casein-kinase-ii and Burkitt-Lymphoma

Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of α catalytic and β regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2α immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-κB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL.

Topics: Antineoplastic Agents; B-Lymphocytes; Blotting, Western; Burkitt Lymphoma; Casein Kinase II; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chaperonins; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Naphthyridines; Phenazines; Phosphorylation; Protein Kinase Inhibitors; Retrospective Studies; RNA, Messenger; Signal Transduction; Transcription Factor RelA

We have analyzed the biosynthesis of casein kinase II. In exponentially growing tissue culture cells, the beta subunit was synthesized in excess of the catalytic subunit (alpha). A substantial fraction of newly synthesized beta was degraded within the first hour. The remaining fraction of beta was incorporated into holoenzyme. In contrast, little degradation of newly synthesized alpha subunit was observed and most was quickly and efficiently incorporated into holoenzyme. The assembly of beta with alpha was paralleled by an increase in apparent molecular mass of beta due to phosphorylation. The subcellular distribution of newly synthesized [35S]Met-labelled casein kinase II and of enzyme labelled and chased in the presence of excess unlabelled methionine was very similar and compatible with a nuclear localization. The degradation of the excess beta subunit occurred through a non-lysosomal proteolytic system with a very low ATP requirement.

Topics: Animals; Burkitt Lymphoma; Casein Kinase II; Cell Line; Chickens; Humans; Kinetics; Lymphocytes; Lymphoma; Methionine; Phosphorylation; Protein Serine-Threonine Kinases; Subcellular Fractions; Time Factors; Tumor Cells, Cultured

Myc proteins have been implicated in the regulation of cell growth and differentiation. The identification of Max, a basic region/helix-loop-helix/leucine zipper protein, as a partner for Myc has provided insights into Myc's molecular function as a transcription factor. Recent evidence indicates that the relative abundance of Myc and Max is important to determine the level of specific gene transcription. In this report we have identified two major in vivo phosphorylation sites in Max (Ser-2 and -11) which can be modified in vitro by casein kinase II (CKII). Phosphorylation of these sites modulates DNA-binding by increasing both the on- and off-rates of Max homo- as well as Myc/Max heterodimers. In addition, our data indicate that the steady state binding of the shorter version of Max (p21) to DNA was similar yet its rate of dissociation faster than that of longer version of Max (p22). These data argue that different Max complexes have different kinetic properties and that these can be modified by CKII phosphorylation. We propose this as an important biological mechanism by which different dimeric complexes can exchange with varying efficiencies on DNA, thereby responding to changes in cell growth conditions.

Topics: Amino Acid Sequence; Base Sequence; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Basic-Leucine Zipper Transcription Factors; Burkitt Lymphoma; Casein Kinase II; Cell Division; DNA-Binding Proteins; DNA, Neoplasm; Electrophoresis, Polyacrylamide Gel; Humans; Molecular Sequence Data; Peptide Mapping; Phosphorylation; Precipitin Tests; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc; Serine; Transcription Factors; Transcription, Genetic; Tumor Cells, Cultured