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

CD30 is a member of the tumor necrosis factor superfamily and a surface marker for Hodgkin's disease. Normal activated T cells and several virally transformed T or B cell lines also show CD30 expression. The interaction of CD30 with its ligand induces cell death or proliferation, depending on the cell type. In this report we characterize the signals mediated by the intracellular domain of CD30 and show that, in combination with signal(s) transduced by the T cell receptor, the multimerization of CD30 cytoplasmic domain induces Fas(CD95)-independent cell death in T cell hybridomas. Deletion analysis shows that the COOH-terminal 66 amino acids of CD30 are required to induce cell death. Using the yeast two-hybrid system, we have identified that the same region of CD30 interacts with tumor necrosis factor receptor-associated factor (TRAF)1 and TRAF2. These results indicate that TRAF1 and/or TRAF2 play an important role in cell death in addition to their previously identified roles in cell proliferation.
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PMID:T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors. 862 80

CD30 is a member of the tumor necrosis factor (TNF) receptor superfamily. CD30 is expressed on normal activated lymphocytes, on several virally transformed T- or B-cell lines and on neoplastic cells of Hodgkin's lymphoma. The interaction of CD30 with its ligand induces pleiotropic effects on cells resulting in proliferation, differentiation, or death. The CD30 cytoplasmic tail interacts with TNF receptor-associated factors (TRAFs), which have been shown to transduce signals mediated by TNF-R2 and CD40. We demonstrate here that TRAF2 also plays an important role in CD30-induced NF-kappa B activation. We also show that TRAF2-mediated activation of NF-kappa B plays a role in the activation of HIV transcription induced by CD30 cross-linking. Detailed site-directed mutagenesis of the CD30 cytoplasmic tail reveals that there are two independent binding sites for TRAF, each interacting with a different domain of TRAF. Furthermore, we localized the TRAF-C binding site in CD30 to a 5-7 amino acid stretch.
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PMID:CD30/TNF receptor-associated factor interaction: NF-kappa B activation and binding specificity. 879 Mar 94

CD30 is a lymphoid cell-specific surface receptor which was originally identified as an antigen expressed on Hodgkin's lymphoma cells. Activation of CD30 induces the nuclear factor kappaB (NF-kappaB) transcription factor. In this study, we define the domains in CD30 which are required for NF-kappaB activation. Two separate elements of the cytoplasmic domain which were capable of inducing NF-kappaB independently of one another were identified. The first domain (domain 1) mapped to a approximately 120-amino-acid sequence in the membrane-proximal region of the CD30 cytoplasmic tail, between residues 410 and 531. A second, more carboxy-terminal region (domain 2) was identified between residues 553 and 595. Domain 2 contains two 5- to 10-amino-acid elements which can mediate the binding of CD30 to members of the tumor necrosis factor receptor-associated factor (TRAF) family of signal transducing proteins. Coexpression of CD30 with TRAF1 or TRAF2 but not TRAF3 augmented NF-kappaB activation through domain 2 but not domain 1. NF-kappaB induction through domain 2 was inhibited by coexpression of either full-length TRAF3 or dominant negative forms of TRAF1 or TRAF2. In contrast, NF-kappaB induction by domain 1 was not affected by alterations in TRAF protein levels. Together, these data support a model in which CD30 can induce NF-kappaB by both TRAF-dependent and -independent mechanisms. TRAF-dependent induction of NF-kappaB appears to be regulated by the relative levels of individual TRAF proteins in the cell.
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PMID:Induction of nuclear factor kappaB by the CD30 receptor is mediated by TRAF1 and TRAF2. 903 81

CD30 is present on the surfaces of malignant cells from patients with Hodgkin's lymphoma, anaplastic large cell lymphoma, and other lymphomas. The yeast two hybrid genetic screen method was used to identify molecular effectors which mediate CD30 signalling events. Clones corresponding to genes coding for TRAF1, TRAF2, and TRAF3 molecules, postulated to be involved in signalling via the TNF and CD40 receptors, were isolated. In this report, we show that the CD30 intracellular tail contains two motifs that bind TRAFs. The more amino terminal motif, 558PHYPEQET565, binds TRAF2 and 3, while the more carboxyl terminal motif, 576MLSVEEEG583, binds TRAF1 and 2. We show that these amino acid motifs are conserved in TNFRp75 and CD40 and that sequences in these receptors homologous to TRAF-binding sequences found in CD30 can selectively bind the TRAFs in a predictable manner.
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PMID:Binding sites of cytoplasmic effectors TRAF1, 2, and 3 on CD30 and other members of the TNF receptor superfamily. 916 96

