Polo like kinase 2 (PLK2) promotes microglial activation via regulation of the HSP90α/IKKβ pathway [II]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1156083 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30527222_1.fastq.gz | Fastqsanger.gz | |||
| SRR30527222_2.fastq.gz | Fastqsanger.gz | |||
| SRR30527223_1.fastq.gz | Fastqsanger.gz | |||
| SRR30527223_2.fastq.gz | Fastqsanger.gz | |||
| SRR30527224_1.fastq.gz | Fastqsanger.gz |
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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:Polo like kinase 2 (PLK2) promotes microglial activation via regulation of the HSP90α/IKKβ pathway
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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:Transcriptomic profiling was applied to investigate the effects of polo-like kinase 1 inhibition in triple-negative breast cancer.
2022-08-29 | GSE184295 | GEO
Project description:Identify gene expression changes in the absence of Plk2 Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis. Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis. Comparison between Plk2 +/+ (n=3) and Plk2 -/- (n=3) mouse mammary epithelial cells
2014-05-20 | E-GEOD-50003 | biostudies-arrayexpress
Project description:The development of a complex organ requires the proper differentiation and production of appropriate numbers of each of its constituent cell types, as well as their correct positioning within the organ. During Drosophila cardiogenesis, all three of these processes are controlled by jumeau (jumu) and Checkpoint suppressor homologue (CHES-1-like), two genes encoding forkhead transcription factors that were discovered utilizing an integrated genetic, genomic and computational strategy which identified 70 novel genes expressed in the developing Drosophila heart. Both jumu and CHES-1-like are required during asymmetric cell division for the derivation of two distinct cardiac cell types from their mutual precursor, and in symmetric cell division to produce yet a third type of heart cell. jumu and CHES-1-like control the division of cardiac progenitors by regulating the activity of Polo, a kinase involved in multiple steps of mitosis. This pathway demonstrates how transcription factors integrate diverse developmental processes during organogenesis. GFP-positive cells were profiled from Stage 11-12 Drosophila embryos of the following two genotypes: twi-GAL4 UAS-2EGFP/UAS-jumu and twi-GAL4 UAS-2EGFP
2012-01-30 | E-GEOD-34946 | biostudies-arrayexpress
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:We demonstrate that Polo-like kinase 4(PLK4) is overexpressed in human bladder cancer (BC) cell lines and tissues, and its overexpression correlates with poor prognosis. PLK4 inhibition suppresses BC cell growth and induces G1 phase arrest via activating p38/p53/p21 pathway in vitro and in vivo. The data suggest that PLK4 might serve as a novel molecular target for BC treatment.
2021-07-29 | GSE180958 | GEO
Project description:Identify gene expression changes in the absence of Plk2 Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis. Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis.
2014-05-20 | GSE50003 | GEO