Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “CK2”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources
PubMed2000

Significance of protein kinase CK2 nuclear signaling in neoplasia.

Many stimuli play a role in influencing the structure and function of chromatin and nuclear matrix through post-translational modifications of the component proteins in these dynamic structures. We propose that the protein serine/threonine kinase CK2 (formerly casein kinase II) is one such agent that is involved in signal transduction in the nuclear matrix and chromatin in response to a variety of stimuli. Protein kinase CK2 appears to undergo rapid modulations in its association with nuclear matrix and nucleosomes in response to mitogenic signals and is involved in the phosphorylation of a variety of intrinsic proteins in these structures depending on the state of genomic activity. In addition, its association or loss from the nuclear matrix may also influence the apoptotic activity in the cell. CK2 has been found to be dysregulated in virtually all the neoplasias examined and nuclear association appears to be an important facet of its expression in tumor cells. We hypothesize that CK2 provides a functional paradigm linking the nuclear matrix and chromatin structures. Identification of precise loci of action of CK2 in these structures and how they influence the morphological appearance of the nucleus under normal and abnormal growth conditions would be an important future direction of investigation. J. Cell. Biochem. Suppl. 35:130-135, 2000. Published 2001 Wiley-Liss, Inc.

Animals↗
PubMed2007

Tetrabromocinnamic acid (TBCA) and related compounds represent a new class of specific protein kinase CK2 inhibitors.

Abnormally high constitutive activity of protein kinase CK2, levels of which are elevated in a variety of tumours, is suspected to underlie its pathogenic potential. The most widely employed CK2 inhibitor is 4,5,6,7-tetrabromobenzotriazole (TBB), which exhibits a comparable efficacy toward another kinase, DYRK1 a. Here we describe the development of a new class of CK2 inhibitors, conceptually derived from TBB, which have lost their potency toward DYRK1 a. In particular, tetrabromocinnamic acid (TBCA) inhibits CK2 five times more efficiently than TBB (IC50 values 0.11 and 0.56 microM, respectively), without having any comparable effect on DYRK1 a (IC50 24.5 microM) or on a panel of 28 protein kinases. The usefulness of TBCA for cellular studies has been validated by showing that it reduces the viability of Jurkat cells more efficiently than TBB through enhancement of apoptosis. Collectively taken, the reported data support the view that suitably derivatized tetrabromobenzene molecules may provide powerful reagents for dissecting the cellular functions of CK2 and counteracting its pathogenic potentials.

Adenosine Triphosphate↗
PubMed2004

C-terminal region of protein kinase CK2 alpha: How the structure can affect function and stability of the catalytic subunit.

A novel mutant of the catalytic alpha subunit of human protein kinase CK2 (CK2 alpha) was designed in an attempt to clarify the role of the carboxylic-terminal segment characteristic of vertebrates, excluding fish. Starting from the sequence alignments, we constructed a phylogenetic tree of the primary structure of CK2 alpha. On this basis, we substituted two distal prolines with alanines (PA 382-384). Theoretical calculations and spectropolarimetry measurements, performed both on native and mutant subunits, indicate an increased content of alpha-helix after this double amino acidic substitution. In order to clarify the structure/function relationship of the C-terminal region, we verified if the structural change affects the catalytic activity of CK2 alpha. The mutant exhibits slightly increased phosphorylation efficiency, but reduced ability to transfer phosphate in comparison with the native subunit. At last, we compared the thermal stability of the mutant with respect to the native subunit and we tested the proteolytic degradability. The observation that the PA 382-384 mutant exhibits an increased thermal and proteolytic stability suggests that this mutant could be employed to solve the three-dimensional (3D) structure of human CK2 alpha and to overcome difficulties in crystallizing the native form.

Amino Acid Sequence↗
PubMed2004

Effects of phosphorylation by protein kinase CK2 on the human basal components of the RNA polymerase II transcription machinery.

