Study of the effect of Protein Kinase CK2 alpha prime in the transcriptional deficits associated with Huntington's disease
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ABSTRACT:
PROVIDER: PRJNA673700 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12960900_1.fastq.gz | Fastqsanger.gz | |||
| SRR12960900_2.fastq.gz | Fastqsanger.gz | |||
| SRR12960901_1.fastq.gz | Fastqsanger.gz | |||
| SRR12960901_2.fastq.gz | Fastqsanger.gz | |||
| SRR12960902_1.fastq.gz | Fastqsanger.gz |
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Project description:Protein kinase CK2 alpha prime (CK2a') is preferentially upregulated in the striatum of patients with HD and in different cellular and mouse models of HD. CK2a' happloinsufficiency in the zQ175 HD mouse model restored several HD-like phenotypes. We hypothesized that CK2a' neuronal up-regulation is linked to key transcriptional alterations in the zQ175 mouse model. We found that CK2a' haploinsufficiency rescued the expression of genes associated with synaptogenesis and glutamatergic signaling whose upstream regulator seems to be alpha-synuclein. These transcriptomic studies revealed a conection between CK2a', alpha-synuclein dysfunction and transcriptional changes in key signaling pathways.
2022-06-23 | GSE160586 | GEO
Project description:Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene for which no therapies are available. HTT mutation causes protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated the role of protein kinase CK2α', a kinase upregulated in MSNs in HD and previously associated with Parkinson's disease (PD), in the regulation of neuroinflammation and synaptic function in HD. We used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α' (zQ175:CK2α'(±)). CK2α' haploinsufficiency in zQ175 mice resulted in decreased levels of pro-inflammatory cytokines, HTT aggregation, astrogliosis and transcriptional alterations of synaptic genes related to glutamatergic signaling. zQ175:CK2α'(±) mice also presented increased frequency of striatal miniature excitatory postsynaptic currents (mEPSCs), an indicator of synaptic activity, and improved motor coordination compared to zQ175 mice. Neuropathological and phenotypic changes mediated by CK2α' were connected to alpha-synuclein (α-syn) dysregulation and correlated with differences in α-syn serine 129 phosphorylation (pS129-α-syn), a post-translational modification involved in α-synucleinopathy and shown to be regulated by CK2 in PD. pS129-α-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatum of patients with HD, and it decreased in zQ175:CK2α'(±) mice. Collectively, our data established a novel connection between CK2α', neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggested common molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2α' inhibition as a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD.
| S-EPMC9164558 | biostudies-literature
Project description:Maf-family basic motif leucine zipper protein NRL specifies rod photoreceptor cell fate during retinal development and, in concert with homeodomain protein CRX and other regulatory factors, controls the expression of most rod-expressed genes including the visual pigment gene RHO (rhodopsin). Transcriptional regulatory activity of NRL is modulated by post-translational modifications (PTMs), specially phosphorylation, and mutations in phosphosites can lead to retinal degeneration. During our studies to elucidate NRL-mediated transcriptional regulation, we identified Protein Kinase CK2 in NRL-enriched complexes bound to RHO promoter-enhancer regions and in NRL-enriched high molecular mass fractions from the bovine retina. The presence of CK2 in NRL complexes was confirmed by co-immunoprecipitation from developing and adult mouse retinal extracts. Bioinformatic and mass spectrometry analysis indicated potential phosphorylation of NRL at Ser117 residue by CK2. Co-transfection of Csnk2a1 cDNA encoding CK2 with NRL and CRX reduced the bovine Rho promoter-driven luciferase expression in HEK293 cells, and mutagenesis of NRL-Ser117 residue to Ala restored the reporter gene expression. In concordance, overexpression of CK2 in the mouse retina in vivo by electroporation resulted in reduction of Rho promoter-driven DsRed reporter gene expression. RNA-seq analysis of CK2-electroporated retina revealed altered expression of many transcriptional targets of NRL. Thus, our studies demonstrate an important role of CK2 in context-dependent fine-tuning of NRL function, consequently modulating the expression of rod photoreceptor genes.
2024-04-06 | GSE171665 | GEO
Project description:Protein kinase 2 (CK2) is a serine/threonine kinase composed of two catalytic subunits (CK2α and/or CK2α') and two regulatory subunits (CK2β). CK2 has been shown to promote cancer progression by regulating the NF-κB, PI3K/AKT/mTOR, JAK/STAT and HIF-1α pathways, and also plays a critical role for immune cell development and function. However, the potential involvement of CK2 in CD8+ T-cell function has not explored. Here, we demonstrate that CK2 protein levels and kinase activity are enhanced upon CD8+ T-cell activation. CK2α deficiency results in impaired CD8+ T-cell activation and proliferation upon TCR stimulation. Furthermore, CK2α is involved in CD8+ T-cell metabolic reprogramming during activation through regulating the AKT/mTOR signaling pathway. Lastly, using a Listeria monocytogenes infection model, we demonstrate that CK2α is required for CD8+ T-cell expansion, maintenance and effector function in both primary and memory immune responses. Taken together, our study implicates CK2 as an important regulator of CD8+ T-cell activation and differentiation both in vitro and in vivo.
