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Review
. 2016 Oct 4;7(40):66310-66322.
doi: 10.18632/oncotarget.11624.

IκBζ: an emerging player in cancer

Marie Willems  1 , Nadège Dubois  1 , Lucia Musumeci  1 , Vincent Bours  1 , Pierre A Robe  1   2
Affiliations
Review

IκBζ: an emerging player in cancer

Marie Willems et al. Oncotarget. .

Abstract

IκBζ, an atypical member of the nuclear IκB family of proteins, is expressed at low levels in most resting cells, but is induced upon stimulation of Toll-like/IL-1 receptors through an IRAK1/IRAK4/NFκB-dependent pathway. Like its homolog Bcl3, IκBζ can regulate the transcription of a set of inflamatory genes through its association with the p50 or p52 subunits of NF-κB. Long studied as a key component of the immune response, IκBζ emerges as an important regulator of inflammation, cell proliferation and survival. As a result, growing evidence support the role of this transcription factor in the pathogenesis number of human hematological and solid malignancies.

Keywords: IκBζ; NF-κB pathway; cancer; nuclear IκB protein; perspectives.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors have no conflict of interest with respect to the topic of this manuscript.

Figures

Figure 1
Figure 1. Schematic representation of the IκB family of proteins
A. The cytoplasmic IκB proteins. Notes: PEST: domain rich in proline, glutamic acid, serine and threonine; AR: ankyrin-repeat; NES: nuclear export signal; NIS: nuclear import signal; RHD: Rel homology domain; GRR: glycine-rich region. b. The nuclear IκB proteins. Notes: AR: ankyrin-repeat; NLS: nuclear localization signal; TAD: transactivating domain.
Figure 1
Figure 1. Schematic representation of the IκB family of proteins
A. The cytoplasmic IκB proteins. Notes: PEST: domain rich in proline, glutamic acid, serine and threonine; AR: ankyrin-repeat; NES: nuclear export signal; NIS: nuclear import signal; RHD: Rel homology domain; GRR: glycine-rich region. b. The nuclear IκB proteins. Notes: AR: ankyrin-repeat; NLS: nuclear localization signal; TAD: transactivating domain.
Figure 2
Figure 2. Stable induction of IκBζ
Barely detectable in resting cells, IκBζ is induced by lipopolysaccharide (LPS) and IL-1β. Both Toll-like receptor (TLR) and IL-1R share a similar cytoplasmic TIR domain that binds the MyD88 adaptator protein. Under stimulation, MyD88 recruits IRAK1 and IRAK4 leading to the dissociation of IRAK1 and its binding to TRAF6. The complex IRAK1/TRAF6 activates then TAK1 which in turn induces NF-κB translocation. The mRNA stabilization of IκBζ depends upon the recruitment of IRAK1 to the TIR domain of the IL-1R and TLR receptors as well as on a 165-nucleotides sequence present in the 3′-UTR of the IκBζ mRNA. Notes: LPS: lipopolysaccharides; IL-1β: interleukin 1β; TLR: toll-like receptor; IL-1R: IL-1 receptor; IRAK1/4: interleukin-1 receptor-associated kinase 1/4; TRAF6: TNF receptor-associated factor 6; TAK1: transforming growth factor beta-activated kinase 1; IκB: inhibitor of κB ; IKK: IκB kinase.
Figure 3
Figure 3. In silico analysis of serine/thréonine and tyrosine- containing motives in IκBζ functional domains
Notes: JNK1: c-Jun N-terminal kinase 1; Pim1: serine/threonine-protein kinase pim-1; NeK10: NIMA-related kinase 10; ATR: ataxia telangiectasia and Rad3 related; ERK2: extracellular signal-regulated kinase 2; LRRK2: leucine-rich repeat kinase 2; EGFR: epidermal growth factor receptor; ErbB3: erb-b2 receptor tyrosine kinase 3; CHK2: checkpoint kinase 2; MEK4: mitogen-activated protein kinase kinase 4; PKC: protein kinase C; CKII: casein kinase 2.
Figure 4
Figure 4. IκBζ function in gene régulation
A. After NF-κB activation through diverse stimuli, IκBζ is transcribed and transiently induced. Under these conditions, IκBζ acts as a inhibitor of the homodimer p50/p50 or the heterodimer p50/p65 through a negative feedback loop B. Upon specific stimulation with LPS or IL-1β leading to IκBζ mRNA stabilization and protein expression, IκBζ forms a ternary complex with p50 and p65 on the promoter of target genes and activates or repress their transcription. Notes: IKK: IκB kinase; IκB: inhibitor of κB; NF-κB: nuclear factor of κB.
Figure 5
Figure 5. IκBζ and its involvment in cancer
Schematic representation of the potential upstream regulators of IκBζ as well as the IκBζ targets and their relative biological effects. Notes: Tax: transactivator of pX; FUS: fused in sarcoma; DDIT3: DNA damage-inducible transcript 3; Bcl3: B cell lymphoma 3; NF-κB: nuclear factor of κB; STAT3: signal transducer and activator of transcription 3.
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