Persistent nuclear accumulation of protein kinase CK2 during the G1-phase of the cell cycle does not depend on the ERK1/2 pathway but requires active protein synthesis

ABSTRACT Protein kinase CK2 is a multifunctional enzyme which has long been described as a stable heterotetrameric complex resulting from the association of two catalytic (α or α′) and two regulatory (β) subunits. To track the spatiotemporal dynamics of CK2 in living cells, we fused its catalytic α and regulatory β subunits with green fluorescent protein (GFP). Both CK2 subunits contain nuclear localization domains that target them independently to the nucleus. Imaging of stable cell lines expressing low levels of GFP-CK2α or GFP-CK2β revealed the existence of CK2 subunit subpopulations exhibiting differential dynamics. Once in the nucleus, they diffuse randomly at different rates. Unlike CK2β, CK2α can shuttle, showing the dynamic nature of the nucleocytoplasmic trafficking of the kinase. When microinjected in the cytoplasm, the isolated CK2 subunits are rapidly translocated into the nucleus, whereas the holoenzyme complex remains in this cell compartment, suggesting an intramolecular masking of the nuclear localization sequences that suppresses nuclear accumulation. However, binding of FGF-2 to the holoenzyme triggers its nuclear translocation. Since the substrate specificity of CK2α is dramatically changed by its association with CK2β, the control of the nucleocytoplasmic distribution of each subunit may represent a unique potential regulatory mechanism for CK2 activity.

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Protein kinase CK2 activates the atypical Rio1p kinase and promotes its cell-cycle phase-dependent degradation in yeast

FEBS Journal ◽

10.1111/j.1742-4658.2007.05993.x ◽

2007 ◽

Vol 274 (17) ◽

pp. 4654-4667 ◽

Cited By ~ 18

Author(s):

Michaela Angermayr ◽

Elisabeth Hochleitner ◽

Friedrich Lottspeich ◽

Wolfhard Bandlow

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Protein Kinase Ck2 ◽

Cell Cycle Phase ◽

Cycle Phase ◽

Kinase Ck2

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The regulatory β-subunit of protein kinase CK2 regulates cell-cycle progression at the onset of mitosis

Oncogene ◽

10.1038/onc.2008.146 ◽

2008 ◽

Vol 27 (37) ◽

pp. 4986-4997 ◽

Cited By ~ 38

Author(s):

C W Yde ◽

B B Olsen ◽

D Meek ◽

N Watanabe ◽

B Guerra

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Protein Kinase Ck2 ◽

Cell Cycle Progression ◽

Β Subunit ◽

Cycle Progression ◽

Kinase Ck2

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Cell cycle dependent regulation of protein kinase CK2 signaling to the nuclear matrix

Journal of Cellular Biochemistry ◽

10.1002/jcb.10438 ◽

2003 ◽

Vol 88 (4) ◽

pp. 812-822 ◽

Cited By ~ 24

Author(s):

Huamin Wang ◽

Shihui Yu ◽

Alan T. Davis ◽

Khalil Ahmed

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Nuclear Matrix ◽

Protein Kinase Ck2 ◽

Cycle Dependent ◽

Kinase Ck2

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Protein kinase CK2 in gene control at cell cycle entry

Molecular and Cellular Biochemistry ◽

10.1007/s11010-005-2951-1 ◽

2005 ◽

Vol 274 (1-2) ◽

pp. 189-200 ◽

Cited By ~ 5

Author(s):

Walter Pyerin ◽

Thomas Barz ◽

Karin Ackermann

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Protein Kinase Ck2 ◽

Gene Control ◽

Cell Cycle Entry ◽

Kinase Ck2

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Down-regulation of CK2α correlates with decreased expression levels of DNA replication minichromosome maintenance protein complex (MCM) genes

Scientific Reports ◽

10.1038/s41598-019-51056-5 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Susanne Schaefer ◽

Thomas K. Doktor ◽

Sabrina B. Frederiksen ◽

Kathleen Chea ◽

Mirka Hlavacova ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Cell Proliferation ◽

