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PubMed2006

Casein kinase 2 inhibition decreases hypoxia-inducible factor-1 activity under hypoxia through elevated p53 protein level.

HIF-1 (hypoxia-inducible factor-1) is the main transcription factor involved in the adaptation of cells to hypoxia. In addition to regulation of HIF-1alpha protein level, HIF-1 activity is also enhanced by several pathways involving asparagine hydroxylation and phosphorylation. Here, we investigated the relationship between casein kinase 2 (CK2), p53 and HIF-1. An increase in p53 protein level and transcriptional activity was observed when CK2 was inhibited by different inhibitors under normoxia and hypoxia. This increase was in parallel with a decrease in HIF-1 activity without changes in HIF-1alpha protein level, indicating a regulation of its transcriptional activity. Similar results were obtained using CK2alpha siRNA. Ectopic overexpression of p53 also led to an inhibition of HIF-1 activity. Conversely, CK2 inhibition had no effect in p53-null cells indicating that the inhibitory effect of CK2 inhibitors requires the presence of p53. p53 activity was not required because overexpression of a p53 mutated in its DNA-binding domain exerted the same effect as wild-type p53 and because the effect of CK2 inhibitors was still observed when p53 activity was inhibited by pifithrin-alpha. Since CK2 activity is increased in hypoxic conditions, this process provides one more mechanism to ensure enhanced HIF-1 activity under such conditions.

Carcinoma, Hepatocellular↗

PubMed2005

Casein kinase II phosphorylation regulates alphaNAC subcellular localization and transcriptional coactivating activity.

The subcellular localization of the alphaNAC coactivator is regulated, but the signaling pathways controlling its nucleocytoplasmic shuttling and coactivation function are not completely characterized. We report here that casein kinase II (CK2) phosphorylated alphaNAC on several phosphoacceptor sites, especially in an amino-terminal cluster. Deletion or mutation of the clustered CK2 sites induced nuclear accumulation of alphaNAC in cells. alphaNAC also localized to the nucleus when endogenous CK2 activity was inhibited by quercetin or 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). These observations suggested that phosphorylation by CK2 might play a signaling role in the nuclear export of alphaNAC. Interestingly, inhibition of the chromosome region maintenance 1 (CRM1) exportin by leptomycin B (LMB) led to accumulation of alphaNAC in the nucleus. We conclude that CK2 phosphorylation of the N-terminal cluster corresponds to the signal for alphaNAC's nuclear export via a CRM1-dependent pathway. Finally, the nuclear accumulation of the protein resulting from the lack of CK2 phosphorylation mediated a slight but significant increase of the alphaNAC coactivating function on AP-1 transcriptional activity. Thus, alphaNAC's exit from the nucleus and capacity to potentiate transcription appear dependent on its phosphorylation status.

Active Transport, Cell Nucleus↗

PubMed1999

Dissecting subdomains involved in multiple functions of the CK2beta subunit.

We have characterized several subdomains of the beta subunit of protein kinase CK2. The N-terminal half of the protein exhibits a pseudo-substrate segment in tandem with a polyamine binding domain responsible for the activation of the kinase by these polybasic compounds. Study of the chemical features of this polyamine binding site showed that polyamine analogs exhibiting the highest affinity for CK2 are the best CK2 activators. Mutational analysis disclosed that glutamic residues lying in the polyacidic region of the CK2beta subunit are involved in the interaction with polyamine molecules and allowed the delineation of an autonomous binding domain. Furthermore, this regulatory domain was shown to mediate the association of CK2 with plasma membrane. The C-terminal domain of the CK2beta subunit plays a role in the oligomerization of the kinase since it was observed that a truncated form of this subunit lacking its 33-last amino acids was incompetent for the assembly of polymeric forms of CK2. Altogether, our results support the notion that the beta subunit of CK2 is a modular protein made by the association of interdependent domains that are involved in its multiple functions.

Affinity Labels↗

PubMed1994

Modulation of the molecular organization and activity of casein kinase 2 by naturally occurring polyamines.