Although Hodgkin's disease is highly responsive to treatments that cause apoptosis, it remains resistant to the physiological mechanisms intended to cause cell death. Presumably, the Reed-Sternberg cell defies endogenous apoptosis, persists, accumulates, and manifests the malignant disorder seen clinically. The Reed-Sternberg cell expresses several members of the tumor necrosis factor receptor superfamily. This family of receptors is involved in both activation and proliferation of cells, as well as either protection from or initiation of apoptosis in cells expressing these surface proteins. Signals from these receptors affect transcription. We reasoned that the activation state and resistance to apoptosis of Reed-Sternberg cells might be attributable to dysregulation of genes controling these processes. To determine gene expression by Reed-Sternberg cells, we developed a method of micromanipulation, global reverse transcription, and the reverse transcription-polymerase chain reaction and applied it to 51 single Reed-Sternberg cells and their variants from six cases of Hodgkin's disease. This report analyzes the gene expression of bcl-xs, bcl-xl, bax-alpha, bax-beta, fadd, fas, fas ligand (fas L), ice, TNF-alpha, TNF-beta, TNFR1, TNFR2, TRAF1, TRAF2, TRAF3, cIAP2, and tradd at the level of mRNA in the single Reed-Sternberg cells and their variants. The findings here suggest a molecular mechanism for the activated state and in vivo survival occurring in untreated Reed-Sternberg cells of Hodgkin's disease.
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PMID:Gene expression by single Reed-Sternberg cells: pathways of apoptosis and activation. 951 44

The latent membrane protein 1 (LMP1) oncogene of Epstein-Barr virus (EBV) is selectively expressed in the Reed-Sternberg (RS) cells of EBV-associated Hodgkin's disease (HD). However, no differences in clinical presentation and course are found between EBV positive and EBV negative forms of HD suggesting a common pathogenetic mechanism. We have studied the LMP1 associated signaling pathways and their dominant negative inhibition in the myelomonocytic HD-MyZ and the B-lymphoid L-428 HD cell lines. In both EBV negative cell lines expression of LMP1 is associated with the formation of multinuclear RS cells. Dominant negative inhibition of NF-kappa B mediated signaling at the step of I kappa B-alpha phosphorylation results in increased cell death with only a few typical RS cells resistant to overexpression of the dominant negative inhibitor I kappa B-alpha-N delta 54. However, dominant negative inhibition of NF-kappa B mediated signaling at the early step of TRAF2 interaction results in the formation of multinuclear cells in both cell lines and, in addition, in clusters of small mononuclear cells in the HD-MyZ cell line. In HD-MyZ cells overexpression of the powerful JBD-inhibitor of the JNK signal transduction pathway is restricted to small cells and never observed in RS cells. These small cells undergo apoptosis as shown by the TUNEL technique. Apoptosis of small cells is still observed after co-transfection of JBD and LMP1 but in addition a few apoptotic HD-MyZ cells with large fused nuclear masses are identified suggesting that specific inhibition of JNK leads also to apoptosis of LMP1 induced RS cells. Thus, activation of the JNK signaling pathway is also important in the formation of Reed-Sternberg cells. Our findings are consistent with a model where all three LMP1 associated functions, i.e. NF-kappa B mediated transcription, TRAF2 dependent signaling, and c-Jun activation act as a common pathogenetic denominator of both EBV negative and EBV positive HD.
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PMID:Latent membrane protein 1 associated signaling pathways are important in tumor cells of Epstein-Barr virus negative Hodgkin's disease. 1059 17

Although eosinophilic granulocytes are frequently observed in lymphatic tissue of Hodgkin's patients, no substantial data reveal the prognostic role, if any, of tissue eosinophilia. Thus, eosinophilia was analyzed histologically in 1511 diagnostic biopsy specimens of patients treated under protocol therapy of the German Hodgkin's Lymphoma Study Group between 1988 and 1994. Prominent eosinophilia was seen in 38% of cases, which differed among the histologic types of Hodgkin's disease (HD): none in lymphocyte predominant, 14% in lymphocyte rich classical, 40% in nodular sclerosis grade 1 (NS-1), 55% in nodular sclerosis grade 2, 43% in mixed cellularity (MC), and 54% in lymphocyte depleted. In a multivariate analysis, tissue eosinophilia proved to be the strongest prognostic factor for freedom from treatment failure (P <. 001) and overall survival (P <.001) in a stage-stratified model. Among NS-1 patients, the effect was highly significant. In MC, no significant effect of eosinophilia on survival could be demonstrated. Eosinophils secrete CD30 ligand that is capable of binding to CD30 positive HD cells. The activation of TRAF2, followed by NF-kappaB, which occurs on CD30L/CD30 binding, may explain the neoplastic proliferation and apoptosis protection of HD cells. TRAF2 is also activated by EBV-LMP expression, which is detectable in the majority of MC but not NS cases. In addition to the possibility that eosinophils are only passive indicators for other unknown prognostic determinants, it may be concluded that the positive clinical outcome of eosinophilia-negative NS cases could be due to lower NF-kappaB activity. (Blood. 2000;95:1207-1213)
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PMID:Tissue eosinophilia correlates strongly with poor prognosis in nodular sclerosing Hodgkin's disease, allowing for known prognostic factors. 1066 92

