Abstract
Little is known of how protein kinase CK2 genes are regulated, and it is unclear whether there are mechanisms of transcriptional coordination. Response elements present in the promoter sequences of the human catalytic (CK2α) and regulatory (CK2β) subunit genes have been examined for the significance in transcriptional control using reporter gene assays, electrophoretic mobility shift assays, site-directed mutagenesis, ectopic protein expressions, and transcript assessments. Most strikingly, in both promoters the regions of highest transcriptional activity contain two adjoining, completely identical and conserved Ets1 response elements, and both the mutation of motifs and the overexpression of Ets1 affect significantly transcriptional activity. Also in common are Sp1 response elements that cooperate with Ets1, and Sp1 is phosphorylatable by CK2 holoenzyme but not by individual CK2α, the phosphorylation negatively affecting DNA binding. CK2α and CK2β transcript levels and stoichiometries of mRNA species turned out quite constant in cultured cells despite progressing through various stages of proliferation and differentiation. The data seem to indicate transcriptional coordination of the human genes encoding CK2α and CK2β based on an Ets1 double motif common to both genes cooperating with Sp1 motifs and amenable to negative feedback control by the gene products which, following complexation into CK2 holoenzyme, could phosphorylate Sp1 (and Ets1?) and thus downregulate transcription and contribute to the observed constant cellular CK2α and CK2β transcripts situation.
Similar content being viewed by others
References
Hathaway GM, Traugh JA: Casein kinases - multipotential protein kinases. Curr Topics Cell Regulation 21: 101–127, 1982
Pinna LA: Casein kinase 2: An ‘eminence grise’ in cellular regulation? Biochem Biophys Acta 1054: 267–284, 1990
Tuazon PT, Traugh JA: Casein kinase I and II - multipotential serine protein kinases: Structure, function, and regulation. Adv Sec Mess Phosphoprot Res 23: 123–164, 1991
Litchfield DW, Lüscher B: Casein kinase II in signal transduction and cell cycle regulation. Mol Cell Biochem 127/128: 187–199, 1993
Issinger OG: Casein kinases: Pleiotropic mediators of cellular regulation. Pharmac Ther 59: 1–30, 1993
Ahmed K: Significance of the casein kinase system in cell growth and proliferation with emphasis on studies of the androgenic regulation of the prostate. Cell Mol Biol Res 40: 1–11, 1994
Pyerin W: Human casein kinase II: Structures, genes, expression and requirement in cell growth stimulation. Adv Enzyme Regul 34: 225–246, 1994
Allende JE, Allende CC: Protein kinases. 4. Protein kinase CK2: An enzyme with multiple substrates and a puzzling regulation. FASEB J 9: 313–323, 1995
Pyerin W, Ackermann K, Lorenz P: Casein kinases. In: F. Marks (ed). Protein Phosphorylation. Verlag Chemie, Weinheim, 1996, pp 117–174
Pinna LA, Meggio F: Protein kinase CK2 ('casein kinase-2') and its implication in cell division and proliferation. Prog Cell Cyc Res 3: 77–97, 1997
Glover CVC: On the physiological role of casein kinase II in Saccharomyces cerevisiae. Prog Nucleic Acid Res Mol Biol 59: 95–133, 1998
Wirkner U, Voss H, Lichter P, Weitz S, Ansorge W, Pyerin W: Human casein kinase II subunit alpha: Sequence of a processed (pseudo)gene and its localization on chromosome 11. Biochim Biophys Acta 1131: 220–222, 1992
Wirkner U, Voss H, Lichter P, Ansorge W, Pyerin W: The human gene (CSNK2A1) coding for the casein kinase II subunit α is located on chromosome 20 and contains tandemly arranged Alu repeats. Genomics 19: 257–326, 1994
Wirkner U, Voss H, Ansorge W, Pyerin W: Genomic organization and promoter identification of the human protein kinase CK2 catalytic subunit alpha (CSNK2A1). Genomics 48: 71–78, 1998
Wirkner U, Pyerin W: CK2alpha loci in the human genome: Structure and transcriptional activity. Mol Cell Biochem 191: 59–64, 1999