2022-06-21 | GSE175941 | GEO
Project description:CK2 binds to actively transcribed regions in the genome and regulates transcriptional elongation. Identification of genome-wide binding sites of CK2?, and examination of the effect of Pol II binding upon CK2 inhibition in LNCaP cells
2014-09-30 | E-GEOD-58607 | biostudies-arrayexpress
Project description:Casein Kinase 2 (CK2) is an evolutionarily conserved kinase protein that phosphorylates a plethora of cellular target protein involved in processes including DNA repair, cell cycle control, and circadian rhythms. CK2 is functionally conserved across all eukaryotes, although the substrate proteins identified in targeted experiments on a diverse range of complex tissues are often different. A growing interest exists to identify conserved, core signalling principles essential to eukaryotic life. To efficiently study generic roles of CK2 in the cellular circadian clock, we used a minimal eukaryotic model organism (Ostreococcus tauri). Overexpression of CK2 leads to a slow circadian rhythm, verifying functional conservation of CK2 in cellular timekeeping. CK2 activity contributes more strongly to the clock around dusk than around dawn, and analysis of the phospho-proteome at this time revealed a strong overrepresentation of potential CK2 sites. Large changes to the phospho-proteome are reported here upon overexpression of CK2, identifying a set of CK2-responsive phospho-sites. To identify more CK2-specific phosphorylation events, the phospho-proteome of cells treated with CK2 inhibitor were analysed and compared to the overexpression lines. We thus report a full inventory of the CK2-responsive phospho-proteome to inform studies into CK2 activity in the circadian clock of more complex tissues, as science moves to understand and modulate cellular circadian rhythms to help us negate the negative effects of shiftwork or cross-continental travel.
2015-08-11 | PXD000975 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE33149: Substrate selectivity for semisynthetic CK2 proteins with various posttranslational modifications GSE33150: Substrate selectivity for semisynthetic CK2 proteins with Pin1 Refer to individual Series
2011-10-24 | E-GEOD-33151 | biostudies-arrayexpress
Project description:CK2 binds to actively transcribed regions in the genome and regulates transcriptional elongation.
2014-09-30 | GSE58607 | GEO
Project description:Crohn’s disease (CD) is one of the major forms of inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract. CD is associated with aberrant Th1 and Th17 responses accompanied by high levels of IFN-g and IL-17, respectively. Protein kinase 2 (CK2) is a highly conserved serine-threonine kinase that is involved in several signal transduction pathways which regulate inflammatory responses. CK2 promotes Th17 cell differentiation and suppresses the generation of Foxp3+ regulatory T cells. The function of CK2 in CD4+ T-cells during the pathogenesis of CD is unknown. We utilized T-cell induced colitis model, transferring CD45RBhi naïve CD4+ T-cells from CK2afl/fl littermate control and CK2afl/fldLck-Cre mice into Rag1-/- mice. We demonstrate that CD4+ T-cells from CK2afl/fldLck-Cre mice fail to induce wasting disease and significant intestinal inflammation, which is associated with decreased IL-17A+, IFN-g+ and double positive IL-17A+ IFN-g+ CD4+ T-cells in the spleen and colon. Further, we determine that CK2a regulates CD4+ T-cell proliferation through a cell-intrinsic manner. CK2a is also important in controlling CD4+ T-cell responses by regulating NFAT2, which is vital for T-cell activation and proliferation. Thus, our data demonstrate that CK2a contributes to the pathogenesis of colitis by promoting CD4+ T-cell proliferation and Th1 and Th17 responses, and that targeting CK2 kinase activity may be a novel therapeutic treatment for CD patients.
2020-08-05 | GSE131965 | GEO
Project description:Protein Ser/Thr kinase CK2 is involved in a myriad of cellular processes including cell growth and proliferation by phosphorylating hundreds of substrates, yet the regulation process of CK2 function is poorly understood. The CK2 catalytic subunit, CK2α, is modified by O-GlcNAc on Ser347 proximal to a Cdk1 phosphorylation site at Thr344 on the same protein. The substrate selectivity for protein kinase CK2 was examined by performing kinase assays on protein microarrays spotted with 17,000 human proteins. Semisynthetic CK2α proteins were prepared to contain an unmodified C-terminal tail, S-GlcNAc-Serine at S347, or Pfa (non-hyrdolyzeable phosphomimic) at T344. These semisynthetic proteins were used to determine if the posttranslational modifications on CK2 alpha modulate the substrate selectivity for this pleiotropic kinase. The different semisynthetic CK2α proteins were tested alone and in the presence of the regulatory subunit CK2β since it is known that the CK2α subunit is active both in its isolated state and in the heterotetrameric state formed in the presence of the regulatory beta subunit. The CK2β subunit has been shown to modulate CK2 activity with some substrates and not others. In the study presented here, kinase assays were performed using three different semisynthetic CK2 alpha proteins: unmodified C-terminal tail; S-GlcNAc-Ser at 347; and Pfa (phosphomimic) at 344. The semisynthetic proteins were each tested alone and in the presence of the regualatory CK2 beta subunit. There were six different kinase conditions and each condition was performed in duplicate and one no kinase control was performed to eliminate autophorylated proteins.
2011-10-24 | E-GEOD-33149 | biostudies-arrayexpress