Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B-cell lymphoma, which is increasing world wide, includes such varied conditions as post-transplant lymphoproliferative disease (PTLD) and Burkitt's lymphoma. This study has characterized a role for the signalling molecule phosphatidylinositol 3-kinase, PI3K, in the regulation of growth and survival of immortalized B-lymphocytes. Burkitt's lymphoma cells die rapidly following inhibition of PI3K with LY294002, a chemical inhibitor. Furthermore, Epstein-Barr virus (EBV) immortalized B-cells, lymphoblastoid cell lines, which are a model of PTLD, do not die but are growth inhibited. This growth inhibition is due to an accumulation at G1 phase of the cell cycle and is paralleled by a loss of E2F transcriptional activity, which is essential for cell cycle entry. An active form of PI3K promotes E2F transcriptional activity in lymphoblastoid cell lines. Treatment of LCL with LY294002 causes a reduction of the expression of both cyclin D2 and cyclin D3, two key cyclins required for cell cycle progression but does not affect the expression of the EBV latent genes, EBNA2A or LMP-1. LY294002 also causes an increase in p27kip1, a cyclin dependent kinase inhibitor and results in the dephosphorylation of members of the pocket protein family. These data describe a mechanism by which PI3K plays a role in B-lymphocyte growth and suggests that a pathway from PI3K to D-type cyclin expression may provide diagnostic or treatment opportunities.
 ...
PMID:Phosphatidylinositol 3-kinase is essential for the proliferation of lymphoblastoid cells. 1185 Aug 46

The SH2 domain-containing inositol polyphosphate 5-phosphatase (SHIP) is known to play an important role in the negative regulation by FcgammaRIIB of PI3K-dependent signaling cascades activated by the B cell antigen receptor (BCR) as well as several tyrosine-kinase coupled cytokine receptors. However, to date the role of SHIP in the regulation of PI3K-dependent signals elicited by G-protein-coupled receptors (GPCR) such as chemokine receptors has not been investigated. In this study, we report that ligation of the G-protein-coupled chemokine receptor CXCR4 by SDF-1/CXCL12 has no effect on the tyrosine phosphorylation of SHIP in the murine B cell lymphoma A20. However, co-ligation of the B cell antigen receptor and FcgammaRIIB inhibits the PI3K-dependent phosphorylation of PKB and ERK1/2 in response to CXCL12. We have also utilised a constitutively active membrane-localised SHIP mutant expressed in the Jurkat leukaemic T cell line (which do not normally express SHIP), in order to investigate the effect of this mutant on CXCL12 stimulated PI3K-dependent signaling events. Experiments have revealed that CXCL12-mediated PKB phosphorylation, chemotaxis and lipid accumulation are inhibited in the presence of this SHIP mutant. Thus, it appears that heterologous activation of SHIP by non-G-protein-coupled receptor-mediated routes can impinge on PI3K-dependent signaling pathways activated by independently ligated G-protein-coupled chemokine receptors.
 ...
PMID:Heterologous regulation of chemokine receptor signaling by the lipid phosphatase SHIP in lymphocytes. 1603 94

The adaptor protein B cell lymphoma 10 (Bcl10) plays an essential role in the functions of the AgRs in T and B cells. In this study, we report that Bcl10 also plays an important role in mast cells. Bcl10 is expressed in mast cells. Although Bcl10-deficient mast cells undergo normal development, we demonstrate that Bcl10 is essential for specific functions of FcepsilonR. Although Bcl10-deficient mast cells have normal de novo synthesis and release of the lipid mediator arachidonic acid, the mutant cells possess impaired FcepsilonR-mediated degranulation, indicated by decreased serotonin release, and impaired cytokine production, measured by release of IL-6. In addition, Bcl10-deficient mice display impaired IgE-mediated passive cutaneous anaphylaxis. Moreover, although Bcl10-deficient mast cells have normal FcepsilonR-mediated Ca(2+) flux, activation of PI3K, and activation of the three types of MAPKs (ERKs, JNK, and p38), the mutant cells have markedly diminished FcepsilonR-mediated activation of NF-kappaB and decreased activation of AP-1. Thus, Bcl10 is essential for FcepsilonR-induced activation of AP-1, NF-kappaB, degranulation, and cytokine production in mast cells.
 ...
PMID:B cell lymphoma 10 is essential for FcepsilonR-mediated degranulation and IL-6 production in mast cells. 1718 39

Recent studies confirmed that the new cell survival signal pathway of Insulin-PI3K-Akt exerted cyto-protective actions involving anti-apoptosis. This study was undertaken to investigate the potential neuroprotective effects of insulin in the pathogenesis of spinal cord injury (SCI) and evaluate its therapeutic effects in adult rats. SCI was produced by extradural compression using modified Allen's stall with damage energy of 40 g-cm force. One group of rats was subjected to SCI in combination with the administration of recombinant human insulin dissolved in 50% glucose solution at the dose of 1 IU/kg day, for 7 days. At the same time, another group of rats was subjected to SCI in combination with the administration of an equal volume of sterile saline solution. Functional recovery was evaluated using open-field walking, inclined plane tests, and motor evoked potentials (MEPs) during the first 14 days post-trauma. Levels of protein for B-cell lymphoma/leukemia-2 gene (Bcl-2), Caspase-3, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were quantified in the injured spinal cord by Western blot analysis. Neuronal apoptosis was detected by TUNEL, and spinal cord blood flow (SCBF) was measured by laser-Doppler flowmetry (LDF). Ultimately, the data established the effectiveness of insulin treatment in improving neurologic recovery, increasing the expression of anti-apoptotic bcl-2 proteins, inhibiting caspase-3 expression decreasing neuronal apoptosis, reducing the expression of proinflammatory cytokines iNOS and COX-2, and ameliorating microcirculation of injured spinal cord after moderate contusive SCI in rats. In sum, this study reported the beneficial effects of insulin in the treatment of SCI, with the suggestion that insulin should be considered as a potential therapeutic agent.
 ...
PMID:Anti-apoptotic effect of insulin in the control of cell death and neurologic deficit after acute spinal cord injury in rats. 1789 11

The PI3K/AKT pathway might be involved in the development of some certain diffuse large B-cell lymphoma (DLBCL) by as-yet unclear mechanisms. PIK3CA mutations in exons 9 and 20 were investigated in 76 primary human DLBCLs, 3 DLBCL cell lines (LY1, LY8, and LY10), and 9 related samples using polymerase chain reaction-based sequence analysis to assess the possible relevance of PIK3CA mutations in DLBCL to the PI3K/AKT pathway activation. AKT phosphorylation (pAKT) of 3 DLBCL cell lines and 76 primary DLBCL samples was also detected by Western blot and immunohistochemistry. All 3 cell lines showed high levels of pAKT, and 72.4% (55/76) of the DLBCLs expressed pAKT at various levels, indicating the activation of AKT. However, no mutation was found in exons 9 or 20 in PIK3CA in any of the 3 cell lines. Only 1 out of 76 primary DLBCLs (1.32%) harbored an exon 9 mutation, and no exon 20 mutation was detected. The case with mutations contained 3 mutation points. One was c.1634A>C resulting in E545A, which was in a previously reported hotspot. The other 2 were novel c.1658G>C and c.1659delT frameshift mutations. We conclude that the PI3K/AKT pathway is activated in DLBCL and that PIK3CA is rarely mutated in DLBCL, indicating there could be some other PI3K-pathway activation mechanisms operative in DLBCL.
 ...
PMID:Mutations of the PIK3CA gene in diffuse large B cell lymphoma. 1838 59

We have recently demonstrated that nuclear expression of BCL10 predicts Helicobacter pylori (HP) independence of early-stage gastric diffuse large B-cell lymphoma (DLBCL) with histologic evidence of mucosa-associated lymphoid tissue (MALT). In this study, we examined the role of B cell-activating factor of TNF family (BAFF) in mediating BCL10 nuclear translocation and HP independence of gastric DLBCL (MALT). We used immunohistochemistry and immunoblotting to measure the expression of BAFF, pAKT, BCL3, BCL10, and NF-kappaB. Transactivity of NF-kappaB was measured by electromobility shift assay. In lymphoma samples from 26 patients with gastric DLBCL (MALT), we detected aberrant expression of BAFF in 7 of 10 (70%) HP-independent and in 3 of 16 (18.8%) HP-dependent cases (P = .015). BAFF overexpression was associated with pAKT expression (P = .032), and nuclear expression of BCL3 (P = .014), BCL10 (P = .015), and NF-kappaB (P = .004). In B-cell lymphoma Pfeiffer cells, BAFF activated NF-kappaB and AKT; the activated NF-kappaB up-regulated BCL10, and the activated AKT caused formation of BCL10/BCL3 complexes that translocated to the nucleus. Inhibition of AKT by LY294002 (a PI3K inhibitor) blocked BCL10 nuclear translocation, NF-kappaB transactivity, and BAFF expression. Our results indicate that autocrine BAFF signal transduction pathways may contribute to HP-independent growth of gastric DLBCL (MALT).
 ...
PMID:Overexpression of B cell-activating factor of TNF family (BAFF) is associated with Helicobacter pylori-independent growth of gastric diffuse large B-cell lymphoma with histologic evidence of MALT lymphoma. 1862 89

Identification of rational therapeutic targets is an important strategy to improve the cure rate of diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition of the phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward the PI3K/AKT pathway and induces apoptosis. These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K/AKT, and how identifying this signaling route could be translated into clinical initiatives. We found that in normal and malignant B cells, cAMP potently inhibit the phosphorylation and activity of the tyrosine kinase SYK. Using genetic models of gain- and loss-of-function, we demonstrated the essential role for PDE4B in controlling these effects in DLBCL. Furthermore, we used a constitutively active SYK mutant to confirm its central role in transducing cAMP effects to PI3K/AKT. Importantly, given SYK credentials as a therapeutic target in B-cell tumors, we explored the role of PDE4B in these responses. In multiple DLBCL models, we found that genetically, hence specifically, inhibiting PDE4B expression significantly improved the efficacy of SYK inhibitors. Our data defined a hitherto unknown role for cAMP in negatively regulating SYK and indicate that combined inhibition of PDE4B and SYK should be actively pursued.
 ...
PMID:Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL. 1936 27

Upon antigen binding, the BCR transduces a signal culminating in proliferation or in AICD of the B cell. Coreceptor engagement and subsequent modification of the BCR signal pathway are mechanisms that guide the B cell to its appropriate fate. For example, in the absence of coreceptor engagement, anti-sIgM antibodies induce apoptosis in the human Daudi B cell lymphoma cell line. ITIM-bearing B cell coreceptors that potentially may act as negative coreceptors include FcRgammaIIb, CD22, CD72, and CEACAM1 (CD66a). Although the role of CEACAM1 as an inhibitory coreceptor in T cells has been established, its role in B cells is poorly defined. We show that anti-sIgM antibody and PI3K inhibitor LY294002-induced apoptosis are reduced significantly in CEACAM1 knock-down clones compared with WT Daudi cells and that anti-sIgM treatment induced CEACAM1 tyrosine phosphorylation and association with SHP-1 in WT cells. In contrast, treatment of WT Daudi cells with anti-CD19 antibodies does not induce apoptosis and has reduced tyrosine phosphorylation and SHP-1 recruitment to CEACAM1. Thus, similar to its function in T cells, CEACAM1 may act as an inhibitory B cell coreceptor, most likely through recruitment of SHP-1 and inhibition of a PI3K-promoted activation pathway. Activation of B cells by anti-sIgM or anti-CD19 antibodies also leads to cell aggregation that is promoted by CEACAM1, also in a PI3K-dependent manner.
 ...
PMID:Pivotal advance: CEACAM1 is a negative coreceptor for the B cell receptor and promotes CD19-mediated adhesion of B cells in a PI3K-dependent manner. 1964 37

p70S6K/p85S6K and cdc2/cdk1 are members of the serine/threonine protein kinase family. p70S6K/p85S6K is one of the downstream effectors of the PI3K/Akt/mTOR signal transduction pathway. It phosphorylates S6 protein of 40S ribosomal subunit and thus functions in protein synthesis and cell growth. cdc2/cdk1 is a cyclin-dependent protein kinase that controls the cell cycle entry from G2 to M phase. Overexpression of phospho-p70S6K and cdc2/cdk1 has recently been identified in the majority of diffuse large B-cell lymphoma (DLBCL) specimens. Combination of small molecules that target phosphorylation of p70S6K and cdc2/cdk1 synergistically induced cell apoptosis and cell cycle G1 and G2 arrest, suggesting that they are potential molecular targets for DLBCL therapy. This review will summarize recent advances in the study of phospho-p70S6K and cdc2/cdk1 as molecular markers and therapeutic targets for DLBCL. We propose that multilevel inhibition of the PI3K/Akt/mTOR pathway and double brake at the G1 and G2 phases of the cell cycle progression are effective strategies in treating DLBCL that overexpress phospho-p70S6K and cdc2/cdk1.
 ...
PMID:Phospho-p70S6K and cdc2/cdk1 as therapeutic targets for diffuse large B-cell lymphoma. 1961 61

We investigated the role of the leptin receptor (Ob-R) and its relationship with PI3K/AKT activation in diffuse large B-cell lymphoma (DLBCL) clinical samples followed by in vitro studies using a panel of CRC cell lines. Leptin exerts its physiological action through its receptor Ob-R. Overexpression of Ob-R has been implicated in the pathogenesis of a variety of malignancies; however, its role in DLBCL has not been investigated. Using immunohistochemistry on a large cohort of DLBCL samples in a tissue microarray format, Ob-R immunostaining was detected in 86/216 (39.8%). Ob-R overexpression was associated with the catalytic subunit p110 of PI3K (p = 0.0283), activated AKT (p = 0.0003), and antiapoptotic marker XIAP (p = 0.0008) expression. In in vitro analysis using DLBCL cell lines, our data showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of the PI3K/AKT signaling pathway. Pretreatment of DLBCL cells with Ob-R specific small interference RNA or inactivation of PI3K/AKT activity by LY294002 abolished these responses. Altogether, these data suggest that leptin plays a critical role in DLBCL pathogesis through the P13K/AKT pathway via Ob-R.
 ...
PMID:Leptin receptor expression and its association with PI3K/AKT signaling pathway in diffuse large B-cell lymphoma. 2044 80


1 2 3 4 5 6 7 8 9 10 Next >>