Development of a Stabilized Form of the Regulatory CK2β Subunit That Inhibits Cell Proliferation

A number of cancers are characterized by elevated expression of CK2 (formerly casein kinase II), which has been implicated as a key component in cell proliferation and transformation. Two lines of evidence, (a) deregulated expression of CK2 and (b) CK2β ubiquitination and degradation of these in a proteasome-dependent manner prompted further investigation of the regulation of CK2β protein stability. We demonstrate that mutating six surface-exposed lysine residues to arginine (6KR) to interfere with ubiquitin attachment can stabilize CK2β. Examination of 6KR expression in cells revealed increased stability over time and increased its steady-state expression level compared with CK2β. In cells, 6KR was no longer sensitive to proteasome inhibition but maintained an elevated expression level. In our studies, 6KR functioned as a normal CK2 regulatory subunit, because it participated in CK2β dimerization, associated with catalytic subunits, was autophosphorylated, and formed active, stable CK2 tetramers. The physiological role of CK2β stabilization was investigated in cell proliferation assays, which showed a significant decrease in proliferation in cells expressing 6KR compared with CK2β. Overall, our results indicate that a stabilized form of CK2β can be used to inhibit cell proliferation. A number of cancers are characterized by elevated expression of CK2 (formerly casein kinase II), which has been implicated as a key component in cell proliferation and transformation. Two lines of evidence, (a) deregulated expression of CK2 and (b) CK2β ubiquitination and degradation of these in a proteasome-dependent manner prompted further investigation of the regulation of CK2β protein stability. We demonstrate that mutating six surface-exposed lysine residues to arginine (6KR) to interfere with ubiquitin attachment can stabilize CK2β. Examination of 6KR expression in cells revealed increased stability over time and increased its steady-state expression level compared with CK2β. In cells, 6KR was no longer sensitive to proteasome inhibition but maintained an elevated expression level. In our studies, 6KR functioned as a normal CK2 regulatory subunit, because it participated in CK2β dimerization, associated with catalytic subunits, was autophosphorylated, and formed active, stable CK2 tetramers. The physiological role of CK2β stabilization was investigated in cell proliferation assays, which showed a significant decrease in proliferation in cells expressing 6KR compared with CK2β. Overall, our results indicate that a stabilized form of CK2β can be used to inhibit cell proliferation. Fundamental cellular processes such as proliferation and survival involve regulation by CK2 (formerly casein kinase II), 3The abbreviations used are:CK2formerly casein kinase IIHAhemagglutininGFPgreen fluorescent proteinMG132N-carbobenzoxyl-Leu-Leu-leucinalGSTglutathione S-transferasePBSphosphate-buffered salineFACSfluorescence-activated cell sortingUbubiquitinMAPKmitogen-activated protein kinase.3The abbreviations used are:CK2formerly casein kinase IIHAhemagglutininGFPgreen fluorescent proteinMG132N-carbobenzoxyl-Leu-Leu-leucinalGSTglutathione S-transferasePBSphosphate-buffered salineFACSfluorescence-activated cell sortingUbubiquitinMAPKmitogen-activated protein kinase. a serine/threonine protein kinase that is ubiquitously expressed in eukaryotic cells (1Meggio F. Pinna L.A. FASEB J. 2003; 17: 349-368Crossref PubMed Scopus (1103) Google Scholar). Further evidence for its critical role is revealed in the absolute requirement for CK2 for viability in yeast and slime mold and in the requirements for CK2 in the G1/S and G2/M cell cycle transitions in yeast and mammalian cells (2Kikkawa U. Mann S.K. Firtel R.A. Hunter T. Mol. Cell. Biol. 1992; 12: 5711-5723Crossref PubMed Google Scholar, 3Glover C.V. Prog. Nucleic Acids Res. Mol. Biol. 1998; 59: 95-133Crossref PubMed Scopus (176) Google Scholar, 4Lorenz P. Pepperkok R. Ansorge W. Pyerin W. J. Biol. Chem. 1993; 268: 2733-2739Abstract Full Text PDF PubMed Google Scholar, 5Pepperkok R. Lorenz P. Jakobi R. Ansorge W. Pyerin W. Exp. Cell Res. 1991; 197: 245-253Crossref PubMed Scopus (74) Google