<scp>DNA</scp> element downstream of the κ<scp>B</scp> site in the <scp>L</scp>cn2 promoter is required for transcriptional activation by <scp>I</scp>κ<scp>B</scp>ζ and <scp>NF</scp>‐κB p50

Kohda, Akira; Yamazaki, Soh; Sumimoto, Hideki

doi:10.1111/gtc.12162

Cited by 15 publications

(19 citation statements)

References 38 publications

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“…Asp-451 of IB Is Involved in Transcriptional ActivationAs we have shown previously (23), expression of IB along with p50 results in transcriptional activation of the promoter of the lipocalin-2-encoding gene Lcn2 in p50-/IB-deficient mouse embryonic fibroblasts (MEFs) (Nfkb1…”

Section: Resultsmentioning

confidence: 81%

“…3A). To examine the role for Asp-451 of IB in p50-dependent Lcn2 activation, we used p50-/IB-deficient MEFs in which a luciferase reporter is regulated by the Lcn2 promoter (23). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, we have shown recently that a cytosine-rich region downstream of the B site is involved in formation of the active three-species complex IBp50-DNA (23), suggesting that the extra-B site makes a direct contact with p50, IB, or both. It seems thus possible that the arginine-replaceable residues Lys-717 and Lys-719 in ANK7 participate in IB interaction with the Lcn2 promoter DNA.…”

Section: Lys-717 and Lys-719 In Ank7 Of Ib Participate In Complex Formentioning

confidence: 96%

“…Consecutive ANK motifs generally stack together to serve as an underlying architecture of a modular specific protein-interacting interface (30 -32). The ARD of IBs mediates the association with NF-B dimers via direct binding to the NF-B Rel homology region (23,33,34). Although the ARD of nuclear IBs displays a high sequence similarity to that of cytoplasmic IBs except for the additional seventh motif ANK7 (10,12,35,36), the preference for NF-B dimer species differs between the nuclear and cytoplasmic IBs, as described above (7-9, 12, 16, 37).…”

mentioning

confidence: 90%

“…Furthermore, there exists a difference in interaction with B DNA. Although IB␣ promotes the dissociation of a p65-containing dimer from the promoter DNA (38), the nuclear IBs are generally assumed to interact indirectly with the B site via binding to NF-B p50 or p52 (7,8,23,33,34). In addition, we have recently shown that IB interaction with the Lcn2 promoter also requires a region downstream of the B site (23).…”

mentioning

confidence: 99%

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The Nuclear Protein IκBζ Forms a Transcriptionally Active Complex with Nuclear Factor-κB (NF-κB) p50 and the Lcn2 Promoter via the N- and C-terminal Ankyrin Repeat Motifs

Kohda

Yamazaki

Sumimoto

2016

Journal of Biological Chemistry

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The nuclear protein IB, comprising the N-terminal transactivation domain and the C-terminal ankyrin repeat (ANK) domain composed of seven ANK motifs, activates transcription of a subset of nuclear factor-B (NF-B)-dependent innate immune genes such as Lcn2 encoding the antibacterial protein lipocalin-2. Lcn2 activation requires formation of a complex containing IB and NF-B p50, a transcription factor that harbors the DNA-binding Rel homology region but lacks a transactivation domain, on the promoter with the canonical NF-Bbinding site (B site) and its downstream cytosine-rich element. Here we show that IB productively interacts with p50 via Asp-451 in the N terminus of ANK1, a residue that is evolutionarily conserved among IB and the related nuclear IB proteins Bcl-3 and IB NS . Threonine substitution for Asp-451 abrogates direct association with the B-site-binding protein p50, complex formation with the Lcn2 promoter DNA, and activation of Lcn2 transcription. The basic residues Lys-717 and Lys-719 in the C-terminal region of ANK7 contribute to IB binding to the Lcn2 promoter, probably via interaction with the cytosinerich element required for Lcn2 activation; glutamate substitution for both lysines results in a loss of transcriptionally active complex formation without affecting direct contact of IB with p50. Both termini of the ANK domain in Bcl-3 and IB NS function in a manner similar to that of IB to interact with promoter DNA, indicating a common mechanism in which the nuclear IBs form a regulatory complex with NF-B and promoter DNA via the invariant aspartate in ANK1 and the conserved basic residues in ANK7. Nuclear factor-B (NF-B)2 plays central roles in host defense and inflammation as a homo-or heterodimer of NF-B/Rel family proteins by controlling the expression of genes for pro-inflammatory cytokines, chemokines, and antibacterial proteins (1-4). The mammalian NF-B family is composed of five structurally related polypeptides: p50, p52, p105 (the precursor of p50), p100 (the precursor of p52), p65 (also known as RelA), RelB, and c-Rel. They share the Rel homology region, which mediates dimerization, nuclear translocation, binding to specific DNA sequences known as NF-B-binding elements (B sites), and association with one of the IB family proteins (1-4). Among the members of the family, p65, RelB, and c-Rel have an ability to activate transcription by themselves via the C-terminal trans-activation domain, which is absent in the smaller p50 and p52 proteins. In resting cells, NF-B dimers are retained in the cytoplasm by associating with a member of the prototypical/cytoplasmic IB proteins including IB␣, IB␤, and IB⑀ (1-4). Cell activation with appropriate stimuli such as bacterial LPS leads to phosphorylation-induced degradation of cytoplasmic IBs and resultant liberation of NF-B dimers (1, 5, 6). The released NF-B dimers subsequently translocate to the nucleus and thus induce the expression of primary response genes via binding to B sites on their promoter/enhancer regions (1-4).The primarily induced gen...