Yang-Feng TL, Naiman T, Kopatz I, Eli D, Dafni N, Canaani D: Assignment of the human casein kinase II alpha′ subunit gene (CSNK2A1) to chromosome 16p13.2-p13.3. Genomics 19: 173, 1994
Wirkner U, Voss H, Lichter P, Pyerin W: Human protein kinase CK2 genes. Cell Mol Biol Res 40: 489–499, 1994
Albertella MR, Jones H, Thomson W, Olavesen MG, Campbell RD: Localization of eight additional genes in the human major histocompatibility complex, including the gene encoding the casein kinase II β subunit (CSNK2B). Genomics 36: 240–251, 1996
Boehm SK, Gum JR, Erickson RH, Hicks JW, Kim YS: Human dipeptidyl peptidase IV gene promoter: Tissue-specific regulation from a TATA-less GC-rich sequence characteristic of a housekeeping gene promoter. Biochem J 311: 835–843, 1995
Gumina RJ, Kirschbaum NE, Piotrowski K, Newman PJ: Characterization of the human platelet/endothelial cell adhesion molecule-1 promoter: Identification of a GATA-2 binding element. Blood 89: 1260–1269, 1997
Voss H, Wirkner U, Jakobi R, Hewitt NA, Schwager C, Zimmermann J, Ansorge W, Pyerin W: Structure of the gene encoding human casein kinase II subunit beta. J Biol Chem 266: 13706–13711, 1991
Krehan A, Ansuini H, Böcher O, Grein S, Wirkner U, Pyerin W: Transcription factors ets1, NF-kappa B, and Sp1 are major determinants of the promoter activity of the human protein kinase CK2alpha gene. J Biol Chem 275: 18327–18336, 2000
Krehan A, Schmalzbauer R, Böcher O, Ackermann K, Wirkner U, Brouwers S, Pyerin W: Ets1 is a common element in directing transcription of the α and the β gene of human protein kinase CK2. Eur J Biochem 268: 3243–3252, 2001
Kyhse-Andersen J: Electroblotting of multiple gels: A simple apparatus without buffer tank for rapid transfer of proteins from polyacrylamide to nitrocellulose. J Biochem Biophys Meth 10: 203–209, 1984
Kobayashi R, Tashima Y: Visualization of antigen on nitrocellulose membrane by the oxidative coupling reaction of N,N′-dimethyl-p-phenylenediamine and 4-chloro-1-naphthol. Anal Biochem 183: 9–12, 1989
Ackermann K, Fauss J, Pyerin W: Inhibition of cyclic AMP-triggered aromatase gene expression in human choriocarcinoma cells by anti-sense oligodeoxynucleotide. Cancer Res 54: 4940–4946, 1994
Jakobi R, Voss H, Pyerin W: Human phosvitin/casein kinase type II. Molecular cloning and sequencing of full-length cDNA encoding subunit beta. Eur J Biochem 183: 227–233, 1989
Lozeman FJ, Litchfield DW, Piening C, Takio A, Walsh KA, Krebs EG: Isolation and characterization of human cDNA clones encoding the alpha and the alpha′ subunits of casein kinase II Interaction sites between catalytic and regulatory subunits in human protein kinase CK2 holoenzymes as indicated by chemical cross-linking and immunological investigations. Biochemistry 29: 8436–8447, 1990
Bodenbach L, Fauss J, Robitzki A, Krehan A, Lorenz P, Lozeman FJ, Pyerin W: Recombinant human casein kinase II. A study with the complete set of subunits (alpha, alpha′ and beta), site-directed autophosphorylation mutants and a bicistronically expressed holoenzyme. Eur J Biochem 220: 263–273, 1994
Lüscher B, Litchfield DW: Biosynthesis of casein kinase II in lymphoid cell lines. Eur J Biochem 220: 521–526, 1994
Ho IC, Bhat NK, Gottschalk LR, Lindsten T, Thompson CB, Papas TS, Leiden JM: Sequence-specific binding of human Ets-1 to the T cell receptor alpha gene enhancer. Science 250: 814–818, 1990
Seth A, Hodge DR, Thomson DM, Robinson L, Panayiotakis A, Watson DK, Papas TS: Aids Res Hum Retroviruses 9: 1017–1023, 1993
Gill G, Pascal E, Tseng ZH, Tijan R: A glutamine-rich hydrophobic patch in transcription factor Sp1 contacts the dTAFII110 component of the Drosophila TFIID complex and mediates transcriptional activation. Proc Natl Acad Sci USA 91: 192–196, 1994
Carter RS, Bhat NK, Basu A, Avadhani NG: The basal promoter elements of murine cytochrome c oxidase subunit IV gene consist of tandemly duplicated ets motifs that bind to GABP-related transcription factors. J Biol Chem 267: 23418–23426, 1992
