casein-kinase-ii and Lymphoma

This review covers multiple data obtained on genetically modified mice that help to elucidate various intricate molecular mechanisms of lymphomagenesis in humans. We are in a "golden age" of mouse genetics. The mouse is by far the most accessible mammalian system physiologically similar to humans. Transgenic mouse models have illuminated how different genes contribute to human lymphomagenesis. Multiple experiments with transgenic mice have not only confirmed the data obtained for human lymphomas but also gave additional evidence for the role of some genes and cooperative participation of their products in the development of human lymphomas. Genes and gene networks detected on transgenic mice can successfully serve as molecular targets for tumor therapy. This review demonstrates the extraordinary possibilities of transgenic technology, which is presently one of the readily available, efficient, and accurate tools to solve the problem of cancer.

Topics: Animals; Casein Kinase II; Cytokines; Disease Models, Animal; DNA Repair; Genes, cdc; Genes, myc; Genes, Tumor Suppressor; Genes, Viral; Humans; Lymphoma; Mice; Mice, Knockout; Mice, Transgenic; Oncogenes; Protein Serine-Threonine Kinases; Receptors, Cell Surface; Signal Transduction; Transcription Factors; Transgenes

Topics: Animals; Casein Kinase II; Cattle; Cell Division; Cell Transformation, Neoplastic; Lymphocyte Activation; Lymphoma; Mice; Mice, Transgenic; Protein Serine-Threonine Kinases; Signal Transduction; T-Lymphocytes; Theileria parva; Theileriasis

Casein kinase II subunit alpha (CK2α) is highly expressed in many malignant tumor tissues, including lymphomas and leukemia. To investigate the role of CK2α in cell proliferation and apoptosis of malignant lymphomas and leukemia, 2 lymphoma cell lines and one leukemia cell line were infected with CK2α shRNA lentivirus or negative control shRNA lentivirus, and stably infected cell lines were established. Real-time PCR and Western blot results showed that the mRNA and protein levels of CK2α were significantly reduced in CK2α knockdown cells. The tetrazolium-based colorimetric (MTT) assay found that down-regulation of CK2α inhibited the proliferation of these cells. Flow cytometry analysis showed that inhibition of CK2α induced cell cycle arrest and apoptosis of lymphoma and leukemia cells. In accordance with these, down-regulation of CK2α also reduced the protein levels of proliferating cell nuclear antigen (PCNA), cyclinD1, and bcl-2, and increased the protein expression of bax, cleaved caspase-3, cleaved caspase-9, and cleaved poly(ADP ribose) polymerase (PARP). Moreover, knockdown of CK2α impeded the growth of xenograft tumors in vivo. In summary, our study revealed that CK2α may contribute to the development of malignant lymphoma and leukemia, and serve as the therapeutic target of these malignant tumors.

Topics: Apoptosis; Casein Kinase II; Cell Proliferation; Down-Regulation; Humans; Lentivirus; Leukemia; Lymphoma

A blockade of CD44 can interfere with haematopoietic and leukemic stem cell homing, the latter being considered as a therapeutic option in haematological malignancies. We here aimed to explore the molecular mechanism underlying the therapeutic efficacy of anti-CD44. We noted that in irradiated mice reconstituted with a bone marrow cell transplant, anti-CD44 exerts a stronger effect on haematopoietic reconstitution than on T lymphoma (EL4) growth. Nonetheless, in the non-reconstituted mouse anti-CD44 suffices for a prolonged survival of EL4-bearing mice, where anti-CD44-prohibited homing actively drives EL4 cells into apoptosis. In vitro, a CD44 occupancy results in a 2-4-fold increase in apoptotic EL4 cells. Death receptor expression (CD95, TRAIL, TNFRI) remains unaltered and CD95 cross-linking-mediated apoptosis is not affected. Instead, CD44 ligation promotes mitochondrial depolarization that is accompanied by caspase-9 cleavage and is inhibited in the presence of a caspase-9 inhibitor. Apoptosis becomes initiated by activation of CD44-associated phosphatase 2A (PP2A) and proceeds via ERK1/2 dephosphorylation without ERK1/2 degradation. Accordingly, CD44-induced apoptosis could be mimicked by ERK1/2 inhibition, that also promotes EL4 cell apoptosis through the mitochondrial pathway. Thus, during haematopoietic stem cell reconstitution care should be taken not to interfere by a blockade of CD44 with haematopoiesis, which could be circumvented by selectively targeting leukemic CD44 isoforms. Beyond homing/settlement in the bone marrow niche, anti-CD44 drives leukemic T cells into apoptosis via the mitochondrial death pathway by CD44 associating with PP2A. Uncovering this new pathway of CD44-induced leukemic cell death provides new options of therapeutic interference.

Topics: Animals; Antibodies, Neoplasm; Apoptosis; Casein Kinase II; Caspase 9; Cell Line, Tumor; Cell Proliferation; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hematopoiesis; Hyaluronan Receptors; Injections, Intravenous; Injections, Subcutaneous; Lymphoma; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Phosphorylation; Protein Phosphatase 2; T-Lymphocytes; Thymoma; Thymus Neoplasms

Protein kinase CK2 (formerly casein kinase II) is frequently upregulated in human cancers, and transgenic expression of CK2alpha in lymphocytes is oncogenic. Lymphomagenesis is dramatically accelerated by co-expression of a c-myc transgene, suggestive of a synergistic interaction between the kinase and the transcription factor. Since c-myc can be phosphorylated by CK2, we hypothesized that the synergy between CK2 and c-myc might be due to a functional interaction of the two molecules. Pharmacologic inhibition of CK2 activity in cell lines established from CK2alpha transgenic T cell lymphomas reduces their proliferation and concomitantly with this, the steady state levels of c-myc protein decline. This is caused by accelerated c-myc protein turnover, which occurs in a proteasome-dependent manner. Transfection of cells with sense or anti-sense CK2 constructs modulates c-myc protein levels in concert with the alteration in CK2 activity, validating the findings obtained using the kinase inhibitors. Thus, CK2 is a critical regulator of c-myc protein stability and of the proliferation of these T cell lymphomas.