Polyamines have been reported to stimulate casein kinase 2 (CK2) in vitro. We have shown that the phosphorylation of different substrates is diversely stimulated by basic effectors and that the responsiveness of CK2 activity may be influenced by the overall conformation of the protein substrate but also by a specific interaction with the enzyme itself. Our data show that native hetero tetrameric CK2 is a spermine binding protein and a spermine binding site was identified in the N-terminal region of the beta subunit of CK2. We found that recombinant CK2 undergoes a progressive polymerization in low salt conditions, giving rise to three different polymer structures. A ring-like structure formed by the association of four protomers alpha 2 beta 2 was characterized by gel filtration, sucrose density gradient analysis and electron microscopy. Polyamines like spermine, when added under conditions where the enzyme preparation contains a mixture of various oligomers, could trigger their dissociation and their interconversion in the fully active ring structure. These results suggest that in the presence of positive effectors like polyamines, CK2 adopts a ring-like structural organization which may represent the active state of this kinase.

Amino Acid Sequence↗

PubMed1998

Insulin-regulated protein kinases during postnatal development of rat heart.

The control of glucose uptake and glycogen metabolism by insulin in target organs is in part mediated through the regulation of protein-serine/threonine kinases. In this study, the expression and phosphotransferase activity levels of some of these kinases in rat heart ventricle were measured to investigate whether they might mediate the shift in the energy dependency of the developing heart from glycogen to fatty acids. Following tail-vein injection of overnight fasted adult rats with 2 U of insulin per kg body weight, protein kinase B (PKB), the 70-kDa ribosomal S6 kinase (S6K), and casein kinase 2 (CK2) were activated (30-600%), whereas the MAP/extracellular regulated kinases (ERK)1 and ERK2 were not stimulated under these conditions. When the expression levels of the insulin-activated kinases were probed with specific antibodies in ventricular extracts from 1-, 10-, 20-, 50-, and 365-day-old rats, phosphatidylinositol 3-kinase (PI3K), PKB, S6K, and CK2 were downregulated (40-60%) with age. By contrast, ventricular glycogen synthase kinase-3beta (GSK3beta) protein levels were maintained during postnatal development. Similar findings were obtained when the expression of these kinases was investigated in freshly isolated ventricular myocytes, where they were detected predominantly in the cytosolic fraction of the myocytes. Compared to other adult rat tissues such as brain and liver, the levels of PI3K, PKB, S6K, and GSK3beta were relatively low in the heart. Even though CK2 protein and activity levels were reduced by approximately 60% in 365 day as compared to 1-day-old rats, expression of CK2 in the adult heart was as high as detected in any of the other rat tissues. The high basal activities of CK2 in early neonatal heart may be associated with the proliferating state of myocytes.

Amino Acid Sequence↗

PubMed1998

Casein kinase 2 phosphorylation of recombinant rat osteopontin enhances adhesion of osteoclasts but not osteoblasts.

Osteopontin (OP) is a highly phosphorylated bone matrix protein and contains the RGD cell-binding motif, which mediates cell adhesion through integrin receptors that include alpha(v)beta3. Casein kinase 2 (CK2) is a factor-independent serine/threonine kinase, which may be the predominant physiologically relevant kinase for OP phosphorylation. This study was designed to examine the effects of unphosphorylated recombinant rat OP, and CK2-phosphorylated OP (P-OP), on the adhesion and function of mouse osteoclasts (OC) and osteoblast-like cells (UMR 201-10B and UMR 106-06) in vitro. OP significantly increased OC adhesion compared to plastic alone, and cell attachment was further increased at least twofold on OP phosphorylated with CK2. Attachment was dependent on the integrity of the RGD domain and was completely abolished in the presence of 1 mM RGD peptide. Neither CK2 phosphorylation of mutant OP, in which the RGD was converted to RGE or RAD, nor protein kinase C (PKC) phosphorylation of wild-type OP enhanced OC attachment. An antibody to the beta3 integrin subunit, but not anti-mouse CD44 antibody, specifically blocked the proportion of attachment due to phosphorylation of OP. Actin ring formation in OC was increased by plating cells onto OP, with no further increase by phosphorylation. Both OP and CK2-phosphorylated OP enhanced attachment of the two osteoblastic cell lines, compared to plastic, but in contrast to OCs, there was no significant difference with phosphorylation. Osteoblast attachment was totally blocked by 1 mM RGD peptide, but was not influenced by the beta3 integrin antibody. Plating of UMR 201-10B cells onto OP further increased retinoic acid-induced alkaline phosphatase expression. The results suggest that specific phosphorylation of OP is important for interaction with OCs, compared with osteoblastic cells, and that alternative integrins may be important in the interaction between osteoblastic cells and OP compared with OCs.