Scholar, 6Pepperkok R. Lorenz P. Ansorge W. Pyerin W. J. Biol. Chem. 1994; 269: 6986-6991Abstract Full Text PDF PubMed Google Scholar, 7Hanna D.E. Rethinaswamy A. Glover C.V. J. Biol. Chem. 1995; 270: 25905-25914Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). formerly casein kinase II hemagglutinin green fluorescent protein N-carbobenzoxyl-Leu-Leu-leucinal glutathione S-transferase phosphate-buffered saline fluorescence-activated cell sorting ubiquitin mitogen-activated protein kinase. formerly casein kinase II hemagglutinin green fluorescent protein N-carbobenzoxyl-Leu-Leu-leucinal glutathione S-transferase phosphate-buffered saline fluorescence-activated cell sorting ubiquitin mitogen-activated protein kinase. Given the diverse, yet essential, roles of CK2 within the cell, it is important to understand the mechanisms regulating CK2, which are equally as diverse and critical. Furthermore, perturbations in expression or activity of CK2 are associated with human disease. Abnormally high levels of CK2 have been observed in cancers of the breast, prostate, lung, head and neck, and kidney (8Daya-Makin M. Sanghera J.S. Mogentale T. Lipp M. Parchomchuk J. Hogg J. Pelech S. Cancer Res. 1994; 54: 2262-2268PubMed Google Scholar, 9Stalter G. Siemer S. Becht E. Ziegler M. Remberger K. Issinger O.G. Biochem. Biophys. Res. Commun. 1994; 202: 141-147Crossref PubMed Scopus (153) Google Scholar, 10Yenice S. Davis A.T. Gouelli S.A. Akdas A. Limas C. Ahmed K. Prostate. 1994; 24: 11-16Crossref PubMed Scopus (102) Google Scholar, 11Faust R.A. Gapany M. Tristani P. Davis A. Adams G.L. Ahmed K. Cancer Lett. 1996; 101: 31-35Crossref PubMed Scopus (145) Google Scholar, 12Landesman-Bollag E. Romieu-Mourez R. Song D.H. Sonenshein G.E. Cardiff R.D. Seldin D.C. Oncogene. 2001; 20: 3247-3257Crossref PubMed Scopus (267) Google Scholar). Overexpression of catalytic CK2 subunits led to increased proliferation and transformation. By comparison, overexpression of the regulatory CK2 subunit has been associated with decreased proliferation in yeast and mammalian cells, although this inhibitory role has not been universally observed (13Li D. Dobrowolska G. Aicher L.D. Chen M. Wright J.H. Drueckes P. Dunphy E.L. Munar E.S. Krebs E.G. J. Biol. Chem. 1999; 274: 32988-32996Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 14Lebrin F. Chambaz E.M. Bianchini L. Oncogene. 2001; 20: 2010-2022Crossref PubMed Scopus (60) Google Scholar, 15Vilk G. Derksen D.R. Litchfield D.W. J. Cell Biochem. 2001; 84: 84-99Crossref PubMed Scopus (10) Google Scholar). Collectively, these results indicate that CK2 has a profound effect on cell proliferation and suggests that individual CK2 subunits may exert competing effects. CK2 has typically been viewed as a tetrameric complex consisting of two catalytic subunits, CK2α and CK2α′, and one regulatory subunit, CK2β (16Pinna L.A. J. Cell Sci. 2002; 115: 3873-3878Crossref PubMed Scopus (406) Google Scholar, 17Litchfield D.W. Lozeman F.J. Piening C. Sommercorn J. Takio K. Walsh K.A. Krebs E.G. J. Biol. Chem. 1990; 265: 7638-7644Abstract Full Text PDF PubMed Google Scholar, 18Lozeman F.J. Litchfield D.W. Piening C. Takio K. Walsh K.A. Krebs E.G. Biochemistry. 1990; 29: 8436-8447Crossref PubMed Scopus (126) Google Scholar, 19Litchfield D.W. Bosc D.G. Canton D.A. Saulnier R.B. Vilk G. Zhang C. Mol. Cell. Biochem. 2001; 227: 21-29Crossref PubMed Scopus (39) Google Scholar, 20Allende J.E. Allende C.C. FASEB J. 1995; 9: 313-323Crossref PubMed Scopus (587) Google Scholar). Studies investigating CK2 tetramer assembly determined that a dimer of CK2β subunits forms the core of the enzyme, and the catalytic subunits subsequently bind to the CK2β core (21Gietz R.D. Graham K.C. Litchfield D.W. J. Biol. Chem. 1995; 270: 13017-13021Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 22Boldyreff B. Mietens U. Issinger O.G. FEBS Lett. 1996; 379: 153-156Crossref PubMed Scopus (45) Google Scholar, 23Marin O. Meggio F. Sarno S. Pinna L.A. Biochemistry. 