Topics: Animals; Apigenin; Blotting, Western; Casein Kinase II; Cell Division; Cells, Cultured; Emodin; Flavonoids; Glutathione Transferase; Lymphoma; Mice; Mice, Transgenic; Peptide Hydrolases; Phosphorylation; Plasmids; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc; Recombinant Fusion Proteins; T-Lymphocytes

Activation of the basic helix-loop-helix (bHLH) gene TAL-1 (or SCL) is the most frequent gain-of-function mutation in pediatric T cell acute lymphoblastic leukemia (T-ALL). Similarly, mis-expression of tal-1 in the thymus of transgenic mice results in the development of clonal T cell lymphoblastic leukemia. To determine the mechanism(s) of tal-1-induced leukemogenesis, we created transgenic mice expressing a DNA binding mutant of tal-1. Surprisingly, these mice develop disease, demonstrating that the DNA binding properties of tal-1 are not required to induce leukemia/lymphoma in mice. However, wild type tal-1 and the DNA binding mutant both form stable complexes with E2A proteins. In addition, tal-1 stimulates differentiation of CD8-single positive thymocytes but inhibits the development of CD4-single positive cells: effects also observed in E2A-deficient mice. Our study suggests that the bHLH protein tal-1 contributes to leukemia by interfering with E2A protein function(s).

Topics: Adaptor Proteins, Signal Transducing; Adenovirus E2 Proteins; Animals; Basic Helix-Loop-Helix Transcription Factors; Casein Kinase II; CD4 Antigens; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Dimerization; Disease Models, Animal; DNA; DNA-Binding Proteins; Helix-Loop-Helix Motifs; Humans; Leukemia-Lymphoma, Adult T-Cell; LIM Domain Proteins; Lymphoma; Metalloproteins; Mice; Mice, Transgenic; Mutagenesis; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; T-Cell Acute Lymphocytic Leukemia Protein 1; TCF Transcription Factors; Thymoma; Thymus Gland; Thymus Neoplasms; Transcription Factor 7-Like 1 Protein; Transcription Factors

Infection of cattle with the protozoan parasite Theileria parva results in a fatal lymphoproliferative syndrome that is associated with the overexpression of casein kinase II. The role of this enzyme in the pathogenesis of lymphoproliferative disorders was investigated by expressing the catalytic subunit in lymphocytes of transgenic mice. Adult transgenic mice displayed a stochastic propensity to develop lymphoma; co-expression of a c-myc transgene in addition to casein kinase II resulted in neonatal leukemia. Thus, the casein kinase II gene can serve as an oncogene, and its dysregulated expression is capable of transforming lymphocytes in a two-step pathway with c-myc.

Topics: Amino Acid Sequence; Animals; Base Sequence; Casein Kinase II; Cattle; Cell Transformation, Neoplastic; Cloning, Molecular; Gene Expression Regulation, Enzymologic; Gene Rearrangement, T-Lymphocyte; Genes, myc; Leukemia; Lymphocytes; Lymphoma; Mice; Mice, Transgenic; Molecular Sequence Data; Protein Serine-Threonine Kinases; Theileriasis; Up-Regulation

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

In human epidermal carcinoma A431 cells, the beta subunit of casein kinase II is phosphorylated at an autophosphorylation site and at serine 209 which can be phosphorylated in vitro by p34cdc2 (Litchfield, D. W., Lozeman, F. J., Cicirelli, M. F., Harrylock, M., Ericsson, L. H., Piening, C. J., and Krebs, E. G. (1991) J. Biol. Chem. 266, 20380-20389). Given the importance of p34cdc2 in the regulation of cell cycle events, we were interested in examining the phosphorylation of casein kinase II during different stages of the cell cycle. In this study it is demonstrated that the extent of phosphorylation of serine 209 in the beta subunit is significantly increased relative to phosphorylation of the autophosphorylation site when chicken bursal lymphoma BK3A cells are arrested at mitosis by nocodazole treatment. This result suggests that serine 209 is a likely physiological target for p34cdc2. In addition, the alpha subunit of casein kinase II also undergoes dramatic phosphorylation with an associated alteration in its electrophoretic mobility when BK3A cells or human Jurkat cells are arrested with nocodazole. Phosphopeptide mapping studies indicate that p34cdc2 can phosphorylate in vitro the same peptides on the alpha subunit that are phosphorylated in cells arrested at mitosis. These phosphorylation sites were localized to serine and threonine residues in the carboxyl-terminal domain of alpha. Taken together, the results of this study indicate that casein kinase II is a probable physiological substrate for p34cdc2 and suggest that its functional properties could be affected in a cell cycle-dependent manner.

Topics: Animals; Antibodies; Carcinoma, Squamous Cell; Casein Kinase II; Cattle; CDC2 Protein Kinase; Cell Line; Chickens; Chromatography, Ion Exchange; Humans; Lymphoma; Macromolecular Substances; Male; Mitosis; Peptide Mapping; Phosphopeptides; Phosphorylation; Protein Serine-Threonine Kinases; Testis; Trypsin