The effect of IKKβ on estrogen receptor positive breast cancer phenotypes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85683 | GEO | 2016/08/17
SECONDARY ACCESSION(S): PRJNA339054
REPOSITORIES: GEO
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Project description:Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified up-regulated DCLK1 in macrophages in atherosclerotic lesions of ApoE-/- mice fed an HFD and determined that macrophage-specific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL-induced inflammation via NF-κB signaling pathway in primary macrophages. Co-immunoprecipitation followed by LC-MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF-κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF-κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis.
2023-02-27 | PXD039083 | Pride
Project description:Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified up-regulated DCLK1 in macrophages in atherosclerotic lesions of ApoE-/- mice fed an HFD and determined that macrophage-specific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL-induced inflammation via NF-κB signaling pathway in primary macrophages. Co-immunoprecipitation followed by LC-MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF-κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF-κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis.
2022-12-24 | GSE221647 | GEO
Project description:IRAK4 kinase plays a critical role in innate immune responses and inflammation by modulating the TLR/IL-1R signaling pathway, yet the mechanism by which it regulates downstream pathways and transcription factors to induce inflammatory cytokines is unclear. IRAK4 can mediate signaling events by mechanisms both dependent and independent of its kinase activity. Understanding this regulation is important for deciphering the role of IRAK4 and for the development of treatments for inflammatory diseases and cancer. Through transcriptomic and biochemical analyses of primary human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the transcription factor IRF5 which in turn induces inflammatory cytokine and type I interferon transcription in myeloid cells. We also show that IRAK4 kinase activity does not control activation of NF-κB. Following TLR stimulation, translocation of IRF5, but not NF-κB, to the nucleus in human monocytes is abolished by IRAK4 kinase inhibition. In addition, binding of IRF5, but not NF-κB p65, to promoters of inflammatory target genes (TNF-α and IP10) is blocked with an IRAK4 kinase inhibitor. IKKβ, a known activator of IRF5, is phosphorylated in response to TLR mediated signaling, and inhibition of IRAK4 kinase blocks IKKβ phosphorylation. Pharmacological inhibition of IKKβ and TAK1, the upstream kinase of IKKβ, in human monocytes blocks IL-1, IL-6 and TNF-α cytokine production, as well as IRF5 translocation to the nucleus. Taken together, our data suggest a novel mechanism by which IRAK4 kinase activity regulates TAK1 and IKKβ activation, leading to the translocation of IRF5 and induction of inflammatory cytokines in human monocytes.
2017-10-12 | GSE86234 | GEO
Project description:Microglial overactivation is actively involved in the pathogenesis of neurodegenerative diseases. Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. Here, we identified PLK2 as an important early response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuated LPS-induced expression of pro-inflammatory factors such as IL-1β, IL-6, COX2, TNF-α, and iNOS in microglial cells via suppressing the IKKβ-NF-κB signaling pathway. Notably, overexpression of PLK2 induced expression of pro-inflammatory factors and NF-κB transcriptional activation in the absence of inflammatory stimuli. Mechanistically, co-immunoprecipitation experiments revealed association between PLK2 and IKKβ, whereas GST pull-down assay showed no direct interaction between PLK2 and IKKβ. Proteomic analysis and in vitro kinase assay identified heat shock protein 90 alpha (HSP90α), a regulator of IKKβ activity, as a novel PLK2 substrate. Knockdown or pharmacological inhibition of HSP90α abolished PLK2-mediated activation of NF-κB transcriptional activity and microglial inflammatory activation. Furthermore, phosphoproteomic analysis pinpointed Ser252 and Ser263 on HSP90α as novel phosphorylation targets of PLK2. Subsequent functional studies demonstrated that re-expression of phosphor-dead mutation of these two phosphorylation sites on HSP90α failed to rescue the PLK2-induced activation of the NF-κB signaling. Lastly, conditional knockout of PLK2 in microglial cells dramatically ameliorated neuroinflammation and subsequent dopaminergic neuron loss in an intracranial LPS-induced mouse PD model. The present study revealed, for the first time, that PLK2 promoted microglial activation through the phosphorylation of HSP90α and subsequent activation of the IKKβ-NF-κB signaling pathway. Consequently, PLK2 emerges as a potential therapeutic target for the amelioration of neuroinflammation-related diseases.
