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The Regulation of the JNK Cascade and Programmed Cell Death by NF-κB: Mechanisms and Functions

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Trends in Stem Cell Proliferation and Cancer Research

Abstract

The nuclear factor κB (NF-κB) family is an evolutionarily conserved family of transcription factors that play a central role in immune and inflammatory responses. They also play a pivotal role in cell survival, whereby activation of NF-κB antagonizes programmed cell death induced by tumor necrosis factor receptors and other cell death signals. The prosurvival function of NF-κB has been implicated in a wide range of biological processes, including the development and homeostasis of the immune system and liver. It has also been implicated in the pathogenesis of numerous diseases, including cancer, chronic inflammation, and certain hereditary disorders. The protective activity of NF-κB can also hamper tumor cell killing inflicted by radiation or chemotherapeutic drugs, thereby promoting resistance to cancer treatments. This prosurvival activity of NF-κB involves the suppression of sustained c-Jun N-terminal kinase (JNK) activation and of the accumulation of cytotoxic reactive oxygen species. NF-κB mediates this function by inducing the transcription of target genes, whose products inhibit the JNK signaling pathway and suppress accumulation of reactive oxygen species through their antioxidant functions. The development of specific inhibitors that target the critical downstream NF-κB-regulated genes that promote survival in cancer and other diseases potentially holds a key to developing specific and effective therapeutic strategies to combat these disorders.

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Abbreviations

AP-1:

Activator protein 1

ASK1:

Apoptosis-signal-regulating kinase 1

BHA:

Butylated hydroxyanisole

CAC:

Colitis-associated cancer

cFLIP:

Cellular FLICE-inhibitory protein

cIAP:

Cellular inhibitor of apoptosis

CK2:

Casein kinase 2

ConA:

Concavalin A

FADD:

Fas-associated death domain

FHC:

Ferritin heavy chain

Gadd:

Growth arrest and DNA damage inducible

HCC:

Hepatocellular carcinoma

IAP:

Inhibitor of apoptosis

IκB:

Inhibitor of nuclear factor κB

IKK:

Inhibitor of nuclear factor κB kinase

JNK:

c-Jun N-terminal kinase

LUBAC:

Linear ubiquitin chain assembly complex

MAP2K:

Mitogen-activated protein kinase kinase

MAP3K:

Mitogen-activated protein kinase kinase kinase

MAPK:

Mitogen-activated protein kinase

MDR2:

Multidrug resistance 2

MEF:

Mouse embryonic fibroblast

MKP:

Mitogen-activated protein kinase phosphatase

Mn-SOD:

Manganese superoxide dismutase

NEMO:

Nuclear factor κB essential modulator

NF-κB:

Nuclear factor κB

PCD:

Programmed cell death

RIP:

Receptor-interacting protein

ROS:

Reactive oxygen species

Smac:

Second mitochondria-derived activator of caspases

TAK1:

Transforming growth factor β activated kinase 1

TNF:

Tumor necrosis factor

TNF-R1:

Type 1 tumor necrosis factor α receptor

TNF-R2:

Type 2 tumor necrosis factor α receptor

TRADD:

Tumor necrosis factor receptor associated death domain

TRAF:

Tumor necrosis factor receptor associated factor

XIAP:

X-chromosome-linked inhibitor of apoptosis

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Acknowledgments

This work was supported in part by Medical Research Council Developmental Pathway Funding Scheme grant G0901436 and Cancer Research UK program grant A15115 to G.F.

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  1. Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK

    Jason Bennett, Marta Moretti, Anil K. Thotakura, Laura Tornatore & Guido Franzoso

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Correspondence to Guido Franzoso .

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  1. Instituto de Ciências Biológicas, Departamento de Bioquímica, Universidade Federal de Minas Gerais, Belo Horizonte, São Paulo, Brazil

    Rodrigo R. Resende

  2. Depto. Bioquímica, Universidade de São Paulo Inst. Química, São Paulo, São Paulo, Brazil

    Henning Ulrich

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Bennett, J., Moretti, M., Thotakura, A.K., Tornatore, L., Franzoso, G. (2013). The Regulation of the JNK Cascade and Programmed Cell Death by NF-κB: Mechanisms and Functions. In: Resende, R., Ulrich, H. (eds) Trends in Stem Cell Proliferation and Cancer Research. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6211-4_12

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