Actins↗

PubMed2005

Role for casein kinase 2 in the regulation of HIF-1 activity.

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1alpha subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1alpha degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the beta subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the alpha subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2alpha, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxia-induced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1alpha protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive.

Casein Kinase II↗

PubMed1995

Modulation of resistance to cisplatin by amphotericin B and aphidicolin in human larynx carcinoma cells.

The aim of this study was to examine whether resistance to cisplatin [cis-diamminedichloroplatinum (II)] (CDDP) could be overcome by amphotericin B, cyclosporin A and aphidicolin in two sublines of human larynx carcinoma HEp2 cells. The sensitivity of parental and cisplatin-resistant CA3 and CK2 cells to amphotericin B, cyclosporin A and aphidicolin, and also the effects of these drugs (given in maximal nontoxic concentrations) on cisplatin sensitivity were determined by clonogenic survival assay. CA3 and CK2 cells were sensitive to amphotericin B, and resistant to cyclosporin A and aphidicolin, compared with their parental cells. Amphotericin B increased cisplatin toxicity 2-fold in CA3 cells and 2.7-fold in CK2 cells, while it had no effect in parental HEp2 cells. Cyclosporin A did not influence the sensitivity of examined cells to cisplatin. The sensitizing effect of aphidicolin was more obvious in cisplatin-resistant cells. Cisplatin toxicity was increased by aphidicolin: 1.5-fold in HEp2 cells, 2-fold in CA3 cells, and 1.9-fold in CK2 cells. Therefore, the resistance to cisplatin in human larynx carcinoma CA3 and CK2 cells can be partially reversed by amphotericin B and aphidicolin.

Amphotericin B↗

PubMed2005

Casein kinase 2, circadian clocks, and the flight from mutagenic light.

Circadian clocks play a fundamental role in biology and disease. Much has been learned about the molecular underpinnings of these biological clocks from genetic studies in model organisms, such as the fruit fly, Drosophila melanogaster. Here we review the literature from our lab and others that establish a role for the protein kinase CK2 in Drosophila clock timing. Among the clock genes described thus far, CK2 is unique in its involvement in plant, fungal, as well as animal circadian clocks. We propose that this reflects an ancient, conserved function for CK2 in circadian clocks. CK2 and other clock genes have been implicated in cellular responses to DNA damage, particularly those induced by ultraviolet (UV) light. The finding of a dual function of CK2 in clocks and in UV responses supports the notion that clocks evolved to assist organisms in avoiding the mutagenic effects of daily sunlight.

Animals↗

PubMed1996

Golgi apparatus mammary gland casein kinase: monitoring by a specific peptide substrate and definition of specificity determinants.

The casein kinase from the Golgi apparatus of lactating mammary gland (GEF-CK) is distinct from ubiquitous 'casein kinases' termed protein kinases CK1 and CK2 and appears to define a family of secretory pathways protein kinases that phosphorylate seryl residues followed by an acidic residue at position +2. In this report we show that a new synthetic peptide substrate derived from beta-casein (beta[28-40]) is suitable for the fast, efficient and selective monitoring of GEF-CK, being unaffected by CK1 and CK2, and we define the consensus sequence of this protein kinase as being Ser-Xaa-Glu/SerP, distinct from that of CK2 (Ser/Thr-X-X-Glu/Asp/SerP/TyrP). In particular, the failure to recognize Asp as crucial specificity determinant prevents the phosphorylation of the specific CK2 peptide substrate RRRADDSDDDDD by GEF-CK. Thus, peptide substrates are now available for the fast and specific monitoring of all the three classes of 'casein kinases', CK1, CK2 and GEF-CK.