TNFR-associated factors (TRAFs) constitute a family of adapter proteins that associate with particular TNF family receptors. Humans and mice contain six TRAF genes, but little is known about their in vivo expression at the single cell level. The in vivo locations of TRAF1, TRAF2, TRAF5, and TRAF6 were determined in human and mouse tissues by immunohistochemistry. Striking diversity was observed in the patterns of immunostaining obtained for each TRAF family protein, suggesting their expression is independently regulated in a cell type-specific manner. Dynamic regulation of TRAFs was observed in cultured PBLs, where anti-CD3 Abs, mitogenic lectins, and ILs induced marked increases in the steady-state levels of TRAF1, TRAF2, TRAF5, and TRAF6. TRAF1 was also highly inducible by CD40 ligand in cultured germinal center B cells, whereas TRAF2, TRAF3, TRAF5, and TRAF6 were relatively unchanged. Analysis of 83 established human tumor cell lines by semiquantitative immunoblotting methods revealed tendencies of certain cancer types to express particular TRAFs. For example, expression of TRAF1 was highly restricted, with B cell lymphomas consistently expressing this TRAF family member. Consistent with results from tumor cell lines, immunohistochemical analysis of 232 non-Hodgkin lymphomas revealed TRAF1 overexpression in 112 (48%) cases. TRAF1 protein levels were also elevated in circulating B cell chronic lymphocytic leukemia specimens (n = 49) compared with normal peripheral blood B cells (p = 0.01), as determined by immunoblotting. These findings contribute to an improved understanding of the cell-specific roles of TRAFs in normal tissues and provide evidence of altered TRAF1 expression in lymphoid malignancies.
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PMID:TNFR-associated factor family protein expression in normal tissues and lymphoid malignancies. 1104 39

Tumor necrosis factor receptor-associated factors (TRAFs) are a recently established group of proteins involved in the intracellular signal transduction of several members of the tumor necrosis factor receptor (TNFR) superfamily. Recently, specific members of the TRAF family have been implicated in promoting cell survival as well as activation of the transcription factor NF-kappaB. We investigated the constitutive expression of TRAF1 and TRAF2 in Hodgkin and Reed-Sternberg (HRS) cells from archived paraffin-embedded tissues obtained from 21 patients diagnosed with classical Hodgkin's disease (HD). In a selective portion of cases, examination of HRS cells for Epstein-Barr virus (EBV)-encoded RNA was performed by in situ hybridization, and the results were compared with the magnitude of TRAF1 and TRAF2 staining. We also determined the TRAF profile in the classical HD cell lines L428, KMH2, and HS445 by Western blotting using a series of antibodies that specifically recognize the six individual TRAF family proteins (TRAF1-TRAF6). Moderate to high constitutive expression of TRAF1 and TRAF2 were found in 19 of 21 and 20 of 21 cases of classical HD, respectively. Of the remaining cases, one case showed weak expression of TRAF1, and another case showed weak expression of both proteins. No relationship was found between the staining intensity of the TRAF proteins and EBV expression in HRS cells. Strong constitutive expression of TRAF1 was also identified in the HD cell line L428, compared with the relatively weak expression observed in KMH2 and HS445. All three HD cell lines showed strong expression of TRAF2 protein and moderate, comparatively equal expression of TRAF4 and TRAF6. In contrast, TRAF3 was not expressed in the HD cell lines. Although KMH2 showed weak expression, the remaining HD cell lines also lacked TRAF5 protein. These data demonstrate that constitutive expression of TRAF1 and TRAF2 is a characteristic feature of HRS cells from both patient and cell line specimens. Furthermore, with the exception of TRAF1 expression, HRS cells from the three HD cell lines showed similar TRAF protein expression patterns. Overall, these findings demonstrate the expression of several TRAF proteins in HD. Significantly, the altered regulation of selective TRAF proteins may reflect HRS cell response to stimulation from the microenvironment and potentially contribute both to apoptosis resistance and cell maintenance of HRS cells.
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PMID:Expression of the tumor necrosis factor receptor-associated factors (TRAFs) 1 and 2 is a characteristic feature of Hodgkin and Reed-Sternberg cells. 1114 29

The tumour necrosis factor receptor-associated factors (TRAFs) 1 and 2 participate in the signal transduction of various members of the tumour necrosis factor receptor (TNFR) family, including TNFR1, TNFR2, CD40, CD30, and the Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP1). Previous in situ hybridization studies have demonstrated TRAF1 transcripts in the malignant cells of the majority of Hodgkin's disease (HD) tumours, where the expression of TRAF1 was higher in EBV-associated tumours than in their EBV-negative counterparts. In order to determine whether TRAF1 and also TRAF2 were expressed at the protein level in HD and whether there was any relationship to EBV status, immunohistochemistry has been used to detect these proteins in a series of HD specimens. TRAF1 protein was detected more frequently in Hodgkin/Reed-Sternberg (HRS) cells from EBV-positive tumours than in their EBV-negative counterparts. This difference was statistically significant (p=0.01). In contrast, TRAF2 expression by HRS cells appeared to be independent of EBV status. Using a sequential labelling approach, co-localization of LMP1 with either TRAF1 or TRAF2 was also demonstrated in HRS cells from EBV-positive tumours.
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PMID:Expression of the tumour necrosis factor receptor-associated factors 1 and 2 in Hodgkin's disease. 1140 Jan 43


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