Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lymphotoxin-beta receptor (LT-betaR) has been shown to be the receptor for the membrane-bound lymphotoxin heterotrimers LTalpha1/beta2 and LTalpha2/beta1. The extracellular domain of LT-betaR shows extensive similarity with members of the tumor necrosis factor receptor family, while its cytoplasmic domain is distinct and lacks any inherent enzymatic activity. This suggests that the interaction of LT-betaR with other molecules might be important for signal transduction. Here we demonstrate the association of a fusion protein, comprising glutathione S-transferase and the cytoplasmic domain of LT-betaR (GST-LT-betaR(CD)), with several proteins in the size range 29-80 kDa from HepG2 cell lysates. We present evidence that two of these proteins are serine/threonine kinases, which associate with amino acids 324-377 of the cytoplasmic domain of LT-betaR and phosphorylate this receptor. The characteristics of these novel kinases indicate that they are distinct from the previously described tumor necrosis factor receptor-associated kinases. This suggests the presence of novel signal transduction pathway(s) for LT-betaR.
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PMID:Serine/threonine kinase activity associated with the cytoplasmic domain of the lymphotoxin-beta receptor in HepG2 cells. 920 35

The present research establishes standard two-dimensional (2-D) maps for control, reactive lymph node and non-Hodgkin's lymphoma (mantle cell lymphoma, MCL). Medium sensitivity, mass spectrometry compatible colloidal Coomassie has revealed a total of ca. 750 spots in each of the maps. Comparison of 2-D maps by statistical packages, such as the PDQuest, established up- and downregulation of a total of ca. 145 spots, with positive variations of up to 10-folds and negative variations of up to 13-folds in both MCL biopsies' protein extracts. Qualitative and quantitative variations in the two lymphoma samples are consistent. More than 20 proteins have been so far identified by matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF)-mass spectrometry, with an additional five spots, which gave very good spectra but could not be matched to any of the presently available databases. Some of the spots, such as the 78 kDa glucose-regulated protein precursor and the glutathione S-transferase P, appear to be in common with other tumors, such as lung adenocarcinoma. Others may simply reflect overall changes in cellular metabolism and growth rate that occur during malignancy and thus might turn out to be in common with any cell population receiving any kind of stress. Some (notably T-cell leukemia/lymphoma protein 1A, TCL1, found to be 10-fold overexpressed) appear to be specific of the non-Hodgkin's lymphoma here studied. Western blot and immunohistochemical analyses were applied to obtain further information about stathmin (Op18) and TCL1, respectively.
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PMID:Two-dimensional molecular profiling of mantle cell lymphoma. 1287 73

Several chemicals have been associated with risk of non-Hodgkin's lymphoma (NHL), many of which are substrates for N-acetyltransferase (NAT) and glutathione S-transferase (GST) enzymes. We investigated the association between polymorphisms in genes coding for these enzymes and NHL risk in a population-based study (389 cases and 535 controls). NAT1 slow genotype was associated with a slightly increased risk in women [odds ratios (OR) = 1.4; 95% confidence interval (CI) = 0.9-2.3], but not in men. NAT2 slow genotype was not associated with risk in either sex. The two slow genotypes of NAT1 and NAT2 combined were associated with a minor increase of risk in women (OR = 1.4; 0.8-2.4). There was no association with the GSTM1 or GSTT1 null genotype in either sex, irrespective of histological subtypes. Individuals with GSTP1 Val homozygotes had non-significant excessive risk of marginal zone lymphoma (OR = 1.8; 0.6-5.1) and 'other' B-cell NHLs (OR = 1.6; 0.7-3.6), but lower risk of diffuse large B-cell lymphoma (OR = 0.2; 0.1-0.96). Risk did not elevate with an increasing number of high-risk GST alleles in either sex. In summary, although NAT1, NAT2, GSTM1, GSTT1, or GSTP1 polymorphisms do not appear to be associated with NHL risk overall, there might be gender-specific and subtype-specific associations that require confirmation.
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PMID:Association of NAT and GST polymorphisms with non-Hodgkin's lymphoma: a population-based case-control study. 1572 81

