Beyond NF-κB activation: nuclear functions of IκB kinase α

Huang, Wei-Chien; Hung, Mien‐Chie

doi:10.1186/1423-0127-20-3

Cited by 95 publications

(82 citation statements)

References 87 publications

(164 reference statements)

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“…In that study, increased cytosolic IKKα was suggested to increase the phosphorylation of IKKα by Akt, thereby leading to nuclear accumulation of IKKα and supporting the diverse functions of IKKα such as apoptosis, tumor suppression, actions on the immune system, cell proliferation and chromatin remodeling in an NF-κB independent manner (14). In addition, the increased cytosolic IκBα observed in our Bifidobacterium spp.…”

Section: Discussionmentioning

confidence: 80%

Bifidobacterium species lower serum glucose, increase expressions of insulin signaling proteins, and improve adipokine profile in diabetic mice

Hosaka

Nguyen

et al. 2015

Biomed. Res.

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This study, using C57BL/6J mice with streptozotocin (STZ)-induced diabetes, aimed to determine whether Bifidobacterium species (spp.) both induces the expressions of proteins in the insulin signaling pathway and enhances the expressions of certain adipocytokines. The protein expressions of IκB kinase alpha (IKKα), IκB kinase beta (IKKβ), nuclear factor-kappaB inhibitor alpha (IκBα), and the mitogen-activated protein kinase (MAPK) pathway were also investigated. Oral administration of Bifidobacterium spp. reduced blood glucose levels significantly and increased the protein expressions of insulin receptor beta, insulin receptor substrate 1, protein kinase B (Akt/PKB), IKKα, and IκBα. Extracellular-signal-regulated kinase 2 (ERK2) showed increased expression. Bifidobacterium spp. also induced the adiponectin expression and decreased both macrophage chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) expression. In addition, IKKβ, c-Jun NH 2 -terminal kinase (JNK) and p38 MAP kinase expressions showed no significant changes in both groups. In conclusion, Bifidobacterium spp. may be the promising bacteria for treating diabetes.Strains including B. bifidum, B. longum, B. infantis, and B. animalis are Bifidobacterium spp., which comprise genus of gram-positive, non-motile, often branched anaerobic bacteria. Bifidobacteria are used as probiotics for supporting digestion in many countries. To date, several studies have demonstrated the benefits of probiotics in managing metabolic disorders including diabetes. At present, there are research groups focusing on this novel concept. Dietary supplementation with multiple probiotic strains, including L. acidophilus, L. casei, L. rhamnosus, L. bulgaricus, B. breve, B. longum, and S. thermophi-

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Section: Discussionmentioning

confidence: 80%

Bifidobacterium species lower serum glucose, increase expressions of insulin signaling proteins, and improve adipokine profile in diabetic mice

Hosaka

Nguyen

et al. 2015

Biomed. Res.

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“…Although the ability of IKKα to restore NF-κB signaling (data not shown) and rescue tumor invasion in MDA-MB-231 and MDA-MB-468 cells following CITED2 knockdown (Fig. 5B and C) implicates involvement of the NF-κB pathway, it should be noted that IKKα can also exert NF-κB-independent effects (36). Thus, further investigation is required not only to assess the mechanism whereby CITED2 modulates NF-κB activity, but also to determine the extent of its contribution to the pro-metastatic effects of CITED2, as well as the ultimate effectors of its action.…”

Section: Discussionmentioning

confidence: 93%

CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKα

Jayaraman

Doucet

Lau

et al. 2016

Molecular Cancer Research

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Previously, we identified the transcriptional co-activator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, CITED2 expression was stably reduced in the human breast cancer cell lines MDA-MB-231 and MDA-MB-468, which are metastatic in animal models. While CITED2 knockdown had no effect on cell proliferation, cell migration and invasion were significantly reduced, as was the establishment of metastasis following intra-cardiac administration in athymic nude mice. To explore the mechanism behind these effects, gene expression following CITED2 knockdown in MDA-MB-231 cells by cDNA microarray was performed. As confirmed at the mRNA and protein levels in both MDA-MB-231 and MDA-MB-468 cells, expression of the NF-κB regulator IKKα was significantly reduced along with several NF-κB targets with known roles in metastasis (OPN, MMP9, uPA, SPARC, IL-11 and IL-1β). Further, ChIP assay revealed recruitment of CITED2 to the promoter of IKKα, indicating a direct role in regulating its expression. Consistent with reduced IKKα expression, CITED2 knockdown inhibited both canonical and non-canonical NF-κB signaling. Finally, restoration of IKKα expression following CITED2 knockdown in MDA-MB-231 and MDA-MB-468 cells rescued their invasive ability. Collectively, these data demonstrate that CITED2 modulates metastatic ability in human breast cancer cells, at least in part, through the regulation of IKKα. Implications The current study highlights the role of CITED2 in facilitating breast cancer metastasis, partly via regulation of IKKα.

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“…Phosphorylation of IκB induces its degradation and releases NF-κB which then translocates to the nucleus to regulate gene expression. In addition to this canonical NF-κB pathway, most recent evidence supports that IKKα can also regulate cellular function via NF-κB-independent manner including phosphorylation of histone in nucleus (39). Here we show that Th17 differentiation is stimulated by IKKα-dependent phosphorylation of RORγt at serine 376 (S376), whereas IKKα-independent phosphorylation of RORγt at serine 484 inhibits Th17 differentiation.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Th17 Differentiation by IKKα-Dependent and -Independent Phosphorylation of RORγt

Wang

Zhang

et al. 2017

The Journal of Immunology

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Transcription factor retinoid acid-related orphan receptor gamma t (RORγt) transcriptionally regulates the genes required for differentiation of T helper 17 (Th17) cells that mediate both protective and pathogenic immunity. However, little is known about the function of post-translational modifications in the regulation of RORγt activity. Mass spectrometric analysis of immunoprecipitated RORγt from Th17 cells identified multiple phosphorylation sites. Systematic mutation analysis of the identified phosphorylation sites find that phosphorylation of serine 376 (S376) enhances whereas phosphorylation of serine 484 (S484) inhibits Th17 differentiation. IKKα binds and phosphorylates RORγt at S376 but not S484. Knockdown of IKKα, dominant negative IKKα and RORγt mutants incapable of interacting with IKKα all decrease Th17 differentiation. Furthermore, nonphosophorylatable RORγt mutant (S376A) impairs whereas phosphomimetic mutant (S376E) stimulates Th17 differentiation independent of IKKα. Therefore, IKKα-dependent phosphorylation of S376 stimulated whereas IKKα-independent phosphorylation of S484 inhibited RORγt function in Th17 differentiation.

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Beyond NF-κB activation: nuclear functions of IκB kinase α

Cited by 95 publications

References 87 publications

<i><b>Bifidobacterium</b></i><b> species lower serum glucose, increase expressions of insulin signaling proteins, and improve adipokine profile in diabetic </b><b>mice </b>

<i><b>Bifidobacterium</b></i><b> species lower serum glucose, increase expressions of insulin signaling proteins, and improve adipokine profile in diabetic </b><b>mice </b>

CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKα

Regulation of Th17 Differentiation by IKKα-Dependent and -Independent Phosphorylation of RORγt

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