Phosphoproteomic Landscape of AML Cells Treated with the ATP-Competitive CK2 Inhibitor CX-4945

Casein kinase 2 (CK2) regulates a plethora of proteins with pivotal roles in solid and hematological neoplasia. Particularly, in acute myeloid leukemia (AML) CK2 has been pointed as an attractive therapeutic target and prognostic marker. Here, we explored the impact of CK2 inhibition over the phosphoproteome of two cell lines representing major AML subtypes. Quantitative phosphoproteomic analysis was conducted to evaluate changes in phosphorylation levels after incubation with the ATP-competitive CK2 inhibitor CX-4945. Functional enrichment, network analysis, and database mining were performed to identify biological processes, signaling pathways, and CK2 substrates that are responsive to CX-4945. A total of 273 and 1310 phosphopeptides were found differentially modulated in HL-60 and OCI-AML3 cells, respectively. Despite regulated phosphopeptides belong to proteins involved in multiple biological processes and signaling pathways, most of these perturbations can be explain by direct CK2 inhibition rather than off-target effects. Furthermore, CK2 substrates regulated by CX-4945 are mainly related to mRNA processing, translation, DNA repair, and cell cycle. Overall, we evidenced that CK2 inhibitor CX-4945 impinge on mediators of signaling pathways and biological processes essential for primary AML cells survival and chemosensitivity, reinforcing the rationale behind the pharmacologic blockade of protein kinase CK2 for AML targeted therapy.

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Integrated lncRNA and mRNA Transcriptome Analyses in the Ovary of Cynoglossus semilaevis Reveal Genes and Pathways Potentially Involved in Reproduction

Frontiers in Genetics ◽

10.3389/fgene.2021.671729 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yani Dong ◽

Likang Lyu ◽

Daiqiang Zhang ◽

Jing Li ◽

Haishen Wen ◽

...

Keyword(s):

Signaling Pathways ◽

Target Genes ◽

Enrichment Analysis ◽

Mapk Signaling ◽

Cynoglossus Semilaevis ◽

Gene Set Enrichment Analysis ◽

Functional Enrichment ◽

Biological Processes ◽

Tongue Sole ◽

Oocyte Meiosis

Long non-coding RNAs (lncRNAs) have been reported to be involved in multiple biological processes. However, the roles of lncRNAs in the reproduction of half-smooth tongue sole (Cynoglossus semilaevis) are unclear, especially in the molecular regulatory mechanism driving ovarian development and ovulation. Thus, to explore the mRNA and lncRNA mechanisms regulating reproduction, we collected tongue sole ovaries in three stages for RNA sequencing. In stage IV vs. V, we identified 312 differentially expressed (DE) mRNAs and 58 DE lncRNAs. In stage V vs. VI, we identified 1,059 DE mRNAs and 187 DE lncRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DE mRNAs were enriched in ECM-receptor interaction, oocyte meiosis and steroid hormone biosynthesis pathways. Furthermore, we carried out gene set enrichment analysis (GSEA) to identify potential reproduction related-pathways additionally, such as fatty metabolism and retinol metabolism. Based on enrichment analysis, DE mRNAs with a potential role in reproduction were selected and classified into six categories, including signal transduction, cell growth and death, immune response, metabolism, transport and catabolism, and cell junction. The interactions of DE lncRNAs and mRNAs were predicted according to antisense, cis-, and trans-regulatory mechanisms. We constructed a competing endogenous RNA (ceRNA) network. Several lncRNAs were predicted to regulate genes related to reproduction including cyp17a1, cyp19a1, mmp14, pgr, and hsd17b1. The functional enrichment analysis of these target genes of lncRNAs revealed that they were involved in several signaling pathways, such as the TGF-beta, Wnt signaling, and MAPK signaling pathways and reproduction related-pathways such as the progesterone-mediated oocyte maturation, oocyte meiosis, and GnRH signaling pathway. RT-qPCR analysis showed that two lncRNAs (XR_522278.2 and XR_522171.2) were mainly expressed in the ovary. Dual-fluorescence in situ hybridization experiments showed that both XR_522278.2 and XR_522171.2 colocalized with their target genes cyp17a1 and cyp19a1, respectively, in the follicular cell layer. The results further demonstrated that lncRNAs might be involved in the biological processes by modulating gene expression. Taken together, this study provides lncRNA profiles in the ovary of tongue sole and further insight into the role of lncRNA involvement in regulating reproduction in tongue sole.