Epidemiologic studies have failed to establish clearly whether agricultural pesticides contribute to the genesis of non-Hodgkin's lymphoma (NHL). Discordant results may be related to variation in susceptibility factors, including metabolism gene polymorphisms that might influence lymphocyte exposures to active pesticide metabolites. Associations between NHL and polymorphisms that may be relevant to pesticide metabolism have been assessed, including CYP1A1 and glutathione S-transferase variants, but the results are not highly informative because estimates were based on small numbers and convenience samples of cases and controls. Butyrylcholinesterase and paraoxonase (PON1) enzyme variants associated with altered activity and acute organophosphate toxicity are strong candidate susceptibility factors for pesticides and NHL, but others may be identified as knowledge of pesticide metabolism and relevant polymorphisms improves. Studies of metabolic susceptibility must be large and include information on specific exposures and subtypes of NHL for results to further the understanding of the relation between agricultural pesticides and NHL.
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PMID:Metabolic susceptibility to agricultural pesticides and non-Hodgkin's lymphoma. 1619 Jan 46

Chemotherapy of non-Hodgkin's lymphoma is frequently hampered by drug resistance. The monoclonal antibody rituximab specifically targets the CD20 antigen and sensitizes B-cell lymphoma cells to standard anticancer drugs. In the present investigation, we analyzed, whether a combination of rituximab and artesunate may act in a complementary manner and eventually synergize in tumor cell killing. Artesunate is an anti-malarial drug, which also exerts profound activity towards cancer cells. While rituximab alone was minimally cytotoxic, rituximab increased cytotoxicity to artesunate in Ramos cells. Artesunate induced apoptosis, induced Fas/CD95 expression and the formation of reactive oxygen species (ROS) and resulted in a breakdown of mitochondrial membrane potential. This argues for the involvement of both receptor-driven extrinsic and mitochondrial intrinsic routes of apoptosis. Rituximab increased Fas/CD95 expression and ROS formation and decreased mitochondrial membrane potential ultimately leading to increased apoptosis induced by artesunate. The transcription factors YY1 and Sp1 are upstream regulators of apoptosis by controlling the expression of apoptosis-regulating genes. YY1 and Sp1 were down-regulated and Fas/CD95 was up-regulated by rituximab and artesunate indicating that artesunate activated the Fas/CD95 pathway and that rituximab increased the susceptibility of tumor cells to artesunate-induced apoptosis. Furthermore, rituximab affected the expression of antioxidant genes. The antibody decreased artesunate-induced up-regulation of catalase expression and increased artesunate-induced down-regulation of glutathione S-transferase-phi expression. Manganese-dependent superoxide dismutase expression was not changed by artesunate. Antioxidant proteins may help to detoxify artesunate-induced ROS. Rituximab reversed the artesunate-induced expression changes of antioxidant genes and, hence, reduced the detoxification capacity of Ramos cells. The effects of rituximab on antioxidant genes represent a novel mechanism of rituximab for chemosensitization.
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PMID:Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate. 1951 62

Hepatitis C virus (HCV) infects B lymphocytes and induces mixed cryoglobulinemia and B cell non-Hodgkin's lymphoma. The molecular mechanism for the pathogenesis of HCV infection-mediated B cell disorders remains obscure. To identify the possible role for HCV nonstructural 5A (NS5A) protein in B cells, we generated the stable B cell lines expressing Myc-His tagged NS5A. Immunoprecipitation study in the presence or absence of pervanadate (PV) implied that NS5A was tyrosine phosphorylated by pervanadate (PV) treatment of the cells. Therefore we examined pull-down assay by using glutathione S-transferase (GST)-fusion proteins of various Src homology 2 (SH2) domains, which associates with phosphotyrosine within a specific amino acid sequence. The results showed that NS5A specifically bound to SH2 domain of Fyn from PV-treated B cells in addition to Src homology 3 (SH3) domain. Substitution of Arg(176) to Lys in the SH2 domain of Fyn abrogated this interaction. Deletion mutational analysis demonstrated that N-terminal region of NS5A was not required for the interaction with the SH2 domain of Fyn. Tyr(334) was identified as a tyrosine phosphorylation site in NS5A. Far-western analysis revealed that SH2 domain of Fyn directly bound to NS5A. Fyn and NS5A were colocalized in the lipid raft. These results suggest that NS5A directly binds to the SH2 domain of Fyn in a tyrosine phosphorylation-dependent manner. Lastly, we showed that the expression of NS5A in B cells increased phosphorylation of activation loop tyrosine in the kinase domain of Fyn. NS5A containing ligand for both SH2 and SH3 domains enhances an aberrant autophosphorylation and kinase activity of Fyn in B cells.
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PMID:HCV NS5A protein containing potential ligands for both Src homology 2 and 3 domains enhances autophosphorylation of Src family kinase Fyn in B cells. 2307 15