Carter RS, Avadhani NG: Cooperative binding of GA-binding protein transcription factors to duplicated transcription initiation region repeats of the cytochrome c oxidase subunit IV gene. J Biol Chem 269: 4381–4387, 1994
Wasylyk B, Hahn SL, Giovane A: The Ets family of transcription factors. Eur J Biochem 211: 7–18, 1993
Pearson BE, Nasheuer H-P, Wang TS: Human DNA polymerase alpha gene: Sequences controlling expression in cycling and serum-stimulated cells. Mol Cell Biol 11: 2081–2095, 1991
Yamaguchi M, Hayashi Y, Matsukage A: Mouse DNA polymerase beta gene promoter: Fine mapping and involvement of Sp1-like mouse transcription factor in its function. Nucl Acids Res 16: 8773–8787, 1988
Jolliff K, Li Y, Johnson LF: Multiple protein-DNA interactions in the TATAA-less mouse thymidylate synthase promoter. Nucl Acid Res 19: 2267–2274, 1991
Clevers HC, Dunlap S, Wileman TE, Terhorst C: Human CD3-epsilon gene contains three miniexons and is transcribed from a non-TATA promoter. Proc Natl Acad Sci 85: 8156–8160, 1988
Siu G, Wurster A, Lipsick JS, Hedrick SM: Expression of the CD4 gene requires a Myb transcription factor. Mol Cell Biol 12: 1592–1604, 1992
Sucharov C, Basu A, Carter RS, Avadhani NH: A novel transcriptional initiator activity of the GABP factor binding ets sequence repeat from the murine cytochrome c oxidase Vb gene. Gene Express 5: 93–111, 1995
Crepieux P, Coll J, Stehelin D: The Ets family of proteins: Weak modulators of gene expression in quest for transcriptional partners. Crit Rev Oncogen 5: 615–638, 1994
Dittmer J, Pise-Masison CA, Clemens KE, Choi K-S, Brady JN: Interaction of human T-cell lymphotropic virus type I Tax, Ets1, and Sp1 in transactivation of the PTHrP P2 promoter. J Biol Chem 272: 4953–4958, 1997
Ackermann K, Pyerin W: Protein kinase CK2alpha may induce gene expression but unlikely acts directly as a DNA-binding transcription-activating factor. Mol Cell Biochem 191: 129–134, 1999
Gunther M, Frebourg T, Laithier M, Fossar N, Bouziane-Ouartini M, Lavialle C, Brison O: An Sp1 binding site and the minimal promoter contribute to overexpression of the cytokeratin 18 gene in tumorigenic clones relative to that in nontumorigenic clones of a human carcinoma cell line. Mol Cell Biol 15: 2490–2499, 1995
VanDijk MA, Holthuizen PE, Sussenbach JS: Elements required for activation of the major promoter of the human insulin-like growth factor II gene. Mol Cell Biol 88: 175–185, 1992
Wu RL, Chen T-T, Sun T-T: Functional importance of an Sp1-and an NFκB-related nuclear protein in a keratinocyte-specific promoter of rabbit K3 keratin gene. J Biol Chem 269: 28450–28459, 1994
Biggs JR, Kudlow JE, Kraft AS: The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells. Biol Chem 271: 901–906, 1996
Kollmar R, Sukow KA, Spongale SK, Farnham PJ: Start site selection at the TATA-less carbamoyl-phosphate synthase (glutamine-hydrolyzing)/aspartate carbamoyltransferase/dihydroorotase promoter. J Biol Chem 269: 2252–2257, 1994
Block KL, Shou Y, Poncz M: An Ets/Sp1 interaction in the 5′-flanking region of the megakaryocyte-specific alpha IIb gene appears to stabilize Sp1 binding and is essential for expression of this TATA-less gene. Blood 88: 2071–2080, 1996
Sun SC, Elwood J, Beraud C, Greene WC: Human T-cell leukemia virus type I Tax activation of NF-kappa B/Rel involves phosphorylation and degradation of I kappa B alpha and RelA (p65)-mediated induction of the c-rel gene. Mol Cell Biol 14: 7377–7384, 1994
Armstrong SA, Barry DA, Leggett RW, Mueller CR: Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA binding activity. J Biol Chem 272: 13489–13495, 1997
Cochet C, Chambaz EM: Oligomeric structure and catalytic activity of G type casein kinase. Isolation of the two subunits and renaturation experiments. J Biol Chem 258: 1403–1406, 1983
Ole-MoiYoi OK: Casein kinase II in theileriosis. Science 267: 834–836, 1995
Seldin DC, Leder P: Casein kinase II alpha transgene-induced murine lymphoma: Relation to theileriosis in cattle. Science 267: 894–897, 1995