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The protein kinase CK2 inhibitor TBB mediates up-regulation of MEK3/6 and p38δ activities, down-regulation of ERK1/2 activity and induction of G1/S arrest in normal human epidermal autocrine proliferating keratinocytes

Journal of Dermatological Science ◽

10.1016/j.jdermsci.2011.04.005 ◽

2011 ◽

Author(s):

Antonia Rumenova Isaeva ◽

Vanyo Ivanov Mitev

Keyword(s):

Protein Kinase ◽

Protein Kinase Ck2 ◽

Down Regulation ◽

Normal Human ◽

Kinase Ck2 ◽

Ck2 Inhibitor

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SGC-CK2-1 Is an Efficient Inducer of Insulin Production and Secretion in Pancreatic β-Cells

Pharmaceutics ◽

10.3390/pharmaceutics14010019 ◽

2021 ◽

Vol 14 (1) ◽

pp. 19

Author(s):

Mandy Pack ◽

Claudia Götz ◽

Selina Wrublewsky ◽

Mathias Montenarh

Keyword(s):

Protein Kinase ◽

Protein Kinase Ck2 ◽

High Specificity ◽

Insulin Production ◽

Biological Functions ◽

Β Cells ◽

Pancreatic Β Cells ◽

Storage Vesicles ◽

Kinase Ck2 ◽

Ck2 Inhibitor

The pyrazolopyrimidine based compound SGC-CK2-1 is a potent and highly specific CK2 inhibitor and a new tool to study the biological functions of protein kinase CK2 irrespective from off-target effects. We used this compound in comparison with the well-established CK2 inhibitor CX-4945 to analyze the importance of CK2 for insulin production and secretion from pancreatic β-cells. Both inhibitors affected the proliferation and viability of MIN6 cells only marginally and downregulated the endogenous CK2 activity to a similar level. Furthermore, both inhibitors increased the message for insulin and boosted the secretion of insulin from storage vesicles. Thus, regarding the high specificity of SGC-CK2-1, we can clearly attribute the observed effects to biological functions of protein kinase CK2.

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Protein Kinase CK2 and Dysregulated Oncogenic Inflammatory Signaling Pathways

Protein Kinase CK2 Cellular Function in Normal and Disease States ◽

10.1007/978-3-319-14544-0_15 ◽

2015 ◽

pp. 259-280 ◽

Cited By ~ 2

Author(s):

Etty N. Benveniste ◽

G. Kenneth Gray ◽

Braden C. McFarland

Keyword(s):

Protein Kinase ◽

Signaling Pathways ◽

Protein Kinase Ck2 ◽

Inflammatory Signaling ◽

Kinase Ck2

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Mature miR-99a Upregulation in the Amniotic Fluid Samples from Female Fetus Down Syndrome Pregnancies: A Pilot Study

Medicina ◽

10.3390/medicina55110728 ◽

2019 ◽

Vol 55 (11) ◽

pp. 728

Author(s):

Anda-Cornelia Vizitiu ◽

Danae Stambouli ◽

Anca-Gabriela Pavel ◽

Maria-Cezara Muresan ◽

Diana Maria Anastasiu ◽

...

Keyword(s):

Down Syndrome ◽

Amniotic Fluid ◽

Signaling Pathways ◽

Functional Enrichment ◽

Chromosome 21 ◽

Female Fetus ◽

Expression Levels ◽

Qrt Pcr ◽

Second Trimester Screening ◽

The Impact

Background and Objective: Although Down syndrome is the most frequent aneuploidy, its pathogenic molecular mechanisms are not yet fully understood. The aim of our study is to quantify—by qRT-PCR—the expression levels of both the mature forms and the pri-miRNAs of the microRNAs resident on chromosome 21 (miR(21)) in the amniotic fluid samples from Down syndrome singleton pregnancies and to estimate the impact of the differentially expressed microRNAs on Down syndrome fetal heart and amniocytes transcriptomes. Materials and methods: We collected amniotic fluid samples harvested by trained obstetricians as part of the second trimester screening/diagnostic procedure for aneuploidies to assess the trisomy 21 status by QF-PCR and karyotyping. Next, we evaluated—by Taqman qRT-PCR—the expression levels of both the mature forms and the pri-miRNA precursors of the microRNAs resident on chromosome 21 in amniotic fluid samples from singleton Down syndrome and euploid pregnancies. Further, we combined miRWalk 3.0 microRNA target prediction with GEO DataSets analysis to estimate the impact of hsa-miR-99a abnormal expression on Down syndrome heart and amniocytes transcriptome. Results: We found a statistically significant up-regulation of the mature form of miR-99a, but not pri-miR-99a, in the amniotic fluid samples from Down syndrome pregnancies with female fetuses. GATHER functional enrichment analysis of miRWalk3.0-predicted targets from Down syndrome amniocytes and fetal hearts transcriptome GEODataSets outlined both focal adhesion and cytokine–cytokine receptor interaction signaling as novel signaling pathways impacted by miR-99a and associated with cardiac defects in female Down syndrome patients. Conclusions: The significant overexpression of miR-99a, but not pri-miR-99a, points towards an alteration of the post-transcriptional mechanisms of hsa-miR-99a maturation and/or stability in the female trisomic milieu, with a potential impact on signaling pathways important for proper development of the heart.

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