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

Yde, Christina Westmose; Olsen, Birgitte Brinkmann; Meek, David W.; Watanabe, Nobumoto; Guerra, Bárbara

doi:10.1038/onc.2008.146

Cited by 51 publications

(48 citation statements)

References 32 publications

(48 reference statements)

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“…Moreover, it has also been reported that CK2 can modulate NF-B activity by phosphorylation of Rel-A (p65) NF-kappa B subunit or by promoting the degradation of its inhibitory subunit IkB. 40 Recently, Yde and collaborators 41 have suggested that CK2␤ regulates G 2 /M transition by controlling stabilization of Wee1 and its subsequent inhibitory phosphorylation of CDK1 on Tyr15 pointing to CK2 as a key regulator of cell cycle progression in lung cancer cells. Our results add important information to the complex network of cell proliferation and cell cycle controlled by CK2 and further research efforts will be required to uncover the precise mechanism.…”

Section: Discussionmentioning

confidence: 99%

CK2β Is Expressed in Endometrial Carcinoma and Has a Role in Apoptosis Resistance and Cell Proliferation

Pallarés

Llobet

Santacana

et al. 2009

The American Journal of Pathology

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Protein kinase CK2 (CK2) is a serine/threonine kinase that participates in important cellular processes. We have recently demonstrated that CK2 plays a role in resistance to TRAIL/Fas-induced apoptosis in endometrial carcinoma (EC) by regulating FLIP. Here , we assessed the immunohistochemical expression of CK2␤ in EC and checked its role in cell proliferation and anchorage-independent cell growth. CK2␤ immunostaining was assessed in two tissue microarrays , one constructed from paraffin-embedded blocks of 95 ECs and another from 70 samples of normal endometrium. CK2␤ expression was correlated with histological type; grade and stage; cell proliferation (Ki-67) and apoptotic index; immunostaining for cyclin D1 , PTEN , AKT , ␤-catenin , and FLIP. Moreover , the Ishikawa EC cell line was subjected to down-regulation of CK2 by shRNA. CK2␤ expression was frequent in EC (nuclear , 100%; cytoplasmic , 87.5%). The staining was more intense in EC than in normal endometrium (P ‫؍‬ 0.000) , and statistically correlated with AKT , PTEN , ␤-catenin , and FLIP. In EC , CK2␤ expression correlated with cell proliferation. Knock-down of CK2␤ blocked colony formation of EC in soft agar , and also resulted in decreased expression of cyclin D1 and ERK phosphorylation. The results confirm that CK2␤ is widely expressed in EC , and suggest a role in cell proliferation and anchorage-independent cell growth.

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Section: Discussionmentioning

confidence: 99%

CK2β Is Expressed in Endometrial Carcinoma and Has a Role in Apoptosis Resistance and Cell Proliferation

Pallarés

Llobet

Santacana

et al. 2009

The American Journal of Pathology

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“…Recently, a genome-wide survey of protein kinases required for cell progression into cultured Drosophila melanogaster S2 cells by doublestranded RNA demonstrated that CK2␤ is required for centrosomal normality (1). In the same vein, downregulation of CK2␤ by small interfering RNA (siRNA) results in delayed cell cycle progression in cultured mammalian cells (42). Finally, in a genetic screen for mutations affecting the central brain of Drosophila, a hypomorphic allele of D. melanogaster CK2␤ has been isolated, and that study suggested a role for CK2␤ in cell proliferation or cell survival during brain development (15).…”

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confidence: 99%

Disruption of CK2β in Embryonic Neural Stem Cells Compromises Proliferation and Oligodendrogenesis in the Mouse Telencephalon

Huillard

Ziercher

Blond

et al. 2010

Molecular and Cellular Biology

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Genetic programs that govern neural stem/progenitor cell (NSC) proliferation and differentiation are dependent on extracellular cues and a network of transcription factors, which can be regulated posttranslationally by phosphorylation. However, little is known about the kinase-dependent pathways regulating NSC maintenance and oligodendrocyte development. We used a conditional knockout approach to target the murine regulatory subunit (beta) of protein kinase casein kinase 2 (CK2␤) in embryonic neural progenitors. Loss of CK2␤ leads to defects in proliferation and differentiation of embryonic NSCs. We establish CK2␤ as a key positive regulator for the development of oligodendrocyte precursor cells (OPCs), both in vivo and in vitro. We show that CK2␤ directly interacts with the basic helix-loop-helix (bHLH) transcription factor Olig2, a critical modulator of OPC development, and activates the CK2-dependent phosphorylation of its serine-threonine-rich (STR) domain. Finally, we reveal that the CK2-targeted STR domain is required for the oligodendroglial function of Olig2. These findings suggest that CK2 may control oligodendrogenesis, in part, by regulating the activity of the lineage-specific transcription factor Olig2. Thus, CK2␤ appears to play an essential and uncompensated role in central nervous system development.Casein kinase 2 (CK2) is a conserved serine/threonine kinase with more than 300 substrates, mostly proteins related to transcription-directed signaling (27). CK2 is a heterotetrameric holoenzyme formed by two catalytic subunits, ␣ and ␣Ј, that associate with a dimeric building block of regulatory ␤ subunits (␣ 2 ␤ 2 ). CK2␤ modulates the substrate specificity of the CK2 enzymatic activity, and its architecture is consistent with its role as a docking partner for other interacting proteins (4). We previously demonstrated that disruption of CK2␤ function in mice results in postimplantation lethality. Moreover, many attempts to generate CK2␤ Ϫ/Ϫ embryonic stem (ES) cells failed, suggesting an essential role of mammalian CK2␤ for ES cell viability (2).The function of CK2␤ for cell cycle progression has been investigated, but its precise role is largely unknown. The cell proliferation function of CK2␤ was first characterized in human fibroblasts, by use of antisense oligodeoxynucleotides and microinjection of specific antibodies (19,26). Recently, a genome-wide survey of protein kinases required for cell progression into cultured Drosophila melanogaster S2 cells by doublestranded RNA demonstrated that CK2␤ is required for centrosomal normality (1). In the same vein, downregulation of CK2␤ by small interfering RNA (siRNA) results in delayed cell cycle progression in cultured mammalian cells (42). Finally, in a genetic screen for mutations affecting the central brain of Drosophila, a hypomorphic allele of D. melanogaster CK2␤ has been isolated, and that study suggested a