1997; 36: 7192-7198Crossref PubMed Scopus (46) Google Scholar, 24Graham K.C. Litchfield D.W. J. Biol. Chem. 2000; 275: 5003-5010Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 25Chantalat L. Leroy D. Filhol O. Nueda A. Benitez M.J. Chambaz E.M. Cochet C. Dideberg O. EMBO J. 1999; 18: 2930-2940Crossref PubMed Scopus (134) Google Scholar, 26Canton D.A. Zhang C. Litchfield D.W. Biochem. J. 2001; 358: 87-94Crossref PubMed Scopus (35) Google Scholar). CK2β is phosphorylated at serine 209 in a cell-cycle-dependent manner by p34cdc2 in vitro and in mammalian cells (27Zhang C. Vilk G. Canton D.A. Litchfield D.W. Oncogene. 2002; 21: 3754-3764Crossref PubMed Scopus (67) Google Scholar, 28Litchfield D.W. Lozeman F.J. Cicirelli M.F. Harrylock M. Ericsson L.H. Piening C.J. Krebs E.G. J. Biol. Chem. 1991; 266: 20380-20389Abstract Full Text PDF PubMed Google Scholar, 29Litchfield D.W. Bosc D.G. Slominski E. Biochim. Biophys. Acta. 1995; 1269: 69-78Crossref PubMed Scopus (28) Google Scholar, 30Meggio F. Boldyreff B. Marin O. Issinger O.G. Pinna L.A. Eur. J. Biochem. 1995; 230: 1025-1031Crossref PubMed Scopus (28) Google Scholar). CK2β autophosphorylation at serines 2 and 3 is mediated by the catalytic subunits of CK2 (28Litchfield D.W. Lozeman F.J. Cicirelli M.F. Harrylock M. Ericsson L.H. Piening C.J. Krebs E.G. J. Biol. Chem. 1991; 266: 20380-20389Abstract Full Text PDF PubMed Google Scholar, 31Boldyreff B. James P. Staudenmann W. Issinger O.G. Eur. J. Biochem. 1993; 218: 515-521Crossref PubMed Scopus (35) Google Scholar). Although neither phosphorylation event is completely understood, there are indications that autophosphorylation of CK2β enhances its stability (27Zhang C. Vilk G. Canton D.A. Litchfield D.W. Oncogene. 2002; 21: 3754-3764Crossref PubMed Scopus (67) Google Scholar). Detailed investigation of CK2β protein stability and turnover revealed that CK2β exhibits a biphasic degradation pattern (32Luscher B. Litchfield D.W. Eur. J. Biochem. 1994; 220: 521-526Crossref PubMed Scopus (78) Google Scholar). More specifically, CK2β is normally expressed at a higher level than the catalytic subunits of CK2, allowing some CK2β to be incorporated into CK2 and the CK2β is with a of than (32Luscher B. Litchfield D.W. Eur. J. Biochem. 1994; 220: 521-526Crossref PubMed Scopus (78) Google Scholar). Furthermore, the observed ubiquitination of CK2β and the of CK2β protein proteasome inhibition that of CK2β it for degradation (27Zhang C. Vilk G. Canton D.A. Litchfield D.W. Oncogene. 2002; 21: 3754-3764Crossref PubMed Scopus (67) Google Scholar). We that the stability of CK2β be by that its in CK2β protein levels may the mechanisms that the of CK2 on cell which may be important in the of In this a form of that exhibits stability in Further the 6KR protein and its effect on cell proliferation. K.C. Litchfield D.W. J. Biol. Chem. 2000; 275: 5003-5010Abstract Full Text Full Text PDF PubMed Scopus (77) Google was into the of the was used to the lysine residues of CK2β and to a of lysine of CK2β. The and and lysine to arginine into the to and and CK2β or 6KR by CK2β or 6KR into the to the in and was by 6KR into the and of the was Litchfield D.W. J. Cell Biochem. 1997; PubMed Scopus Google Scholar). a ubiquitin was D. CK2α and into and as D.G. Graham K.C. Saulnier R.B. Zhang C. D. R.D. Litchfield D.W. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). a was G. and or by into the and or into the of the by and have been (28Litchfield D.W. Lozeman F.J. Cicirelli M.F. Harrylock M. Ericsson L.H. Piening C.J. Krebs E.G. J. Biol. Chem. 1991; 266: 20380-20389Abstract Full Text PDF PubMed Google Scholar, D.W. B. Lozeman F.J. Krebs E.G. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). the and the was green fluorescent protein a of and of and to or to was Cell and and cells maintained in with and at in an of the Litchfield D.W. J. Cell Biochem. 