development, progression, and therapy. Given the role that NF-kappaB plays both in tumor cells and in the tumor microenvironment, recent findings underscore the NF-kappaB signaling pathway as a promising target for cancer prevention and treatment.

The Rel/NF-B family of transcription factors is key for immune and inflammatory responses and also controls cell proliferation and apoptosis. The v-Rel oncoprotein of reticuloendotheliosis virus strain T (Rev-T) is the most potent oncogenic member of this family. Both v-Rel and its cellular homologue c-Rel transform primary splenic lymphocytes in vitro and cause fatal leukemia/lymphomas in chickens and transgenic mice (5,9,17,22,23,33,38,39). This agrees with the implication of Rel/NF-B in the pathogenesis and chemoresistance of many hematopoietic and solid tumors, including primary mediastinal B-cell lymphomas (PMBCL) and classical Hodgkin's lymphoma, in which constitutively high levels of nuclear c-Rel protein are necessary for tumor cell survival and proliferation (3,4,14,18,20,27,49). Additionally, some PMBCL and follicular lymphomas harbor c-rel gene mutations that decrease c-Rel's transactivation potency and enhance its transforming activity in primary chicken lymphocytes (45). This is consistent with the increased transforming phenotype conferred by certain mutations in v-Rel and c-Rel and indicates that modulation of Rel's transcriptional activity can significantly affect its oncogenicity (12,43,44).The Rel proteins bind to B DNA sites as homo-or heterodimers with other NF-B family members via their N-terminal Rel homology domain (RHD), which also mediates nuclear localization and association with inhibitory IB subunits.

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