We have investigated the role of phosphorylation by vertebrate protein kinase CK2 on the activity of the General Transcription Factors TFIIA, TFIIE, TFIIF, and RNAPII. The largest subunits of TFIIA, TFIIE, and TFIIF were phosphorylated by CK2 holoenzyme. Also, RNA polymerase II was phosphorylated by CK2 in the 214,000 and 20,500 daltons subunits. Our results show that phosphorylation of TFIIA, TFIIF, and RNAPII increase the formation of complexes on the TATA box of the Ad-MLP promoter. Also, phosphorylation of TFIIF increases the formation of transcripts, where as phosphorylation of RNA polymerase II dramatically inhibits transcript formation. Furthermore, we demonstrate that CK2 beta directly interacts with RNA polymerase II, TFIIA, TFIIF, and TBP. These results strongly suggest that CK2 may play a role in regulating transcription of protein coding genes.

Adenoviridae↗
PubMed2006

CK2 signaling in androgen-dependent and -independent prostate cancer.

Protein serine/threonine kinase casein kinase 2 (CK2) is a key player in cell growth and proliferation but is also a potent suppressor of apoptosis. CK2 has been found to be dysregulated in all the cancers that have been examined, including prostate cancer. Investigations of CK2 signaling in the prostate were originally initiated in this laboratory, and these studies have identified significant functional activities of CK2 in relation to normal prostate growth and to the pathobiology of androgen-dependent and -independent prostate cancer. We present a brief overview of these developments in the context of prostate biology. An important outcome of these studies is the emerging concept that CK2 can be effectively targeted for cancer therapy.

Androgens↗
PubMed1996

Protein kinase CK2: biphasic kinetics with peptide substrates.

The regulatory beta-subunit of the protein kinase CK2 modulates the salt optimum for alpha-subunit activity. In the presence of salt the beta-subunit is stimulatory while in the absence of salt it is inhibitory. In the presence of 150 mM NaCl CK2 has linear kinetics (Lineweaver-Burk) for the synthetic substrate RRRDDDSDDD with an apparent Km of 60 microM. In contrast, CK2 displayed biphasic kinetics for the peptide substrate when assayed in the absence of added NaCl. Biphasic kinetics were also obtained for other peptides but not for calsequestrin or casein. Recombinant alpha-subunit had strictly linear kinetics in the absence of added NaCl with an apparent Km of 104 microM. Preincubation of CK2 with ATP/Mg2+ or GTP/Mg2+, but not adenosine/Mg2+ or Mg2+ alone, resulted in kinetics that were near linear. This change in kinetics was dependent on enzyme conditions of low salt CK2 displays biphasic kinetics for peptide substrates, the biphasic kinetics require the presence of the beta-subunit, and ATP/Mg2+ binding reverses the effect.

Adenosine Triphosphate↗
PubMed1994

Asymmetric expression of protein kinase CK2 subunits in human kidney tumors.

Renal clear cell carcinomas and the corresponding ipsilateral control tissues were investigated for protein kinase CK2 activity and subunit ratio. The average protein kinase CK2 activity from 21 different kidney samples was 318 U/mg and that from the corresponding tumors 610 U/mg. The subunit ratio of protein kinase CK2 alpha in tumors/normal tissue (T/N) was 1.58 and that of the protein kinase CK2 beta (T/N) was 2.65. The data suggest that the generally described increase in protein kinase CK2 activity in tumor cells may to some extent result from a deregulation in subunit biosynthesis or degradation. This at least partly owing to the presence of excess enzymatically active protein kinase alpha-subunit but also to a significantly higher presence of the non-catalytic beta-subunit.

Adenocarcinoma, Clear Cell↗
PubMed1996

Phosphorylation of HIV-1 Rev protein: implication of protein kinase CK2 and pro-directed kinases.