1997; PubMed Scopus Google Scholar). cells and with cells in cell with and used or at and of cellular protein by the of 227: PubMed Scopus Google Scholar). to and the and and with or and as the was the cells, of cells was used to the number of that protein levels be compared and to for degradation assays, of cells with or with to inhibit protein time to 3 cells and cell proteasome inhibition assays, cells with or with of N-carbobenzoxyl-Leu-Leu-leucinal a proteasome to cells and cell protein of and of protein was by and and and by cells as and cell as on of protein and or as and for at with used for CK2 kinase or the by as cell with of protein with of to the for at with to CK2β with with and with by the with of for by as ubiquitination as in and by of protein with of in for 2 at The was with and by with of by as protein was protein or and protein was with and with at with for at by and and with or the of or protein determined by into CK2 and at CK2 as CK2 kinase on in activity in a of The was by 2 to 2 and by 2 of at for and by of and by and to and of into was which is to the catalytic activity by the CK2 cell cycle cells as with or and the to cells in 2 in a in with and by into and at with A by for at in the and cells on a at a of than Cell cycle and Cell cells maintained in at a of with of or and of a with of used as a was and 3 cells for with 2 with and in in at for by with of to The number of as levels to of the number of was used to cells as with or maintained in to protein expression the cells with with and for at in with of of cells for at in of cell and of protein was used for as that was to the on an in in in and to for or of in that CK2β is and by the proteasome (27Zhang C. Vilk G. Canton D.A. Litchfield D.W. Oncogene. 2002; 21: 3754-3764Crossref PubMed Scopus (67) Google Scholar). further the mechanisms CK2 in CK2β protein stability be by ubiquitination of the of CK2β revealed that of the lysine residues in human CK2β are Examination of the of CK2β six and that to be surface-exposed and for ubiquitination these six and further the of CK2β than and and not in the are surface-exposed because are on the The and are within the and are important for CK2β protein on this the six surface-exposed in CK2β to arginine to ubiquitin attachment protein the of lysine in CK2β with to its is important to that the used to of CK2β not lysine important is the of the ubiquitination Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). on this that of and of the may be to degradation of CK2β. of this a number of lysine or lysine residues of CK2β and the of lysine in the regulation of CK2β protein the steady-state expression levels of the lysine in was expressed at levels to with the of in protein was in or and with as in the of surface-exposed not the of CK2β to degradation by the as by the of with Collectively, these results that of a lysine is to CK2β stability by ubiquitin of CK2β and of was in investigated the of lysine in CK2β on steady-state expression of the lysine and as as and increased steady-state expression compared with and showed an in the level of as by a with compared with and the lysine and decreased protein to protein and degradation of these Two or lysine to arginine in to no protein that of as as two lysine residues the of CK2β to be was the of proteasome-dependent degradation of observed with of or lysine The was for further investigation because it the in expression compared with and it showed the of Furthermore, was of a of stabilized forms of CK2β and because of its six surface-exposed the ubiquitination but have the on CK2β Examination of the of on protein was stabilized in cells, that it may no longer be and no longer sensitive to proteasome this cells with or with of expressed or protein be in or protein with of protein that was not by proteasome inhibition Furthermore, increased levels of compared with that is incorporated into CK2 and it is subsequently indicate that is a protein the ubiquitination of CK2β and cells with or in the or of with a to protein and protein was in or cells with and a of these in and are at that to forms of CK2β. of and in a of compared with in to the higher levels of that are observed the cells with or in the or of and with an in protein was observed for but not these results that of the six surface-exposed of CK2β the of CK2β to be and Examination of 6KR the stability of compared with over cells with or with to inhibit protein CK2β not which was because levels of CK2 tetramer and subunits have been to protein of not 3 that protein been stabilized in cells and with as in the of 6KR as a of the of its to form with CK2 the of to bind CK2β was protein was in or cells with or or and was of CK2β or 6KR was The of 6KR to bind 6KR was by or cell expressing and CK2β or to and be results indicate that 6KR is of CK2β in cells, that it be incorporated into tetrameric the of 6KR to