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

Members of the TNF receptor superfamily are type I membrane glycoproteins with limited homology (overall homologies: 25%-30%) in the extracellular domain containing variable numbers of cysteine-rich repeats. In contrast, the TNF ligand superfamily members (with the exception of LT-alpha) are type II membrane glycoproteins with limited homology to TNF (overall homologies: 20%) in the extracellular region. TNF and LT-alpha are trimeric proteins and are composed of beta-strands forming a beta-jellyroll, the homology of the beta-strand regions for the TNF ligand superfamily members suggests a similar trimeric or multimeric complex formation for the other members. A genetic linkage, as evidence for evolutionary relatedness, is also found by chromosomal cluster for CD30, CD120b, 4-1BB and OX40 to 1p36; CD27, CD120a and TNFR-RP to 12p13; TNF, LT-alpha and LT-beta to 6p21; CD27L and 4-1BBL to 19p13; CD95L and OX40L to 1q25. TNF, LT-alpha and LT-beta and their receptors (CD120a, CD120b, TNFR-RP) interact in a complex fashion. Other family members, however, show a one ligand/one receptor binding principle. Signals can also be transduced through at least some of the ligands. TNF superfamily ligands are involved in induction of cytokine secretion, upregulation of adhesion molecules, activation antigens and costimulatory proteins, all known to amplify stimulatory and regulatory signals that occur during immune responses. On the other hand, differences in the distribution, kinetics of induction and requirements for induction support the view of a defined role for each of the ligands for T-cell-mediated immune activities. The shedding of members of the TNF receptor superfamily could limit the signals mediated by the corresponding ligands, as a functional regulatory mechanism. Induction of cytotoxic cell death is another common functional feature of this cytokine family (TNF, LT-alpha, CD30L, CD95L and 4-1BBL). Further studies have to identify unique versus redundant biological and physiological functions for each of the TNF superfamily ligands. In addition to other cytokines primary H-RS cell frequently express at least TNF, LT-alpha, CD27L and CD30L, but not CD40L. Furthermore, H-RS cells express several TNF receptors, such as CD30, CD40, CD95, CD120a, CD120b and 4-1BB. The TNF-like ligands might support growth and activation of HD-associated tumor cells and/or interact with surrounding reactive bystander cells, particularly T-cells. The different interactions between H-RS cells and surrounding reactive bystander cells are part of the pathobiology of HD. Detailed functional analysis have to confirm the predicted biological activities of TNF, LT-alpha, CD27L, CD30L, CD40L, CD95L, 4-1BBL and gp34/OX40L for the H-RS cell/T-cell interactions with impact on tumor growth and pathogenesis of HD. TNF and LT-alpha/CD120a and CD120b, CD30/CD30L, and CD40/CD40L are clearly critical elements in the deregulated network of interactive signals between H-RS cells and surrounding bystander cells with membrane-associated and cytokine-mediated events. Several TNFR superfamily members are also candidates for novel treatment protocols, including CD30 and CD40.
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PMID:Structural and biological features of the TNF receptor and TNF ligand superfamilies: interactive signals in the pathobiology of Hodgkin's disease. 883 4

Human lymphotoxin-alpha (LT alpha) is found in a secreted form and on the surface of lymphocytes as a complex with a second related protein called lymphotoxin-beta (LT beta). Both secreted human LT alpha and TNF have similar biological activities mediated via the TNF receptors, whereas the cell surface LT alpha beta complex binds to a separate receptor called the LT beta receptor (LT beta R). The murine LT alpha and LT beta (mLT alpha and mLT beta) proteins have never been characterized. When recombinant mLT alpha was produced by either of several methods, the protein had a very low specific activity relative to that of human LT alpha in the conventional WEHI 164 cytotoxicity bioassay. The weak activity observed was inhibited by a soluble murine TNF-R55 Ig fusion protein (mTNF-R55-Ig), but not by mLT beta R-Ig. Coexpression of both mLT alpha and a soluble version of mLT beta in insect cells led to an LT alpha beta form that was cytotoxic in the WEHI 164 assay via the LT beta R. To determine whether natural mLT alpha-like forms with cytotoxic activity comparable to that of secreted human LT alpha were secreted from primary spleen cells, splenic lymphocytes were activated in various ways, and their supernatants were analyzed for cytotoxic activity. Using specific Abs to distinguish between mTNF and mLT, a TNF component was readily detected; however, there was no evidence for a secreted mLT alpha cytotoxic activity using this assay. Combined, these observations suggest that secreted mLT alpha may not play a role in the mouse via interactions with TNF-R55, and the ramifications of this hypothesis are discussed.
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PMID:Cytotoxic activities of recombinant soluble murine lymphotoxin-alpha and lymphotoxin-alpha beta complexes. 931 28