HIV-1 Rev transactivator is readily phosphorylated at separate regions by protein kinase CK2 and MAP kinase. Protein kinase CK1 cannot replace CK2 as phosphorylating agent and cdc2 only slowly phosphorylates Rev at one of the two sites affected by MAP kinase. Mutational analysis shows that Ser-8 and, to a lesser extent, Ser-5 are phosphorylated by CK2. In contrast, a mutation (R14TV-->EED) which suppresses Rev activity dramatically enhances Rev phosphorylation either in vitro by CK2 or in vivo, suggesting that phosphorylation by CK2 could play a role in Rev down-regulation.

Amino Acid Sequence↗
PubMed2001

Functional conservation between the human, nematode, and yeast CK2 cell cycle genes.

Protein kinase CK2 (formerly casein kinase II) is a highly conserved serine/threonine protein kinase ubiquitous in eukaryotic organisms. Previously, we have shown that CK2 is required for cell cycle progression and essential for the viability of the yeast Saccharomyces cerevisiae. We now report that either the human or the nematode Caenorhabditis elegans CK2alpha catalytic subunit can substitute for the yeast catalytic subunits. Additionally, expression of the human CK2 regulatory subunit (CK2beta) can suppress the temperature sensitivity of either of the two yeast CK2 mutant catalytic subunits. Taken together, these observations reinforce the view that the CK2 cell cycle progression genes have been highly conserved during evolution from yeast to humans, not only in structure but also in function.

Animals↗
PubMed1998

Murine protein kinase CK2 alpha': cDNA and genomic cloning and chromosomal mapping.

Protein kinase CK2 (casein kinase II) is a heterotetrameric enzyme implicated in many essential regulatory pathways in cells. We have determined the sequence of the murine CK2 alpha' cDNA that encodes a 350-amino-acid protein that would have 99 and 98% homology with the human and chicken proteins, respectively, and is also highly homologous to murine CK2 alpha. To clarify the sequence of the 5' end of the cDNA and to elucidate the structure and regulation of the gene, we obtained a bacterial artificial chromosome clone that contains the 35-kb CK2 alpha' gene. The gene consists of 12 small exons; the 5' end, including the first exon and intron, is extremely GC rich and contains a CpG island. The putative promoter contains potential binding sites for a variety of transcriptional factors but appears to lack CCAAT- or TATA-like elements. A polymorphic dinucleotide repeat in the fifth intron allowed us to map the CK2 alpha' gene to murine Chromosome 8.

Amino Acid Sequence↗
PubMed1997

Protein kinase CK2 ("casein kinase-2") and its implication in cell division and proliferation.

Protein kinase CK2 (also termed casein kinase-2 or -II) is a ubiquitous Ser/Thr-specific protein kinase required for viability and for cell cycle progression. CK2 is especially elevated in proliferating tissues, either normal or transformed, and the expression of its catalytic subunit in transgenic mice is causative of lymphomas. CK2 is highly pleiotropic: more than 160 proteins phosphorylated by it at sites specified by multiple acidic residues are known. Despite its heterotetrameric structure generally composed by two catalytic (alpha and/or alpha') and two non catalytic beta-subunits, the regulation of CK2 is still enigmatic. A number of functional features of the beta-subunit which could cooperate to the modulation of CK2 targeting/activity will be discussed.

Amino Acid Sequence↗
PubMed2005

Autophosphorylation at the regulatory beta subunit reflects the supramolecular organization of protein kinase CK2.

Among the features of protein kinase CK2, autophosphorylation at its beta-subunit(s) upon incubation with ATP/Mg++ was early detected as a rapid and stoichiometric event occurring through an intramolecular mechanism as judged from kinetic analyses. The autophosphorylation site was mapped to Ser2 and, to a lesser extent, Ser3 both fulfilling the CK2 consensus sequence (MSSSEEV). The crystal structure of the heterotetrameric holoenzyme, however, is not compatible with an intramolecular autophosphorylation of the N-terminal stretch of either of the two beta subunits. Here we show that efficient "intramolecular" autophosphorylation of the beta subunit is crucially dependent on the formation of oligomers composed by several holoenzyme heterotetrameric protomers. Increasing ionic strength of the incubation medium promoting dissociation of the supramolecular oligomers abrogates beta subunit autophosphorylation, although CK2 catalytic activity, as judged from the phosphorylation of exogenous substrates, is still quite evident. These findings, in conjunction with graphic modelization, support the view that CK2 autophosphorylation at its beta subunits takes place through an "intraoligomeric" mechanism where the beta subunits of a protomer are phosphorylated by the catalytic subunits of another adjacent protomer. It appears therefore that in vivo beta autophosphorylation is symptomatic of supramolecular CK2 oligomers.