bind the catalytic CK2 subunits cells with or in the or of with and with and CK2α and be and or Cell with CK2α and by with and of with CK2α with the of or to form with CK2α or was by and to form with CK2α and these that 6KR is to form CK2 because there was a and CK2α and and because forms of 6KR used to the of 6KR to form CK2 in cells with or with and in kinase with as a phosphorylated was in cells or cells, phosphorylated of CK2 that or protein was in and that a of CK2β in CK2 was results indicate not that 6KR is to form CK2 in cells, but that 6KR not inhibit CK2 kinase of 6KR on Cell some that high levels of CK2β protein cell and because have a degradation form of CK2β to the effect of 6KR on the cell these studies, cells in cells, the steady-state level of 6KR and phosphorylated 6KR protein was elevated compared with CK2β a investigating the effect of 6KR on the cell cycle that a cell cycle may be cells with or and and and the cell cycle of and cells by for time significant in cell cycle be of 6KR on Cell cell cells with or with a by with formed with to the effects. with the and formed the cells the not with a cell cycle overexpression proliferation but not viability C.J. 1999; PubMed Scopus Google Scholar). on this that and to but to to cells the with no effect on cell proliferation proliferation revealed that proliferation to of or cells in to the cells with or no effect on cell proliferation. results that stabilization of CK2β to a significant decrease in cell proliferation that is not mediated by the catalytic subunits and may have in cellular processes such as the cell or in of the Cell of cell proliferation stabilization of CK2β to the is to the CK2 or of CK2β. 6KR be its effect with such as or the decrease in cell proliferation be to the effect that stabilization has on the CK2 of these cell on cells with and and or an the and by there was a significant in the steady-state expression level of in the and of CK2α there was a significant in the of phosphorylated but not in the of CK2α that forms CK2 with our is to that there is no in the of CK2α in the of compared with that there has not been an in CK2 complex expression to the of In not the of by which 6KR be its effect on cell proliferation. Overall, these that the effect of 6KR not stabilization of the CK2 complex or in with but not the that 6KR is the of or CK2 that CK2β was in cells and by the proteasome (27Zhang C. Vilk G. Canton D.A. Litchfield D.W. Oncogene. 2002; 21: 3754-3764Crossref PubMed Scopus (67) Google Scholar). Given this that of one or lysine residues stabilize CK2β protein in cells by the attachment of Examination of the of CK2β revealed that of the lysine residues in six for ubiquitin attachment K. B. Issinger O.G. EMBO J. 2001; 20: PubMed Scopus Google Scholar, J. G. Nucleic Acids Res. 2000; PubMed Scopus Google Scholar). Although of surface-exposed lysine on its showed no significant in steady-state levels compared with of or the of lysine and led to elevated steady-state expression levels and of to ubiquitin attachment is not the that of lysine residues was to CK2β protein degradation by the proteasome is not The in steady-state protein levels in cells with the 6KR in with the that of the ubiquitin attachment that a of CK2β into CK2 and is CK2β is steady-state levels of CK2β within the cell (32Luscher B. Litchfield D.W. Eur. J. Biochem. 1994; 220: 521-526Crossref PubMed Scopus (78) Google Scholar). Given these it is that overexpression of CK2β in the of CK2β CK2β associated with the CK2 catalytic In this the degradation of CK2β and 6KR was inhibition of protein CK2β protein levels decreased the 6KR protein level these results and the that 6KR was no longer sensitive to proteasome inhibition that of on CK2β (6KR) its to at 3 and its to in a stabilized 6KR results in stabilization of of CK2β are not The 6KR protein forms with and 6KR that the is not by mutating lysine to arginine within this Furthermore, 6KR with as as CK2α or CK2α′, that neither lysine in the regulatory of are key residues with the catalytic In forms of CK2β in CK2 complex was of CK2β within a this that CK2 formed are of in 6KR further evidence that active, stable CK2 6KR formed in of a stabilized form of CK2β that to normally as a regulatory