Many faces of NF-kappaB signaling induced by genotoxic stress.
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.
Wu
Zhao-Hui
ZH
Department of Pharmacology, University of Wisconsin-Madison, WI 53706, USA.
Miyamoto
Shigeki
S
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D009153:Mutagens / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009153:Mutagens; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases