cyclin-d1 and Central-Nervous-System-Neoplasms

Mantle cell lymphomas (MCLs) are the prototypic B-cell non-Hodgkin lymphomas defined by cyclin D1 gene (CCND1; or other cyclin D family gene) rearrangements. However, extremely rare cases of diffuse large B-cell lymphomas (DLBCLs) harboring CCND1 rearrangements, resulting in cyclin D1 protein expression, have also been reported. In this report, we describe an unusual primary large B-cell lymphoma of non-germinal center immunophenotype of the central nervous system (CNS) in an elderly male patient, which was negative for CD5 and SOX11, and exhibited cyclin D1 expression. Fluorescence in situ hybridization analysis detected IGH-CCND1 and BCL6 rearrangements. This case may represent the first report of a primary CNS DLBCL with IGH-CCND1 rearrangement. The clinico-pathologic features that can help differentiate primary CNS MCL from primary DLBCL of the CNS with IGH-CCND1 rearrangement are discussed.

Topics: Aged, 80 and over; Biomarkers, Tumor; Biopsy; Central Nervous System Neoplasms; Cyclin D1; Gene Expression; Gene Rearrangement; Humans; Immunohistochemistry; Immunophenotyping; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Male; Oncogene Proteins, Fusion

Products of the Pim (the proviral integration site for the Moloney murine leukemia virus) family of proto—oncogenes possess serine/threonine kinase activity and belong to the Ca2+/calmodulin—dependent protein kinase group. Pim—3, a member of the Pim family is closely linked to the development of a variety of tumors. However, the role of Pim—3 in human glioblastoma remains unknown. In this study, we elucidated the role of Pim—3 in the growth and apoptosis of glioblastoma cells. Western blotting was used for determination of protein levels, and shRNA was used for Pim—3 knockdown. The MTT assay was used to evaluate cell proliferation and flow cytometry was used to determine cell cycle status and the number of apoptotic cells. A mouse xenograft model was established by injecting nude mice with Pim—3—depleted glioblastoma cells in order to determine tumor growth in vivo. We demonstrated that Pim—3 was highly expressed in human glioblastoma cell lines. We also found that knockdown of Pim—3 by specific shRNA slowed decreased proliferation, induced cell cycle arrest in the G0/G1 phase, and increased apoptosis in glioblastoma cells. Pim—3 knockdown potently inhibited the growth of subcutaneously implanted glioblastoma cells in vivo. We further revealed that Pim—3 knockdown induced growth inhibition by reducing the levels of the anti—apoptotic protein Bcl—xl and cell cycle regulatory proteins, including cyclin D1 and Cdc25C, and increasing the levels of the pro—apoptotic protein Bax.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Carcinogenesis; cdc25 Phosphatases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Central Nervous System Neoplasms; Cyclin D1; Disease Models, Animal; Down-Regulation; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glioblastoma; Heterografts; Humans; Mice, Nude; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; RNA, Small Interfering

Previous studies have shown that miR-137 functions as a tumor suppressor in various cancers, but its role in the initiation and development of gliomas is still unknown. Currently, we found that miR-137 exhibited the most significant increase in normal brain tissues compared with glioma specimens, and the miR-137 expression was greatly decreased with the ascending of tumor pathological grades. Furthermore, overexpression of miR-137 in vitro by chemically synthesized miR-137 mimics suppressed the proliferation, inhibited cell cycle arrest in the G1/G0 phase, and induced cell apoptosis. The tumor-suppressive effects of miR-137 were indeed induced by Rac1, which was verified as a direct target of miR-137. These findings indicate that miR-137 inhibits the growth of gliomas cells by directly targeting Rac1, suggesting that miR-137 could be a new important therapeutic strategy for glioma treatment and warrants further investigation.

Topics: Apoptosis; Brain Chemistry; Cell Line, Tumor; Cell Proliferation; Central Nervous System Neoplasms; Cyclin D1; G1 Phase Cell Cycle Checkpoints; Glioma; Humans; Matrix Metalloproteinase 2; MicroRNAs; Neoplasm Grading; Neoplasm Invasiveness; Proto-Oncogene Proteins c-bcl-2; rac1 GTP-Binding Protein; RNA, Small Interfering; Signal Transduction; Transfection

Phosphorylation of Tyr-88/Tyr-89 in the 3(10) helix of p27 reduces its cyclin-dependent kinase (CDK) inhibitory activity. This modification does not affect the interaction of p27 with cyclin-CDK complexes but does interfere with van der Waals and hydrogen bond contacts between p27 and amino acids in the catalytic cleft of the CDK. Thus, it had been suggested that phosphorylation of this site could switch the tumor-suppressive CDK inhibitory activity to an oncogenic activity. Here, we examined this hypothesis in the RCAS-PDGF-HA/nestin-TvA proneural glioma mouse model, in which p21 facilitates accumulation of nuclear cyclin D1-CDK4 and promotes tumor development. In these tumor cells, approximately one-third of the p21 is phosphorylated at Tyr-76 in the 3(10) helix. Mutation of this residue to glutamate reduced inhibitory activity in vitro. Mutation of this residue to phenylalanine reduced the tumor-promoting activity of p21 in the animal model, whereas glutamate or alanine substitution allowed tumor formation. Consequently, we conclude that tyrosine phosphorylation contributes to the conversion of CDK inhibitors from tumor-suppressive roles to oncogenic roles.

Topics: Amino Acid Sequence; Animals; Cell Proliferation; Central Nervous System Neoplasms; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioma; HEK293 Cells; Humans; Mice; Molecular Sequence Data; Mutation; Phosphorylation; Tyrosine

Topics: Adult; Aged; Central Nervous System Neoplasms; Cyclin D1; Female; Humans; Immunophenotyping; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Invasiveness

Brain tumorigenesis is a complex process involving multiple genetic alterations. Cyclin D1 and BAX genes are two of the most important regulators in controlling the normal proliferation and apoptosis of cells, respectively. In this study, we analysed the possibilities of involvement of cyclin D1 and BAX genes in the gliomagenesis.. In determining gene alterations of exon 4 of cyclin D1 gene and exon 6 of BAX gene, all samples were amplified by polymerase chain reaction (PCR) and subsequently by direct sequencing. Our results showed a frameshift mutation (G base deletion) at nucleotide 82 of codon 28 in exon 4 of the cyclin D1 gene and another frameshift mutation with a deletion of C base at nucleotide 153 of exon 6 of the BAX gene in two separate cases of a glioblastoma multiform (WHO Grade IV) sample.. These findings suggest that both cyclin D1 and BAX genes alteration are rarely found in brain tumors. However, the alteration might cause a significant effect of the normal protein production and this might contribute to the development of brain tumorigenesis in Malaysian patients.

Topics: bcl-2-Associated X Protein; Central Nervous System Neoplasms; Cyclin D1; DNA Mutational Analysis; Exons; Glioma; Humans; Mutation; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Although atypical teratoid/rhabdoid tumor (AT/RT) is known to generate through inactivation of the hSNF5/INI1 gene on chromosome 22q, the downstream molecular mechanism remains unclear. We histologically and molecularly reviewed our pediatric brain tumors for unrecognized AT/RTs and evaluated the role of cyclin D1, a potential molecular target of hSNF5/INI1.. We analyzed 16 tumors under three years of age: seven medulloblastomas, three anaplastic ependymomas (E IIIs), two each of supratentorial primitive neuroectodermal tumors (sPNETs) and choroid plexus carcinomas (CPCs), and one each of neuroblastoma and pineoblastoma. Immunohistochemistry for glial fibrillary acidic protein, vimentin, epithelial membrane antigen, smooth muscle actin and cyclin D1 was performed. Polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis with direct sequencing, differential PCR and microsatellite analysis were conducted for hSNF5/INI1mutation, homozygous deletion and loss of heterozygosity (LOH) on 22q, respectively. Because of the presence of rhabdoid cells and the polyimmunophenotypic features, the diagnosis was revised to AT/RT in five (31%) tumors, namely, two E IIIs and one each of medulloblastoma, CPC and pineoblastoma. Three of them harbored such hSNF5/INI1 aberrations as germline single base deletion (492/6 delC) and missense mutation (C157T) together with LOH 22q or homozygous deletion. Cyclin D1 was overexpressed in those three tumors but not in the two that lacked hSNF5/INI1 inactivation.. AT/RT can be misdiagnosed as a variety of tumors, including ependymoma that potentially harbors LOH 22q. Our data indicate that cyclin D1 is a target of hSNF5/INI1in primary tumors.

Topics: Central Nervous System Neoplasms; Child, Preschool; Choroid Plexus Neoplasms; Chromosomal Proteins, Non-Histone; Chromosomes, Human, Pair 22; Cyclin D1; Cytogenetic Analysis; DNA-Binding Proteins; Female; Humans; Infant; Loss of Heterozygosity; Male; Medulloblastoma; Mutation; Neuroblastoma; Pinealoma; Polymorphism, Single Nucleotide; Rhabdoid Tumor; SMARCB1 Protein; Teratoma; Transcription Factors

Protein kinase C (PKC) plays an important role in the regulation of glioma growth; however, the identity of the specific isoform and mechanism by which PKC fulfills this function remain unknown. In this study, we demonstrate that PKC activation in glioma cells increased their progression through the cell cycle. Of the six PKC isoforms that were present in glioma cells, PKC alpha was both necessary and sufficient to promote cell cycle progression when stimulated with phorbol 12-myristate 13-acetate. Also, decreased PKC alpha expression resulted in a marked decrease in cell proliferation. The only cell cycle-regulatory molecule whose expression was rapidly altered and increased by PKC alpha activity was the cyclin-cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1). Coimmunoprecipitation studies revealed that p21(Waf1/Cip1) upregulation was accompanied by an incorporation of p21(Waf1/Cip1) into various cyclin-CDK complexes and that the kinase activity of these complexes was increased, thus resulting in cell cycle progression. Furthermore, depletion of p21(Waf1/Cip1) by antisense strategy attenuated the PKC-induced cell cycle progression. These results suggest that PKC alpha activity controls glioma cell cycle progression through the upregulation of p21(Waf1/Cip1), which facilitates active cyclin-CDK complex formation.

Topics: Cell Cycle; Cell Division; Central Nervous System Neoplasms; Cyclin A; Cyclin B; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclins; Enzyme Activation; Glioma; Humans; Isoenzymes; Oligonucleotides, Antisense; Phorbol Esters; Protein Kinase C; Protein Kinase C-delta; Protein Kinase C-epsilon; Protein Kinase C-theta; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured; Up-Regulation