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Section: Resultsmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Lys-717 and Lys-719 In Ank7 Of Ib Participate In Complex Formentioning

confidence: 96%

mentioning

confidence: 90%

mentioning

confidence: 99%

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The Nuclear Protein IκBζ Forms a Transcriptionally Active Complex with Nuclear Factor-κB (NF-κB) p50 and the Lcn2 Promoter via the N- and C-terminal Ankyrin Repeat Motifs

Kohda

Yamazaki

Sumimoto

2016

Journal of Biological Chemistry

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Cell autonomous and noncell‐autonomous role of NF‐κB p50 in astrocyte‐mediated fate specification of adult neural progenitor cells

Cvijetic

Bortolotto

Manfredi

et al. 2016

Glia

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In previous work, we demonstrated that NF-κB p50 acts as crucial regulator of adult hippocampal neural progenitor cells (ahNPC). Indeed, NF-κB p50 knockout (KO) mice are characterized by remarkably reduced hippocampal neurogenesis. As a follow up to that work, herein we show that when cultured in vitro, ahNPC from wild type (WT) and p50KO mice are not significantly different in their neurogenic potential. This observation prompted us to investigate cell-autonomous and noncell-autonomous consequences of p50 absence on neuronal fate specification of ahNPC. In particular, we focused our attention on astrocytes, known to provide soluble proneurogenic signals, and investigated the influence of WT and p50KO astrocyte conditioned media (ACM) on WT and p50KO ahNPC differentiation. Interestingly, while WT ACM promoted both neuronal and astroglial differentiations, p50KO ACM only supported astroglial differentiation of WT ahNPC. By using a LC-MS/MS approach, we identified some proteins, which are significantly upregulated in p50KO compared with WT astrocytes. Among them, lipocalin-2 (LCN-2) was recognized as a novel astroglial-derived signal regulating neuronal fate specification of ahNPC. Interestingly, LCN-2 proneurogenic effect was greatly reduced in p50KO NPC, where LCN-2 receptor gene expression appeared downregulated. In addition to that, we demonstrated p50KO NPC unresponsiveness to both neuronal and astroglial fate specification signals from WT and p50KO ACM, and we identified a reduced expression of α2δ1, a thrombospondin-1 receptor, as another phenotypic change occurring in ahNPC in the absence of p50. Altogether, our data suggest that dysregulated NPC-astrocyte communication may contribute to a reduced hippocampal neurogenesis in p50KO mice in vivo. GLIA 2016 GLIA 2017;65:169-181.

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Neutrophil gelatinase-associated lipocalin and innate immune responses to bacterial infections

Nasioudis

Witkin

2015

Med Microbiol Immunol

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Neutrophil gelatinase-associated lipocalin (NGAL), an essential component of the antimicrobial innate immune system, is present in neutrophils and multiple other tissues. It prevents iron acquisition by microorganisms by sequestering iron-loaded bacterial siderophores. NGAL also modulates neutrophil functions. Its production is inducible following Toll-like receptor 4 activation and release of pro-inflammatory cytokines. NGAL is employed clinically in the diagnosis of acute kidney injury and may be useful in general in the differential diagnosis of a bacterial-mediated infectious process. Elevated levels of NGAL have been detected in the blood of patients with bacterial urinary tract infection, community-acquired pneumonia, sepsis, as well as in the cerebrospinal fluid and peritoneal fluid of patients with bacterial meningitis and peritonitis. Some bacteria have developed resistance to NGAL-mediated iron sequestration by production of modified siderophores that are not recognized by NGAL.

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DNA element downstream of the κB site in the Lcn2 promoter is required for transcriptional activation by IκBζ and NF‐κB p50

Cited by 15 publications

References 38 publications

The Nuclear Protein IκBζ Forms a Transcriptionally Active Complex with Nuclear Factor-κB (NF-κB) p50 and the Lcn2 Promoter via the N- and C-terminal Ankyrin Repeat Motifs

The Nuclear Protein IκBζ Forms a Transcriptionally Active Complex with Nuclear Factor-κB (NF-κB) p50 and the Lcn2 Promoter via the N- and C-terminal Ankyrin Repeat Motifs

Cell autonomous and noncell‐autonomous role of NF‐κB p50 in astrocyte‐mediated fate specification of adult neural progenitor cells

Neutrophil gelatinase-associated lipocalin and innate immune responses to bacterial infections

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