Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Virtually all mammalian cells express two seemingly redundant cyclin-D-dependent kinases (Cdk4 and Cdk6) and three partner cyclins (D1, D2 and D3) essential for the G(1)-S transition, with predominant expression of Cdk4 and D1 in mesenchymal cells and Cdk6 and D3 in hematopoietic cells. We recently found two novel functions for Cdk6 executed in fibroblasts although unlike Cdk4 it is dispensable for their proliferation. In the rat fibroblast NRK-49F cells, oncogenic stimulation recruits Cdk6 to participate in a step of the cell cycle start that seems to be critical for anchorage-independent S-phase onset. Among the kinase-D-type cyclin combinations, the Cdk6-cyclin-D3 complex has a unique ability to evade inhibition by cyclin-dependent kinase inhibitors and thereby control the cell's proliferative competence under growth-suppressive conditions. We describe here that 2-5-fold overexpression of both Cdk6 and D3 enhances by 5x10(3)-10(6)-fold the susceptibility of the BALB/c3T3 and C3H10T1/2 mouse fibroblast lines to ultraviolet irradiation- as well as 3-methylcholanthrene-induced transformation. This result suggests that deregulated expression of Cdk6 and cyclinD3 may predispose cells to malignant transformation, supporting the recent finding that cyclin D3 activated by chromosomal rearrangement is the causative gene of non-Hodgkin B lymphoma, in which Cdk6 is the major partner kinase.
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PMID:Overexpression of Cdk6-cyclin D3 highly sensitizes cells to physical and chemical transformation. 1259 86

Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) is a powerful method for measurement of gene expression for diagnostic and prognostic studies of non-Hodgkin's lymphomas (NHL). In order for this technique to gain wide applicability, it is critically important to establish a uniform method for normalization of RNA input. In this study, we have determined the best method to quantify the RNA/cDNA input per reaction and searched for the most useful endogenous control genes for normalization of the measurements, based on their abundance and lowest variability between different types of lymphoid cells. To accomplish these aims, we have analyzed the RNA expression of 11 potential endogenous control genes (glyceraldehyde-3-phosphate dehydrogenase, beta-actin, peptidylprolyl isomerase A, beta 2 microglobulin, protein kinase cGMP-dependent, type I, hypoxanthine phosphoribosyltransferase 1, TATA box binding protein, transferrin receptor, large ribosomal protein, beta-glucoronidase and 18S ribosomal RNA). In all, 12 different B- and T-cell lymphoma/leukemia cell lines, 80 B- and T-cell NHL specimens, and resting and activated normal B and T lymphocytes were screened. Normalization of the nucleic acid input by spectrophotometric OD(260) measurement of RNA proved more reliable than spectrophotometric or fluorometric measurements of cDNA or than electrophoretic estimation of the ribosomal and mRNA fractions. The protein kinase cGMP-dependent, type I (PRKG1) and the TBP genes were expressed at common abundance and exhibited the lowest variability among the cell specimens. We suggest that for further lymphoma studies based on the real-time RT-PCR quantification of gene expression, that RNA input in each reaction be equalized between the specimens by spectrophotometric OD(260) measurements. The expression of the gene of interest in different samples should be normalized by concomitant measurement of the PRKG1 and/or the TBP gene products.
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PMID:Optimization of quantitative real-time RT-PCR parameters for the study of lymphoid malignancies. 1268 39

p18INK4c is a cyclin-dependent kinase (CDK) inhibitor that interferes with the Rb-kinase activity of CDK6/CDK4. Disruption of p18INK4c in mice impairs B-cell terminal differentiation and confers increased susceptibility to tumor development; however, alterations of p18INK4c in human tumors have rarely been described. We used a tissue-microarray approach to analyze p18INK4c expression in 316 Hodgkin lymphomas (HLs). Nearly half of the HL cases showed absence of p18INK4c protein expression by Reed-Sternberg (RS) cells, in contrast with the regular expression of p18INK4c in normal germinal center cells. To investigate the cause of p18INK4c repression in RS cells, the methylation status of the p18INK4c promoter was analyzed by methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing. Hypermethylation of the p18INK4c promoter was detected in 2 of 4 HL-derived cell lines, but in none of 7 non-Hodgkin lymphoma (NHL)-derived cell lines. We also detected p18INK4c hypermethylation, associated with absence of protein expression, in 5 of 26 HL tumors. The correlation of p18INK4c immunostaining with the follow-up of the patients showed shorter overall survival in negative cases, independent of the International Prognostic Score. These findings suggest that p18INK4c may function as a tumor suppressor gene in HL, and its inactivation may contribute to the cell cycle deregulation and defective terminal differentiation characteristic of the RS cells.
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PMID:Silencing of the p18INK4c gene by promoter hypermethylation in Reed-Sternberg cells in Hodgkin lymphomas. 1464 11

Ki-1/57, the 57-kDa human protein antigen recognized by the CD30 antibody Ki-1, is a cytoplasmic and nuclear protein that is phosphorylated on serine and threonine residues. When isolated from the Hodgkin's lymphoma analogous cell line L540 Ki-1/57 co-immunoprecipitated with a Thr/Ser protein kinase activity. It has been also found to interact with hyaluronic acid and has therefore been termed intracellular IHABP4 (hyaluronan-binding protein 4). Recent studies demonstrated, however, that Ki-1/57 engages in specific interaction with the chromo-helicase-DNA-binding domain protein 3, a nuclear protein involved in chromatin remodeling and transcription regulation. We used the yeast two-hybrid system to find proteins interacting with Ki-1/57 and identified the adaptor protein RACK1 (receptor of activated kinase 1). Next, we confirmed this interaction in vitro and in vivo, performed detailed mapping studies of the interaction sites of Ki-1/57 and RACK-1, and demonstrated that Ki-1/57 also co-precipitates with protein kinase C (PKC) when isolated from phorbol 12-myristate 13-acetate (PMA)-activated L540 tumor cells and is a substrate for PKC phosphorylation in vitro and in vivo. Interestingly, the interaction of Ki-1/57 with RACK1 is abolished upon activation of L540 cells with PMA, which results in the phosphorylation of Ki-1/57 and its exit from the nucleus. Taken together, our data suggest that Ki-1/57 forms a stable complex with RACK-1 in unstimulated cells and upon PMA stimulation gets phosphorylated on threonine residues located at its extreme C terminus. These events associate Ki-1/57 with the RACK1/PKC pathway and may be important for the regulation of its cellular functions.
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PMID:Ki-1/57 interacts with RACK1 and is a substrate for the phosphorylation by phorbol 12-myristate 13-acetate-activated protein kinase C. 1469 38

The perturbations of the cytokine signaling pathway play an important role in lymphoid/hematopoietic tumors. Aberrant promoter methylation is the major mechanism of gene silencing in tumors. We examined 150 lymphoid/hematopoietic tumors or potential premalignant specimens, 55 control specimens and 12 EBV-transformed B lymphoblastoid cultures and 10 lymphoma/leukemia (L/L) or multiple myeloma (MM) cell lines for the methylation (and, in cell lines, of the expression status) of three genes involved in the cytokine signaling pathway. The genes were: SHP1, a protein tyrosine phosphatase; SYK, a protein kinase; and SOCS1, a suppressor of cytokine signaling. Our major findings were: (1) one or more of the three genes was frequently methylated in L/L and MM cell lines and there was good concordance (90-100%) between methylation and loss of gene expression; (2) treatment of L/L cell lines with a demethylating agent resulted in re-expression of SHP1 protein and downregulation of phosphorylated STAT3 in L/L cell lines; (3) all 55 control specimens and the lymphoblastoid cultures were negative for methylation of the three genes; (4) non-Hodgkin's lymphomas (100%), and leukemias (94%) had almost universal methylation of SHP1 and relatively less frequent (<30%) methylation of SOCS1 and SYK; (5) MM and monoclonal gammopathy of unknown significance (MGUS) had infrequent methylation of SHP1 (<20%), and occasional methylation of SOCS1 and SYK; and (6) comparable methylation frequencies for SOCS1 were observed in MM and MGUS, suggesting that SOCS1 methylation is an early event in MM pathogenesis. At least one gene was methylated in 119 of 130 (93%) of the malignant and 12 of 20 (60%) of the MGUS samples. Our findings demonstrate that the perturbations of cytokine signaling via silencing of these three genes are almost universal in lymphoid/hematopoietic tumors but the patterns of gene methylated for L/L and plasma cell dyscrasias are different.
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PMID:Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors. 1558 Mar 14

Patients with B non-Hodgkin's Lymphoma (NHL) initially respond to conventional chemotherapy. However, relapses and recurrences occur and the patients develop resistance to further treatment. Immunotherapeutic approaches have been considered in the treatment of such patients. Rituximab (chimeric anti-human CD20 monoclonal antibody) is the first anti-cancer monoclonal antibody approved by the FDA for the treatment of B-NHL. It has been used alone or in combination with chemotherapy, and the clinical response rates have been 50% and greater than 95%, respectively. The in vivo mechanism by which rituximab mediates its effects is not clear, though ADCC, CDC and apoptosis have been suggested and supported by several studies. However, many patients do not respond to rituximab or become refractory to rituximab treatment and the underlying mechanism of unresponsiveness is not known. This review describes various molecular signaling pathways modified by rituximab using in vitro B-NHL cell lines as model systems. The findings demonstrate that rituximab treatment modulates the p38 MAPK, the Raf-1/MEK/ERK1/2 and the NF-kappaB pathways. These modifications induced by rituximab were in large part responsible for the down-regulation of the anti-apoptotic gene products Bcl-2/Bcl-xL and chemosensitization of the drug-resistant B-NHL cell lines to various drug-induced apoptosis. Studies on the development of resistance to rituximab were investigated with rituximab-resistant B-NHL clones derived from rituximab-sensitive B-NHL cell lines. The molecular signaling pathways modified by rituximab revealed several novel intracellular targets whose modification could sensitize both rituximab-sensitive and rituximab-resistant B-NHL to drug-induced apoptosis. These in vitro findings provide new possibilities for improving the clinical effectiveness of rituximab as well as for circumventing its resistance.
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PMID:Rituximab-mediated chemosensitization of AIDS and non-AIDS non-Hodgkin's lymphoma. 1593 40

As the primary microtubule organizing center of most eukaryotic cells, centrosomes play a fundamental role in proper formation of the mitotic spindle and subsequent chromosome separation. Normally, the single centrosome of a G1 cell duplicates precisely once prior to mitosis in a process that is intimately linked to the cell division cycle via cyclin-dependent kinase (cdk) 2 activity that couples centrosome duplication to the onset of DNA replication at the G1/S transition. Accurate control of centrosome duplication is critical for symmetric mitotic spindle formation and thereby contributes to the maintenance of genome integrity. Numerical and structural centrosome abnormalities are hallmarks of almost all solid tumors and have been implicated in the generation of multipolar mitoses and chromosomal instability. In addition to solid neoplasias, centrosome aberrations have recently been described in several different hematological malignancies like acute myeloid leukemias, myelodysplastic syndromes, Hodgkin's as well as non-Hodgkin's lymphomas, chronic lymphocytic leukemias and multiple myelomas. In analogy to many solid tumors a correlation between centrosome abnormalities on the one hand and karyotype aberrations as well as clinical aggressiveness on the other hand seems to exist in myeloid malignancies, chronic lymphocytic leukemias and at least some types of non-Hodgkin's lymphomas. Molecular mechanisms responsible for the development of centrosome aberrations are just beginning to be unraveled. In general, two models with distinct functional consequences can be envisioned. First, centrosome aberrations can arise as a consequence of abortive mitotic events and impaired cytokinesis. Second, evidence has been provided that centrosome amplification can also precede genomic instability and arise in normal, diploid cells. Accordingly, this review will focus on recent advances in the understanding of both, causes and consequences of centrosome aberrations in hematological malignancies.
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PMID:Centrosome aberrations in hematological malignancies. 1599 91

Mantle-cell lymphoma (MCL) is a well-defined subtype of B-cell non-Hodgkin's lymphomas (B-NHL), accounts for approximately 6% of all lymphoid neoplasms, and has a median survival of 3 to 4 years. The genetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32) that leads to deregulation and upregulation of Cyclin D1, an important regulator of the G1 phase of the cell cycle. This genetic event is present in virtually all cases of MCL, whereas additional genetic alterations that occur in subsets of MCL have been described. Most of these alterations appear to disturb the cell cycle machinery/interfere with the cellular response to DNA damage, thus making MCL a paradigm for cell cycle and DNA damage response dysregulation in cancer in general. In particular, Cyclin D1 upregulation, genomic amplification of the cyclin-dependent kinase (CDK) -4, deletions of the CDK inhibitor p16(INK4a) and overexpression of BMI-1, a transcriptional repressor of the p16(INK4a) locus, are associated with dysregulation of the cell cycle machinery in MCL. The DNA damage response pathway is affected by frequent alterations of the ataxia-telangiectasia mutated (ATM) kinase as well as occasional inactivation of checkpoint kinase (CHK)-1 and CHK2 that are kinases that act downstream of ATM in response to detection of DNA damage. Moreover, p53 is frequently targeted by alterations in MCL. A recent gene expression profiling study defined the proliferation signature, a quantitative measure of gene expression of proliferation-associated genes as the strongest survival predictor available to date allowing the definition of prognostic MCL subgroups that differ in median survival by more than 5 years.
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PMID:Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. 1615 21