Amino Acid Sequence↗

PubMed2006

Emodin negatively affects the phosphoinositide 3-kinase/AKT signalling pathway: a study on its mechanism of action.

The development of selective cell-permeable inhibitors of protein kinases whose aberrant activation contributes to cell transformation is a promising approach in cancer treatment. Emodin is a natural anthraquinone derivative that exhibits anti-proliferative effects in various cancer cell lines by efficient induction of apoptosis. The phosphoinositide 3-kinase (PI3K)/AKT pathway has been shown to be central in the promotion of cell survival since the alteration of this signalling cascade is a frequent event in human malignancies. Previous published results indicated that treatment of cells with inhibitors of protein kinase CK2, such as emodin, induces apoptosis and that the anti-apoptotic effect of CK2 is partially mediated by target phosphorylation and up-regulation of AKT by CK2. In the present study, a screening with selected CK2 inhibitors induced a variable response with respect to AKT down-regulation, emodin being the most effective, suggesting that other mechanisms other than the inhibition of CK2 were responsible for the emodin-mediated modulation of AKT. We found that emodin does not directly affect AKT kinase. Furthermore, we show that the down-regulation of AKT is due to the emodin-mediated target inhibition of components of the PI3K pathway, which directly or indirectly affect AKT activity, i.e. the mammalian target of rapamycin and the phosphatase and tensin homolog deleted on chromosome 10, but not the phosphoinositide-dependent kinase 1. Taken together, our results highlight a new mechanism by which emodin exerts anti-cancer activity and suggest the further investigation of plant polyphenols, such as emodin, as therapeutic and preventive agents for cancer therapy.

Antineoplastic Agents, Phytogenic↗

PubMed2000

GRP94 hyperglycosylation and phosphorylation in Sf21 cells.

GRP94 is an inducible resident endoplasmic reticulum/sarcoplasmic reticulum (ER/SR) glycoprotein that functions as a protein chaperone and Ca(2+) regulator. GRP94 has been reported to be a substrate for protein kinase CK2 in vitro, although its phosphorylation in intact cells remains unreported. In Sf21 insect cells, overexpression of canine GRP94 led to the appearance of a multiplet of three or more molecular-mass isoforms which was reduced to a single mobility form following treatment of cells with tunicamycin, suggesting stable accumulations of consecutively modified protein. Metabolic labeling of Sf21 cells with (32)P(i) led to a constitutive phosphorylation of GRP94 which, based upon phosphopeptide mapping, occurred specifically on CK2-sensitive sites. Among the GRP94 multiplet, however, only the lowest mobility form of GRP94 was phosphorylated, even though in vitro phosphorylation of GRP94 by CK2 led to phosphorylation of all glycosylated forms. The (32)P(i) incorporation into GRP94 indicated a slow turnover of phosphate incorporation that was unaffected by inhibition of biosynthesis, resulting in a steady-state level of phospho-GRP94 on CK2 sites. These data support a role for protein kinase CK2 in the cell biology for GRP94 and other resident ER/SR proteins that may occur in ER compartments.

Animals↗

PubMed2005

Regulation of myosin-IIA assembly and Mts1 binding by heavy chain phosphorylation.

