Many faces of NF-kappaB signaling induced by genotoxic stress

Abstract

The nuclear factor-kappaB (NF-kappaB) family of dimeric transcription factors plays pivotal roles in physiologic and pathologic processes, including immune and inflammatory responses and development and progression of various human cancers. Inactive NF-kappaB dimers normally exist in the cytoplasm in association with inhibitor proteins belonging to the inhibitor of NF-kappaB (IkappaB) family of related proteins. Activation of NF-kappaB involves its release from IkappaB and subsequent nuclear translocation to induce expression of target genes. Intense research effort has revealed many distinct signaling pathways and mechanisms of NF-kappaB activation induced by immune and inflammatory stimuli. These aspects of NF-kappaB biology have been amply reviewed in the literature. However, those that involve DNA-damaging agents are less well understood, and multiple conflicting pathways and mechanisms have been described in the literature. In this review, we summarize the proposed mechanisms of NF-kappaB activation by various DNA-damaging agents, discuss the significance of such activation in the context of cancer treatment, and highlight some of the critical questions that remain to be addressed in future studies.