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Many faces of NF-κB signaling induced by genotoxic stress

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Abstract

The nuclear factor-κB (NF-κB) 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-κB dimers normally exist in the cytoplasm in association with inhibitor proteins belonging to the inhibitor of NF-κB (IκB) family of related proteins. Activation of NF-κB involves its release from IκB and subsequent nuclear translocation to induce expression of target genes. Intense research effort has revealed many distinct signaling pathways and mechanisms of NF-κB activation induced by immune and inflammatory stimuli. These aspects of NF-κB 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-κB 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.

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Abbreviations

ATM :

ataxia-telangiectasia mutated

ATR :

ataxia-telangiectasia and Rad3 related

CK2 :

casein kinase 2

CPT :

Camptothecin

Dox :

Doxorubicin

DSB :

DNA double-strand break

ELKS :

protein enriched with glutamate, leucine, lysine, and serine

HED-ID :

hypohydrotic ectodermal dysplasia with severe immunodeficiency

HSP :

heat-shock protein

IκB :

inhibitor of NF-κB

IKK :

IκB kinase

IR :

ionizing radiation

MDC1 :

mediator of DNA damage checkpoint 1

MDR1 :

multidrug resistance gene 1

NF-κB :

nuclear factor-kappa B

NEMO :

NF-κB essential modulator

NIK :

NF-κB inducing kinase

RIP :

receptor-interacting protein kinase

TAK :

TGFβ associated kinase

TRAF :

TNF receptor-associated factor

IRAK :

IL-1 receptor-associated kinase

p53BP1 :

p53 binding protein 1

PIASy :

protein inhibitor of activated STATy

PIDD :

p53 induced protein with a death domain

ROS :

reactive oxygen species

UV :

ultraviolet radiation

XP :

xeroderma pigmentosum

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Acknowledgment

We would like to apologize to the many researchers whose contributions were not covered or cited due to limitation of the space or our oversight. Related research in author’s laboratory is supported by NIH (R01CA077474 to S.M.), and a Special Fellowship from the Leukemia and Lymphoma Society to Z.W.

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  1. Department of Pharmacology, University of Wisconsin–Madison, 301 SMI, 1300 University Avenue, Madison, WI, 53706, USA

    Zhao-Hui Wu & Shigeki Miyamoto

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  1. Zhao-Hui Wu
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  2. Shigeki Miyamoto
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Correspondence to Shigeki Miyamoto.

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Wu, ZH., Miyamoto, S. Many faces of NF-κB signaling induced by genotoxic stress. J Mol Med 85, 1187–1202 (2007). https://doi.org/10.1007/s00109-007-0227-9

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  • DOI: https://doi.org/10.1007/s00109-007-0227-9

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