Previous studies suggested that heavy chain phosphorylation regulates non-muscle myosin-II assembly in an isoform-specific manner, affecting the assembly of myosin-IIB, but not myosin-IIA. We re-examined the effects of heavy chain phosphorylation on myosin-IIA filament formation and also examined mts1 binding. We demonstrated that heavy chain phosphorylation by either protein kinase C (PKC) or casein kinase 2 (CK2) inhibits the assembly of myosin-IIA into filaments. PKC phosphorylation had no affect on mts1 binding, but CK2 phosphorylation decreased the affinity of mts1 for the myosin-IIA rod by approximately 6.5-fold. Mts1 destabilized PKC-phosphorylated myosin-IIA filaments and inhibited the assembly of myosin-IIA monomers with maximal inhibition of assembly and promotion of disassembly occurring at a molar ratio of one mts1 dimer per myosin-IIA rod. At this molar ratio, mts1 only weakly disassembled CK2-phosphorylated myosin-IIA filaments and weakly inhibited the assembly of CK2-phosphorylated myosin-IIA monomers. These observations demonstrate that CK2 phosphorylation of the myosin-IIA heavy chain protects against mts1-induced filament disassembly and inhibition of assembly, and suggest that heavy chain phosphorylation provides an additional level of regulation for the mts1-myosin-IIA interaction.

Actin Cytoskeleton↗

PubMed2001

Phosphorylation of the protein encoded by the first open reading frame of the MDG4 transposable element (gypsy) by homologous and heterologous casein kinases type 2.

Homogeneous casein kinase type 2 (CK2) was obtained from oocytes of Rana temporaria and cells of Drosophila melanogaster by chromatography on heparin-Sepharose, phosphocellulose, and Mono Q columns using a Pharmacia FPLC system. The procedure was first successfully used for the purification of CK2 from the Drosophila melanogaster cell culture. It has been shown that the protein encoded by the first open reading frame (ORF) of the gypsy transposable element (MDG4) is an effective protein substrate both for homologous and heterologous CK2 from the oocytes of Rana temporaria in vitro. Both enzymes catalyze the incorporation of two moles of phosphate per mole of protein. The Km and Vmax values for the reaction catalyzed by CK2 from the Drosophila cell culture were 32.5 +/- 2.1 nM and 70.97 +/- 1.89 nmol/min per microg, respectively, and for CK2 from oocytes, these values were 37.6 +/- 2.8 nM and 66.02 +/- 2.15 nmol/min per microg, respectively.

Animals↗

PubMed1999

Globozoospermia in mice lacking the casein kinase II alpha' catalytic subunit.

Protein kinase casein kinase II (Ck2) is a cyclic-AMP and calcium-independent serine-threonine kinase that is composed of two catalytic subunits (alpha and alpha') and two regulatory beta-subunits. Ck2 is not a casein kinase in vivo, but over 100 substrates are known. The highly conserved amino acid sequences of its subunits and their broad expression suggest that Ck2 may have a fundamental role in cell function. Ck2 has been implicated in DNA replication, regulation of basal and inducible transcription, translation and control of metabolism. The Ck2alpha and Ck2alpha' isoforms (products of the genes Csnk2a1 and Csnk2a2, respectively) are highly homologous, but the reason for their redundancy and evolutionary conservation is unknown. We find here that Csnk2a2 is preferentially expressed in late stages of spermatogenesis, and male mice in which Csnk2a2 has been disrupted are infertile, with oligospermia and globozoospermia ('round-headed' spermatozoa). This is the first demonstration of a unique role for a Ck2 isoform in development. The primary spermatogenic defect in Csnk2a2-/- testis is a specific abnormality of anterior head shaping of elongating spermatids; this is the first defined gene that regulates sperm head morphogenesis. As the germ cells differentiate, they are capable of undergoing chromatin condensation, although many abnormal cells are deleted through apoptosis or Sertoli cell phagocytosis. The few that survive to populate the epididymis exhibit head abnormalities similar to those described in human globozoospermia, thus Csnk2a2 may be a candidate gene for these inherited syndromes.

Animals↗

PubMed1998

p53 deficiency and misexpression of protein kinase CK2alpha collaborate in the development of thymic lymphomas in mice.