2024-09-04 | GSE272635 | GEO
Project description:Microglial overactivation is actively involved in the pathogenesis of neurodegenerative diseases. Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. Here, we identified PLK2 as an important early response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuated LPS-induced expression of pro-inflammatory factors such as IL-1β, IL-6, COX2, TNF-α,and iNOS in microglial cells via suppressing the IKKβ-NF-κB signaling pathway.Notably, overexpression of PLK2 induced expression of pro-inflammatory factors and NF-κB transcriptional activation in the absence of inflammatory stimuli. Mechanistically,co-immunoprecipitation experiments revealed association between PLK2 and IKKβ, whereas GST pull-down assay showed no direct interaction between PLK2 and IKKβ. Proteomic analysis and in vitro kinase assay identified heat shock protein 90 alpha (HSP90α), a regulator of IKKβ activity, as a novel PLK2 substrate. Knockdown or pharmacological inhibition of HSP90α abolished PLK2-mediated activation of NF-κB transcriptional activity and microglial inflammatory activation. Furthermore,phosphoproteomic analysis pinpointed Ser252 and Ser263 on HSP90α as novel phosphorylation targets of PLK2. Subsequent functional studies demonstrated that re-expression of phosphor-dead mutation of these two phosphorylation sites on HSP90α failed to rescue the PLK2-induced activation of the NF-κB signaling. Lastly, conditional knockout of PLK2 in microglial cells dramatically ameliorated neuroinflammation and subsequent dopaminergic neuron loss in an intracranial LPS-induced mouse PD model. The present study revealed, for the first time, that PLK2 promoted microglial activation through the phosphorylation of HSP90α and subsequent activation of the IKKβ-NF-κB signaling pathway. Consequently, PLK2 emerges as a potential therapeutic target for the amelioration of neuroinflammation-related diseases.
2024-09-04 | GSE276245 | GEO
Project description:Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis, and its levels are elevated in various human cancers. Recent studies suggest that DCLK1 may relate to inflammatory responses in the mouse model of colitis. However, cellular pathways engaged by DCLK1, and potential substrates of the kinase remain undefined. To understand how DCLK1 regulates inflammatory responses, we utilized the well-established lipopolysaccharide (LPS)-stimulated macrophages and mouse model. Through a range of macrophage-based and cell-free platforms, we discovered that DCLK1 binds directly with the inhibitor of κB kinase β (IKKβ) and induces IKKβ phosphorylation on Ser177/181 to initiate nuclear factor-κB (NF-κB) pathway. Deficiency in DCLK1, achieved by silencing or through pharmacological inhibition, prevented LPS-induced NF-κB activation and cytokine production in macrophages. We further show that mice with myeloid-specific DCLK1 knockout or DCLK1 inhibitor treatment are protected against LPS-induced acute lung injury and septic death. Our studies report a novel functional role of macrophage DCLK1 as a direct IKKβ regulator in inflammatory signaling and suggest targeted therapy against DCLK1 for inflammatory diseases.