Animals↗
PubMed2006

CK2 phosphorylation of SAG at Thr10 regulates SAG stability, but not its E3 ligase activity.

Sensitive to Apoptosis Gene (SAG), a RING component of SCF E3 ubiquitin ligase, was shown to be phosphorylated by protein kinase CK2 at the Thr10 residue. It is, however, unknown whether this phosphorylation is stress-responsive or whether the phosphorylation changes its E3 ubiquitin ligase activity. To address these, we made a specific antibody against the phosphor-SAG(Thr10). Transient transfection experiment showed that SAG was phosphorylated at Thr10 which can be significantly inhibited by TBB, a relatively specific inhibitor of protein kinase CK2. To determine whether this SAG phosphorylation is stress-responsive, we defined a chemical-hypoxia condition in which SAG and CK2 were both induced. Under this condition, we failed to detect SAG phosphorylation at Thr10, which was readily detected, however, in the presence of MG132, a proteasome inhibitor, suggesting that the phosphorylated SAG has undergone a rapid degradation. To further define this, we made two SAG mutants, SAG-T10A which abolishes the SAG phosphorylation and SAG-T10E, which mimics the constitutive SAG phosphorylation. The half-life study revealed that indeed, SAG-T10E has a much shorter protein half-life (2 h), as compared to wild-type SAG (10 h). Again, rapid degradation of SAG-T10E in cells can be blocked by MG132. Thus, it appears that CK2-induced SAG phosphorylation at Thr10 regulates its stability through a proteasome-dependent pathway. Immunocytochemistry study showed that SAG as well as its phosphorylation mutants, was mainly localized in nucleus and lightly in cytoplasm. Hypoxia condition did not change their sub-cellular localization. Finally, an in vitro ubiqutination assay showed that SAG mutation at Thr10 did not change its E3 ligase activity when complexed with cullin-1. These studies suggested that CK2 might regulate SAG-SCF E3 ligase activity through modulating SAG's stability, rather than its enzymatic activity directly.

Antibodies, Phospho-Specific↗
PubMed1996

Structure of protein kinase CK2: dimerization of the human beta-subunit.

Protein kinase CK2 has been shown to be elevated in all so far investigated solid tumors and its catalytic subunit has been shown to serve as an oncogene product. CK2 is a heterotetrameric serine-threonine kinase composed of two catalytic (alpha and/or alpha') and two regulatory beta-subunits. Using the two-hybrid system we could show that the alpha- or alpha'-subunits of CK2 can interact with the beta-subunits of CK2, but not with other alpha- or alpha'-subunits. By comparison, the beta-subunit of CK2 can interact with another beta-subunit. Important amino acids for successful dimerization of the beta-subunit were localized between amino acid residues 156 and 165. Furthermore, we identified residues between amino acid 170 and 180 which antagonize the dimerization.

Binding Sites↗
PubMed1996

Phosphotyrosine specifies the phosphorylation by protein kinase CK2 of a peptide reproducing the activation loop of the insulin receptor protein tyrosine kinase.