Four members of the tumor necrosis factor (TNF) ligand family, TNF-alpha, LT-alpha, LT-beta, and LIGHT, interact with four receptors of the TNF/nerve growth factor family, the p55 TNF receptor (CD120a), the p75 TNF receptor (CD120b), the lymphotoxin beta receptor (LT beta R), and herpes virus entry mediator (HVEM) to control a wide range of innate and adaptive immune response functions. Of these, the most thoroughly studied are cell death induction and regulation of the inflammatory process. Fas/Apo1 (CD95), a receptor of the TNF receptor family activated by a distinct ligand, induces death in cells through mechanisms shared with CD120a. The last four years have seen a proliferation in knowledge of the proteins participating in the signaling by the TNF system and CD95. The downstream signaling molecules identified so far--caspases, phospholipases, the three known mitogen activated protein (MAP) kinase pathways, and the NF-kappa B activation cascade--mediate the effects of other inducers as well. However, the molecules that initiate these signaling events, including the death domain- and TNF receptor associated factor (TRAF) domain-containing adapter proteins and the signaling enzymes associated with them, are largely unique to the TNF/nerve growth factor receptor family.
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PMID:Tumor necrosis factor receptor and Fas signaling mechanisms. 1035 62

Nuclear factor kappaB-inducing kinase (NIK) is a member of the MAP kinase kinase kinase family that was first identified as a component of the TNF-R1-induced NF-kappaB activation pathway (TNF, tumor necrosis factor; nuclear factor kappaB, NF-kappaB). Gene knockout study, however, suggests that NIK is dispensable for TNF-R1- but required for lymphotoxin-beta receptor-induced NF-kappaB activation. A NIK kinase inactive mutant is a potent inhibitor of NF-kappaB activation triggered by various stimuli, suggesting that NIK is involved in a broad range of NF-kappaB activation pathways. To unambiguously identify signaling pathways that NIK participates in, we screened antibody arrays for proteins that are associated with NIK. This effort identified ErbB4, one of the EGF/heregulin receptors, and Grb7, an adapter protein associated with ErbB4 (ErbB, epidermal growth factor receptor family protein; EGF, epidermal growth factor; Grb, growth factor receptor bound). Coimmunoprecipitation experiments demonstrated that NIK interacted with Grb7, as well as Grb10 and Grb14, but not Grb2. Domain mapping experiments indicated that the central GM domain of Grb7 was sufficient for its interaction with NIK. Coimmunoprecipitation experiments also indicated that Grb7 and NIK could be simultaneously recruited into signaling complexes of all known EGF/heregulin receptors, including EGFR, ErbB2, ErbB3, and ErbB4. In reporter gene assays, NIK could potentiate Grb7, ErbB2/ErbB4, and EGF-induced NF-kappaB activation. A NIK kinase inactive mutant could block ErbB2/ErbB4 and EGF-induced NF-kappaB activation. Moreover, EGF/heregulin receptors activated NF-kappaB in wild-type, but not NIK-/- embryonic fibroblasts. Our findings suggest that NIK is a component of the EGF/heregulin receptor signaling complexes and involved in NF-kappaB activation triggered by these receptors.
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PMID:NIK is a component of the EGF/heregulin receptor signaling complexes. 1285 71

This study assessed the roles of the postnatal lymphotoxin-beta receptor (LTbetaR)-mediated signals in the gut-associated lymphoreticular tissues of mice for subsequent regulation of Ag-specific intestinal IgA responses. Blockade of LTbetaR-dependent events by postnatal administration of the fusion protein of LTbetaR and IgG Fc (LTbetaR-Ig) reduced both the size and numbers of Peyer's patches (PP) without influencing the PP microarchitecture. Interestingly, inhibition of LTbetaR-dependent signaling revealed significant reductions in the formation of follicular dendritic cell clusters in mesenteric lymph nodes (MLN). Furthermore, these postnatal signaling events controlled the development of isolated lymphoid follicles (ILF) because treatment with LTbetaR-Ig eliminated the formation of ILF. LTbetaR-Ig-treated mice with altered microarchitecture of MLN and lacking ILF were still able to produce significant Ag-specific mucosal IgA responses after oral immunization; however, the levels were significantly lower than those seen in control mice. These results imply the importance of ILF for Ag-specific intestinal immunity. However, mice treated with both TNFR55-Ig and LTbetaR-Ig in utero, which lack PP and MLN, but retain intact ILF, failed to induce Ag-specific IgA responses after oral immunization. These findings demonstrate that ILF are not essential for induction of intestinal IgA Ab responses to orally administered Ag. Furthermore, the induction of intestinal IgA Ab responses requires the proper maintenance of the MLN microarchitecture, including a follicular dendritic cell network.
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PMID:Role of gut-associated lymphoreticular tissues in antigen-specific intestinal IgA immunity. 1524 Jun 62