2023-03-20 | GSE224030 | GEO
Project description:IKKβ-dependent NF-κB activation is associated with inflammation and tumorigenesis and is critical for innate immunity. Despite risk of immune suppression, pharmacological blockade of IKKβ/NF-κB has been considered as an attractive strategy for treatment of inflammatory diseases and cancer. Unexpectedly, treatment with IKKβ inhibitors caused neutrophilia, which also occurs in mice with inducible IKKβ deletion, termed IkkβΔ mice. IkkβΔ mice show hyperproliferation of granulocyte progenitors and increased neutrophil lifespan. Deletion of IL-1 receptor 1 in IkkβΔ mice restored normal blood cellularity and prevented neutrophil-driven inflammation. However, IkkβΔ/Il-1r1-/- mice, in contrast to IkkβΔ mice, are highly susceptible to bacterial infections indicating that either IKKβ/NF-κB or IL-1R signaling are sufficient for maintaining anti-microbial defenses, but inactivation of both pathways severely compromises innate immunity. Thioglycollate-elicited peritoneal neutrophils were purified from IkkβF/F and IkkβΔ mice using anti-Ly-6G magnetic beads and cultured. Ly-6G+ neutrophils were collected and total RNA was extracted with TRIzol® (Invitrogen) and was purified by RNA micro cleanup Kit (Qiagen). Biotinylated cRNA was synthesized using an RNA Amplification Kit (Ambion) following manufacturer's directions. Biotin-labeled cRNA was hybridized to Illumina Mouse-Ref8 BeadChips (Illumina) and the results were analyzed using BeadStudio v3.1 software. Data analysis and quality control were carried out using Partek® software.
2010-11-12 | E-GEOD-25211 | biostudies-arrayexpress
Project description:IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. Absence of IKKα cause fetal encasement syndrome in human, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and cause combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were kinase dead mutants. Non-canonical NF-κB activation was abolished in stromal and immune cells while the canonical pathway was partially impaired. Reintroducing wild-type CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of bi-allelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding and suggesting IKKα's role in both NF-κB pathways.
2024-11-24 | GSE267600 | GEO
Project description:IKKβ-dependent NF-κB activation is associated with inflammation and tumorigenesis and is critical for innate immunity. Despite risk of immune suppression, pharmacological blockade of IKKβ/NF-κB has been considered as an attractive strategy for treatment of inflammatory diseases and cancer. Unexpectedly, treatment with IKKβ inhibitors caused neutrophilia, which also occurs in mice with inducible IKKβ deletion, termed IkkβΔ mice. IkkβΔ mice show hyperproliferation of granulocyte progenitors and increased neutrophil lifespan. Deletion of IL-1 receptor 1 in IkkβΔ mice restored normal blood cellularity and prevented neutrophil-driven inflammation. However, IkkβΔ/Il-1r1-/- mice, in contrast to IkkβΔ mice, are highly susceptible to bacterial infections indicating that either IKKβ/NF-κB or IL-1R signaling are sufficient for maintaining anti-microbial defenses, but inactivation of both pathways severely compromises innate immunity.
2010-11-12 | GSE25211 | GEO
Project description:Existing data suggest that NF-kappaB signaling is a key regulator of cancer-induced skeletal muscle wasting. However, identification of the components of this signaling pathway and of the NF-κB transcription factors that regulate wasting is far from complete. In muscles of C26 tumor bearing mice, overexpression of d.n. IKKβ blocked muscle wasting by 69%, the IκBα-super repressor blocked wasting by 41%. In contrast, overexpression of d.n. IKKα or d.n. NIK did not block C26-induced wasting. Surprisingly, overexpression of d.n. p65 or d.n. c-Rel did not significantly block muscle wasting. Genome-wide mRNA expression arrays showed upregulation of many genes previously implicated in muscle atrophy. To test if these upregulated genes were direct targets of NF-κB transcription factors, we compared genome-wide p65 or p50 binding to DNA in control and cachectic muscle using ChIP-sequencing. Bioinformatic analysis of ChIP-seq data from control and C26 muscles showed increased p65 and p50 binding to a few regulatory and structural genes but only two of these genes were upregulated with atrophy. The p65 and p50 ChIP-seq data are consistent with our finding of no significant change in protein binding to an NF-κB oligo in a gel shift assay. Taken together, these data support the idea that although inhibition of IκBα, and particularly IKKβ, blocks cancer-induced wasting, the alternative NF-κB signaling pathway is not required. In addition, the downstream NF-κB transcription factors do not regulate the transcriptional changes. These data are consistent with the growing body of literature showing that there are NF-κB-independent substrates of IKKβ and IκBα that regulate physiological processes.
2013-11-15 | GSE48363 | GEO