Learning and memory are critically dependent on basal forebrain cholinergic (BFC) neuron excitability, which is modulated profoundly by leak K(+) channels. Many neuromodulators closing leak K(+) channels have been reported, whereas their endogenous opener remained unknown. We here demonstrate that nitric oxide (NO) can be the endogenous opener of leak K(+) channels in the presumed BFC neurons. Bath application of 1 mM S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced a long-lasting hyperpolarization, which was often interrupted by a transient depolarization. Soluble guanylyl cyclase inhibitors prevented SNAP from inducing hyperpolarization but allowed SNAP to cause depolarization, whereas bath application of 0.2 mM 8-bromoguanosine-3',5'-cyclomonophosphate (8-Br-cGMP) induced a similar long-lasting hyperpolarization alone. These observations indicate that the SNAP-induced hyperpolarization and depolarization are mediated by the cGMP-dependent and -independent processes, respectively. When examined with the ramp command pulse applied at -70 mV under the voltage-clamp condition, 8-Br-cGMP application induced the outward current that reversed at K(+) equilibrium potential (E(K)) and displayed Goldman-Hodgkin-Katz rectification, indicating the involvement of voltage-independent K(+) current. By contrast, SNAP application in the presumed BFC neurons either dialyzed with the GTP-free internal solution or in the presence of 10 muM Rp-8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate sodium salt, a protein kinase G (PKG) inhibitor, induced the inward current that reversed at potentials much more negative than E(K) and close to the reversal potential of Na(+)-K(+) pump current. These observations strongly suggest that NO activates leak K(+) channels through cGMP-PKG-dependent pathway to markedly decrease the excitability in BFC neurons, while NO simultaneously causes depolarization by the inhibition of Na(+)-K(+) pump through ATP depletion.
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PMID:Nitric oxide activates leak K+ currents in the presumed cholinergic neuron of basal forebrain. 1792 63

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults, accounting for nearly 40% of all non-Hodgkin's lymphomas. As cell proliferation is essential for tumor growth, analysis of the cell cycle might give additional information on tumor progression. Although markers distinctive for cell-cycle regulation in DLBCL have been addressed, less attention has been paid to cyclin H in DLBCL with respect to its prognostic and potential therapeutic implications. Cyclin H occurs as a component of the cyclin H/Cdk 7/Mat 1 complex. Cyclin H is also a substrate of protein kinase 2, a ubiquitously expressed serine/threonine protein kinase required for cell viability and cell-cycle progression. We evaluated the expression of cyclin H by immunohistochemistry in 301 DLBCLs in a tissue microarray format. Validation was done by performing quantitative real-time polymerase chain reaction and Western blotting experiments for cyclin H. We studied the relationship between cyclin H expression in comparison to other cyclins (A, B1, D1, D3, and E) and the proliferation marker Ki-67. Reduced or absent cyclin H expression was seen in 14.5% of the DLBCL cases. Interestingly, reduced or absent cyclin H expression was correlated with lower expression of proliferation marker Ki-67 (P < .0001), cyclin B1 (P = .0001), cyclin D3 (P = .0007), and cyclin E (P < .0001). Reduced or absent cyclin H expression was significantly associated with poor overall survival, in both the univariate (P = .0286) and multivariate analysis with International Prognostic Index (P = .0180). Our study demonstrates the independent prognostic value of cyclin H expression in DLBCL and proposes its use as a prognostic marker.
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PMID:Reduced or absent cyclin H expression is an independent prognostic marker for poor outcome in diffuse large B-cell lymphoma. 1840 Feb 56


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