subunit of CK2 is the of CK2β in and its and Although this is significant on its the physiological of CK2β stabilization The tetrameric of CK2, that CK2β within the tetramer to CK2 has the of the and regulation of CK2β. of catalytic subunit of CK2β and as as in of the subunits are two of the lines of evidence CK2 roles for CK2β. evidence suggests a for investigating CK2β protein levels are and the cellular of this In studies, the effect of CK2β overexpression on cellular processes such as cell proliferation that overexpression of CK2β led to inhibition of cell proliferation in cells and that this was to of the of the cell cycle (13Li D. Dobrowolska G. Aicher L.D. Chen M. Wright J.H. Drueckes P. Dunphy E.L. Munar E.S. Krebs E.G. J. Biol. Chem. 1999; 274: 32988-32996Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). By comparison, human cells expressing CK2β and cells, that CK2β overexpression no effect on cell proliferation F. Chambaz E.M. Bianchini L. Oncogene. 2001; 20: 2010-2022Crossref PubMed Scopus (60) Google Scholar, 15Vilk G. Derksen D.R. Litchfield D.W. J. Cell Biochem. 2001; 84: 84-99Crossref PubMed Scopus (10) Google Scholar). In this that overexpression of CK2β in cells not cell proliferation. overexpression of which is degradation to a significant decrease in cell proliferation. CK2 levels not 6KR is it is that the are to 6KR than the CK2 is by the proliferation neither proliferation on of CK2β protein levels may not cell proliferation but it may be a of CK2β protein level In our cell not of 6KR that the inhibition of cell proliferation. in not that increased or decreased in the or of 6KR not that than one or two protein the effect may be in its The of CK2 at of the cell cycle and in the and the G2/M transitions the that expression of 6KR the of cell cycle C.V. Prog. Nucleic Acids Res. Mol. Biol. 1998; 59: 95-133Crossref PubMed Scopus (176) Google Scholar, 6Pepperkok R. Lorenz P. Ansorge W. Pyerin W. J. Biol. Chem. 1994; 269: 6986-6991Abstract Full Text PDF PubMed Google Scholar, 7Hanna D.E. Rethinaswamy A. Glover C.V. J. Biol. Chem. 1995; 270: 25905-25914Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, D.G. B. Litchfield D.W. Mol. Cell. Biochem. 1999; PubMed Google Scholar, O.G. 1993; 59: PubMed Scopus Google Scholar). In of these complex roles of CK2 in the of it is not that not in cell cycle of cells with 6KR as compared with cells with CK2β. In a it is that CK2 has and of which may be by stabilization of CK2β D.W. Biochem. J. 2003; PubMed Scopus Google Scholar). Examination of in not of increased in cells expressing 6KR as by the of cells a that is not the event for the proliferation observed with Overall, that CK2 has been implicated in a of cellular to it is that a number of CK2 to the that of the for the role of 6KR on the of roles for stabilization of the CK2β subunit has the to a number of to or B. Issinger O.G. FEBS Lett. 1997; PubMed Scopus Google Scholar, M. D. Krebs E.G. Mol. Cell. Biol. 1997; 17: PubMed Google Scholar, C. A. L. T. FEBS Lett. 1997; PubMed Scopus (77) Google Scholar, B. Issinger O.G. Oncogene. 2003; PubMed Scopus Google Scholar, Biol. 268: PubMed Scopus Google Scholar). this it is not 6KR its to with of these protein because 6KR to the catalytic subunits of CK2 it is that 6KR form with and that kinase is to bind it is that expression of 6KR activity 6KR expression is to its which is to have an is active, and it is that of CK2β to this B. Issinger O.G. Oncogene. 2003; PubMed Scopus Google Scholar). Furthermore, by Chen and that CK2β and its M. D. Krebs E.G. Mol. Cell. Biol. 1997; 17: PubMed Google and this inhibition is a that is by the of CK2β M. D. Krebs E.G. Mol. Cell. Biol. 1997; 17: PubMed Google allowing for of the this it that expression of stabilized CK2β by the level of CK2β that be by to the In our demonstrate that a stabilized form of CK2β can be by mutating its six to of this the catalytic subunits of CK2, which expression of this stabilized form of CK2β can be used to inhibit proliferation. Given the evidence that CK2 is in and that the catalytic CK2 subunits activity and our that a stabilized form of CK2β is than CK2β in proliferation for CK2 for We are to for for and for

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.