Protein kinase CK2 (casein kinase II) is a serine-threonine protein kinase with many substrates, some of which are involved in cell cycle regulation. CK2 activity is elevated in human solid tumors and leukemia, and dysregulated expression of CK2 induces lymphoma in transgenic mice. Mice that are deficient in p53 also develop lymphomas, and p53 activity may be regulated by CK2 phosphorylation. Here we demonstrate that CK2alpha transgenic mice partially or completely deficient in p53 develop thymic lymphomas at a markedly accelerated rate when compared to p53-deficient mice lacking the transgene. Lymphomas originating from CK2alpha transgenic mice that are heterozygous for p53 generally lose the wild type p53 allele, indicating that loss of p53 is an important step in tumor progression. Moreover, though lymphomas occur as early as 3 weeks of age in the transgenic mice that are nullizygous for p53, they are still monoclonal, indicating that additional stochastic mutations are required for their development. These lymphomas express high levels of myc mRNA and frequently ectopically express Lmo-2, a transcription factor involved in human T cell acute lymphocytic leukemia. The p53-null CK2alpha transgenic lymphomas grow rapidly but are highly prone to apoptosis, suggesting that transformation occurs through synergistic dysregulation of cell cycle control induced by misexpression of CK2 and loss of function of p53.

Animals↗

PubMed2002

Phosphorylation regulates the stability of the regulatory CK2beta subunit.

Protein kinase CK2 is a protein serine/threonine kinase that exhibits elevated expression in a number of cancers and displays oncogenic activity in mice. The regulatory CK2beta subunit has a central role in assembly of functional tetrameric CK2 complexes where it participates in modulation of catalytic activity and substrate specificity. Since overexpression of CK2beta results in elevated levels of CK2 activity, we investigated the molecular mechanisms that control its degradation since perturbations in these pathways could contribute to elevated CK2 in cancer. In this study, we demonstrate that CK2beta is degraded by a proteasome-dependent pathway and that it is ubiquitinated. We have also investigated the role of phosphorylation and a putative destruction box in regulating its stability in cells. Importantly, replacement of three serine residues within the autophosphorylation site of CK2beta with glutamic acid residues resulted in a significant decrease in its degradation indicating that autophosphorylation is involved in regulating its stability. Notably, although the autophosphorylation site of CK2beta is remarkably conserved between species, this is the first functional role ascribed to this site. Furthermore, based on these results, we speculate that alterations in the phosphorylation or dephosphorylation of the regulatory CK2beta subunit could underlie the elevated expression of CK2 that is observed in cancer cells.

Animals↗

PubMed2005

H11 has dose-dependent and dual hypertrophic and proapoptotic functions in cardiac myocytes.

We have shown previously that H11, a serine/threonine kinase, is up-regulated in a heart subjected to ischaemia/reperfusion. In the present study, we have characterized the cellular function of H11, using neonatal rat cardiac myocytes. Although transduction of adenovirus harbouring H11 at low doses increased the cell size, at higher doses it induced apoptosis in cardiac myocytes. Apoptosis was not observed when adenovirus harbouring H11-KI (kinase-inactive mutant of H11) was used, suggesting that the proapoptotic effect of H11 is kinase-dependent. The hypertrophic effect of H11 at high doses was unmasked when apoptosis was inhibited by the caspase inhibitor DEVD-CHO, suggesting that H11 stimulates both hypertrophy and apoptosis in parallel. H11-KI induced hypertrophy even at high doses, indicating that H11 stimulates hypertrophy through kinase-independent mechanisms. H11-KI activated Akt, and cardiac hypertrophy induced by H11-KI was blocked by LY294002, an inhibitor of phosphoinositide 3-kinase. Co-immunoprecipitation analyses indicated that H11 interacts with the alpha subunit of CK2 (casein kinase 2). Overexpression of H11 decreased the kinase activity of CK2. DRB (5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole), an inhibitor of CK2, mimicked the effect of H11, whereas DRB and H11 failed to exhibit additive effects on apoptosis, suggesting that H11 and DRB utilize a common mechanism to induce apoptosis, namely inhibition of CK2. In summary, H11 is a dual-function kinase in cardiac cells: it induces hypertrophy at low doses through kinase-independent activation of Akt, whereas it causes apoptosis at high doses through protein kinase-dependent mechanisms, in particular by physical interaction with and subsequent inhibition of CK2.

Animals↗