Dna Replication ◽

Protein Kinase ◽

Protein Kinase Ck2 ◽

Minichromosome Maintenance ◽

Catalytic Subunits ◽

Expression Levels ◽

Kinase Ck2

Abstract Protein kinase CK2 is a serine/threonine kinase composed of two catalytic subunits (CK2α and/or CK2α’) and two regulatory subunits (CK2β). It is implicated in every stage of the cell cycle and in the regulation of various intracellular pathways associated with health and disease states. The catalytic subunits have similar biochemical activity, however, their functions may differ significantly in cells and in vivo. In this regard, homozygous deletion of CK2α leads to embryonic lethality in mid-gestation potentially due to severely impaired cell proliferation. To determine the CK2α-dependent molecular mechanisms that control cell proliferation, we established a myoblast-derived cell line with inducible silencing of CK2α and carried out a comprehensive RNA-Seq analysis of gene expression. We report evidence that CK2α depletion causes delayed cell cycle progression through the S-phase and defective response to replication stress. Differential gene expression analysis revealed that the down-regulated genes were enriched in pathways implicated in cell cycle regulation, DNA replication and DNA damage repair. Interestingly, the genes coding for the minichromosome maintenance proteins (MCMs), which constitute the core of the replication origin recognition complex, were among the most significantly down-regulated genes. These findings were validated in cells and whole mouse embryos. Taken together, our study provides new evidence for a critical role of protein kinase CK2 in controlling DNA replication initiation and the expression levels of replicative DNA helicases, which ensure maintenance of proliferative potential and genome integrity in eukaryotic cells.

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Cell cycle regulatory protein p27KIP1 is a substrate and interacts with the protein kinase CK2

Journal of Cellular Biochemistry ◽

10.1002/jcb.20027 ◽

2004 ◽

Vol 91 (5) ◽

pp. 865-879 ◽

Cited By ~ 36

Author(s):

Julio C. Tapia ◽

Victor M. Bolanos-Garcia ◽

Muhammed Sayed ◽

Catherine C. Allende ◽

Jorge E. Allende

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Protein Kinase Ck2 ◽

Regulatory Protein ◽

Cell Cycle Regulatory Protein ◽

Kinase Ck2

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Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

International Journal of Molecular Sciences ◽

10.3390/ijms21176234 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6234

Author(s):

Patrycja Wińska ◽

Olena Karatsai ◽

Monika Staniszewska ◽

Mirosława Koronkiewicz ◽

Konrad Chojnacki ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Protein Kinase ◽

P38 Mapk ◽

Protein Kinase Ck2 ◽

Triple Negative ◽

Actin Network ◽

Synergistic Interactions ◽

Kinase Ck2 ◽

Mcf 7

Background: The combination effect of 5-fluorouracil (5-FU) with either CX-4945 or a new inhibitor of protein kinase CK2, namely 14B (4,5,6,7-tetrabromo-1-(3-bromopropyl)-2-methyl-1H-benzimidazole), on the viability of MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines was studied. Methods: Combination index (CI) values were determined using an MTT-based assay and the Chou-Talalay model. The effect of the tested drug combinations on pro-apoptotic properties and cell cycle progression was examined using flow cytometry. The activation of FAK, p38 MAPK, and ERK1/2 kinases and the expression of selected pro-apoptotic markers in MDA-MB-231 cell line after the combined treatment were evaluated by the western blot method. Confocal microscopy was used to examine actin network in MDA-MB-231. Results: Our results showed that a synergistic effect (CI < 1) occurred in MDA-MB-231 after treatment with both combinations of 5-FU with 14B or CX-4945, whereas the combination of 5-FU and 14B evoked an antagonistic effect in MCF-7. We conclude that the synergistic interactions (CI < 1) observed for both the combinations of 5-FU and 14B or CX-4945 in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network. Conclusions: The obtained results support the recent observation that CK2 inhibitors can improve 5-FU-based anticancer therapy and FAK kinase can be an attractive molecular target in breast cancer therapy.

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