Protein kinase CK2 is a ubiquitous Ser/Thr-specific protein kinase responsible for the phosphorylation of many proteins implicated in signal transduction. It phosphorylates both threonyl and seryl residue(s) of the insulin receptor beta-subunit. In this study, a series of peptides, reproducing all the threonyl sites of the intracellular domain of the insulin receptor that display the consensus sequence for CK2, has been synthesized and used as substrate for purified rat liver CK2. The only peptide readily phosphorylated is the one reproducing the activation loop of the insulin receptor (EIYET1160DYYA), including three tyrosines (Y1158, Y1162 and Y1163) whose phosphorylation through an intermolecular autocatalytic process promotes the activation of the receptor kinase. The phosphorylation efficiency of T1160 is increased almost 20-fold if these three tyrosines are previously phosphorylated. By using variably phosphorylated peptides, the tyrosine mainly responsible for such a hierarchical phosphorylation process has been identified as Y1163. It can be concluded, from these data, that T1160 situated in the activation loop of the insulin receptor, represents an excellent target for CK2, its phosphorylation being triggered by the previous autophosphorylation of the three tyrosyl residues surrounding it, with special reference to Y1163. These data are consistent with the implication of CK2 in the regulation of the activation process of the insulin receptor protein tyrosine kinase.

Animals↗
PubMed2004

2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2.

Protein kinase CK2 is a highly pleiotropic enzyme whose high constitutive activity is suspected to be instrumental to the enhancement of the tumour phenotype and to the propagation of infectious diseases. Here we describe a novel compound, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), which is superior to the commonly used specific CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) in several respects. DMAT displays the lowest K(i) value ever reported for a CK2 inhibitor (40 nM); it is cell permeable and its efficacy on cultured cells, both in terms of endogenous CK2 inhibition and induction of apoptosis, is several fold higher than that of TBB. The selectivity of DMAT assayed on a panel of >30 protein kinases is comparable to that of TBB, with the additional advantage of being ineffective on protein kinase CK1 up to 200 microM. These properties make DMAT the first choice CK2 inhibitor for in vivo studies available to date.

Animals↗
PubMed2005

Protein kinase CK2 interacts with Chk2 and phosphorylates Mre11 on serine 649.

The Mre11-Rad50-Nbs1 protein complex has been known to be involved in a variety of DNA metabolic events that involve DNA double-strand breaks (DSBs). The phosphorylation of Mre11 is increased in response to ionizing radiation, which suggests that phosphorylation of Mre11 may be an important regulatory mechanism of this complex. Mre11-phosphorylating kinase activities were observed in Chk2 immunoprecipitates and HeLa nuclear extracts. Through the tandem affinity tagging system and conventional chromatography, this kinase was purified and identified as protein kinase CK2. CK2 phosphorylates Mre11 in vitro. In vitro kinase assay with a series of truncated Mre11 proteins as substrates for CK2 and site-directed mutagenesis showed that serine 649 of Mre11 is mainly phosphorylated by CK2 in vitro. In vivo labeling and phosphopeptide mapping analysis revealed that this phosphorylation occurs in vivo. These data implicate CK2 as a potential upstream regulator of Mre11 function.

Amino Acid Sequence↗
PubMed2005

CK2 regulates in vitro the activity of the yeast cyclin-dependent kinase inhibitor Sic1.

We have previously demonstrated that the cyclin-dependent kinase inhibitor (Cki) Sic1 of Saccharomyces cerevisiae is phosphorylated in vitro by the CK2 kinase on Ser(201) residue. Moreover, we have collected evidence showing that Sic1 is functionally and structurally related to mammalian Cki p27(Kip1) and binds to the mammalian Cdk2/cyclin A complex with a similar mode of inhibition. In this paper, we use SPR analysis to investigate the binding of Sic1 to the catatytic and regulatory subunits of CK2. Evidence is presented showing that phosphorylation of Sic1 at the CK2 consensus site QES(201)EDEED increases the binding of a Sic1-derived peptide to the Cdk2/cyclin A complex, a functional homologue of the yeast Cdk1/Clb5,6. Moreover, Sic1 fully phosphorylated in vitro on Ser(201) by CK2 is shown to be a stronger inhibitor of the Cdk/cyclin complexes than the unphosphorylated protein. Taken together, these data disclose the possibility that CK2 plays a role in the regulation of Sic1 activity.

Amino Acids↗