Kelliher MA, Seldin DC, Leder P: Casein kinase II alpha transgene-induced murine lymphoma: Relation to theileriosis in cattle. EMBO J 15: 5160–5166, 1996
Landesman-Bollag E, Channavajhala PL, Cardiff RD, Seldin DC: p53 deficiency and misexpression of protein kinase CK2alpha collaborate in the development of thymic lymphomas in mice. Oncogene 16: 2965–2974, 1998
Orlandini M, Semplici F, Ferruzzi R, Meggio F, Pinna LA, Oliviero S: Protein kinase CK2alpha′ is induced by serum as a delayed early gene and cooperates with Ha-ras in fibroblast transformation. J Biol Chem 273: 21291–21297, 1998
Yang B-S, Hauser CA, Henkel G, Colman MS, VanBeveren C, Stacey KJ, Hume DA, Maki RA, Ostrowski MC: Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Mol Cell Biol 16: 538–547, 1996
Litchfield DW, Dobrowolska G, Krebs EG: Regulation of casein kinase II by growth factors: A reevaluation. Cell Mol Biol Res 40: 373–381, 1994
Ackerman P, Osheroff N: Regulation of casein kinase II activity by epidermal growth factor in human A-431 carcinoma cells. J Biol Chem 264: 11958–11963, 1989
Faust RA, Gapany M, Tristani P, Davis A, Adams GL, Ahmed K: Elevated protein kinase CK2 activity in chromatin of head and neck tumors: Association with malignant transformation. Cancer Lett 101: 31–35, 1996
Münstermann U, Fritz G, Seitz G, Yiping L, Schneider HR, Issinger O-G: Casein kinase II is elevated in solid human tumours and rapidly proliferating non-neoplastic tissue. Eur J Biochem 189: 251–257, 1990
Daya-Makin M, Sanghera JS, Mogentale TL, Lipp M, Parchomchuk J, Hogg JC, Pelech SL: Activation of a tumor-associated protein kinase (p40TAK) and casein kinase 2 in human squamous cell carcinomas and adenocarcinomas of the lung. Cancer Res 54: 2262–2268, 1994
Bhat NK, Fischinger PJ, Seth A, Watson DK, Papas T: Isolation and characterization of a novel gene expressed in multiple cancers. Int J Oncol 8: 841–846, 1996
Sato M, Morii E, Komori T, Kawahata H, Sugimoto M, Terai K, Shimizu H, Yasui T, Ogihara H, Yasui N, Ochi T, Kitamura Y, Ito Y, Nomura S: Transcriptional regulation of osteopontin gene in vivo by PEBP2-alphaA/CBFA1 and ETS1 in the skeletal tissues. Oncogene 17: 1517–25, 1998
Gambarotta G, Boccaccio C, Giordano S, Ando M, Stella MC, Comoglio PM: Ets up-regulates MET transcription. Oncogene 13: 1911–1917, 1996
McCracken S, Leung S, Bosselut R, Ghysdael J, Miyamoto NG: Myb and Ets related transcription factors are required for activity of the human lck type I promoter. Oncogene 12: 3609–3615, 1994
Majérus M-A, Bibollet-Ruche F, Telliez J-B, Wasylyk B, Bailleul B: Serum, AP-1 and Ets-1 stimulate the human ets-1 promoter. Nucl Acids Res 20: 2699–2703, 1992
Bassuk AG, Leiden JM: A direct physical association between ETS and AP-1 transcription factors in normal human T cells. Immunity 3: 223–237, 1995
McKinlay LH, Tymms MJ, Thomas RS, Seth A, Hasthorpe S, Hertzog PJ, Kola I: The role of Ets-1 in mast cell granulocyte-macrophage colony-stimulating factor expression and activation. J Immunol 161: 4098–5105, 1998
Boldyreff B, Issinger O-G: Structure of the gene encoding the murine protein kinase CK2β subunit. Genomics 29: 253–256, 1995
Hu E, Rubin CS: Casein kinase II from Caenorhabditis elegans. J Biol Chem 265: 5072–5080, 1990
Hu E, Rubin CS: Casein kinase II from Caenorhabditis elegans. J Biol Chem 266: 19796–19802, 1991
Allende CC, Neckelman G, Wilhelm J, Brown J, Allende JE: The promoter region of the CK2α subunit gene of Xenopus laevis. 3rd Int. Symposium on Protein Kinase CK2: From Structure to Function, San Esteban, Chile, Poster Abstracts, January 8-10, 2001
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pyerin, W., Ackermann, K. Transcriptional coordination of the genes encoding catalytic (CK2α) and regulatory (CK2β) subunits of human protein kinase CK2. Mol Cell Biochem 227, 45–57 (2001). https://doi.org/10.1023/A:1013152621029
Issue Date:
DOI: https://doi.org/10.1023/A:1013152621029