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“…revealing a novel component of the complex machinery that operates at the G2/M cell cycle transition (16). In the present study, we attempted to: i) closer investigate the nature of the interaction between Wee1 and the CK2 subunits, ii) map the Wee1 and CK2ß interaction domains and iii) elucidate the functional consequence of their association with respect to Wee1 kinase activity.…”

Section: Discussionmentioning

confidence: 99%

“…The stability of Wee1 is regulated by the CDK1/cyclin B-mediated phosphorylation at Ser123 which creates a phosphodegron recognized by the ß-transducin repeat-containing protein (ß-TrCP) and a docking site for the binding of the polo-like kinase 1 [PLK1, (14,15)]. We found that CK2ß participates in the PLK1-Wee1 complex formation and interacts directly with Wee1 (16 Preparation of cell extract, Western blot analysis and immunoprecipitation. Cell pellets were re-suspended in cold lysis buffer (50 mM Tris/HCl pH 7.5, 150 mM NaCl, 1% Triton X-100, 10% glycerol, 1 mM DTT, 1 mM Na 3 VO 4 , 30 mM ß-glycerophosphate 10 mM NaF and 100 nM okadaic acid) containing a protease inhibitor cocktail (Roche).…”

Section: Introductionmentioning

confidence: 99%

Mapping of the interaction sites between Wee1 kinase and the regulatory β-subunit of protein kinase CK2

Olsen

Kreutzer²,

Watanabe

et al. 2010

Int J Oncol

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Abstract. Somatic Wee1 is a protein kinase that plays a key role in cell cycle progression at the onset of mitosis by phosphorylating CDK1 at the inhibitory Tyr15 amino acid residue. Wee1 is regulated at multiple levels, i.e., phosphorylation, protein-protein association and proteasome-mediated degradation. We have recently shown that the regulatory ß-subunit of protein kinase CK2 participates in PLK1-Wee1 complex formation interacting directly with Wee1 and thereby contributing to the regulation of G2-M cell cycle transition. Here, we show that Wee1 binds CK2ß via two domains comprising amino acids 59-71 and 232-332. By employing deletion mutants of the CK2ß-subunit we also show that two regions between residues 1-5 and 155-170 are necessary for binding Wee1. Furthermore, we demonstrate that the interaction between CK2ß and Wee1 does not modify the kinase activity of the latter, instead CK2ß directly upregulates CDK1 kinase activity by reversing the inhibitory effect which follows Wee1-mediated phosphorylation. Taken together, our findings reinforce the notion that CK2ß is a modulator of protein kinases implicated in cell cycle regulation and exerts functions that are independent of CK2 tetramers. IntroductionProtein kinase CK2 is a highly conserved enzyme ubiquitously expressed among all the eukaryotic organisms investigated so far. It is composed of two catalytic subunits · and/or ·' and two regulatory ß-subunits. CK2 was originally described as an enzyme characterized by a tetrameric structure but evidence suggests that the individual subunits can exist in association with various intracellular proteins (1,2). Because of the broad spectrum of proteins that interact with or are phosphorylated by CK2, it is not surprising that this enzyme is implicated in various intracellular processes ranging from regulation of transcription, DNA replication and repair to survival, proliferation and differentiation (reviewed in refs. 2,3). Numerous studies have also suggested that CK2 exerts a vital function. Indeed it was shown by gene knockout experiments in mammals that both the ·-and ß-subunits are essential for the development of mice (4,5) while lack of expression of the ·'-subunit is not lethal but leads to infertility (6). CK2 has also been linked to the regulation of cell cycle progression in lower as well as higher eukaryotes (reviewed in refs. 7,8).Cell cycle progression is controlled by numerous proteins which act in order to preserve the integrity of the genetic information crucial for the survival of a cell. Entry into mitosis is mainly regulated by CDK1 whose optimal activation is achieved following the association with cyclin B and phosphorylation in the conserved T-loop domain. During interphase, CDK1 activity is maintained low by phosphorylation of two amino acids residues (i.e., Thr14 and Tyr15) catalyzed by Myt1 and Wee1 protein kinases (9,10). Entry into mitosis requires the intervention of the CDC25 dual specificity protein phosphatase family members that catalyze the activating dephosphorylation of CDK...

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

Cited by 51 publications

References 32 publications

CK2β Is Expressed in Endometrial Carcinoma and Has a Role in Apoptosis Resistance and Cell Proliferation

CK2β Is Expressed in Endometrial Carcinoma and Has a Role in Apoptosis Resistance and Cell Proliferation

Disruption of CK2β in Embryonic Neural Stem Cells Compromises Proliferation and Oligodendrogenesis in the Mouse Telencephalon

Mapping of the interaction sites between Wee1 kinase and the regulatory β-subunit of protein kinase CK2

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