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)

The majority of non-Hodgkin's B-cell lymphomas contain a t(14;18) translocation that places the bc12 gene into juxtaposition with the transcriptically active Ig heavy-chain locus, thus deregulating the expression of this proto-oncogene. The bc12 gene product is a membrane-associated mitochondrial protein that regulates cell survival through unknown mechanisms. Although overproduction of the normal protein appears sufficient for conferring a selective growth or survival advantage to B cells, point mutations that alter the coding region of translocated bc12 genes have been described previously by others in a lymphoma cell line. However, it is not known whether somatic mutations that alter BCL2 proteins occur in vivo or whether they result from chemotherapy or arise through other mechanisms. For these reasons, we obtained DNA from the t(14;18)-containing tumors of five patients who had not undergone treatment for their disease, and used a polymerase chain reaction (PCR)-mismatch technique for rapid identification of point mutations in a portion of the bc12 open reading frame (ORF) corresponding to the first 131 aminoacids (aa) of the 239 aa p26 BCL2 protein. DNAs from two t(14;18)-containing cell lines were also analyzed. Point mutations in this region of the bc12 gene ORF were detected in three of five patients' tumors and in both cell lines. PCR-mismatch analysis of bc12 in cell lines and non-Hodgkin's lymphoma cases that lacked the t(14;18) translocation was negative, thus establishing the specificity of these results. DNA sequencing determined that these mutations are predicted to produce aa substitutions in the BCL2 proteins of two of the primary tumors and one of the cell lines. Interestingly, two of the patients contained an identical C----T transition that resulted in a nonconservative aa substitution (proline----serine) at position 59 of the BCL2 protein. Further analysis excluded the possibility that these mutations represented hereditary polymorphisms or PCR artifacts. A cluster of four point mutations within the translocation + bc12 allele of one patient had hallmarks of the somatic hypermutation mechanism that is associated with Ig genes and that contributes to antibody diversity. Because of the region of the bcl2 gene analyzed in these t(14;18) translocations is located nearly 300 kbp from the Ig heavy-chain locus, our data suggest that the Ig gene somatic hypermutation mechanism can act over extreme distances of DNA. It remains to be established whether these somatic mutations that alter BCL2 proteins influence the pathobiology of nonHodgkin's lymphomas.
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PMID:Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas. 133 99

The Hodgkin-associated Ki-1 antigen (CD30) consists of a 120-kDa membrane-associated glycosylated phosphoprotein (Ki-1/120) and a 57-kDa non-glycosylated phosphoprotein (Ki-1/57) which only occurs intracellularly. Both molecules are phosphorylated at serine residues. An analysis of the peptide fragments resulting from staphylococcal V8-protease digestion of the Ki-1/57 molecule revealed identical bands irrespective of the cell source. Only a few bands of the Ki-1/57 digests appeared among the peptide fragments of the Ki-1/120 membrane antigen. The protein kinase activity was tested for both forms of the Ki-1 antigen. The Ki-1/120, devoid of the Ki-1/57 molecule, was immunoprecipitated from cell lysates of Hodgkin-analogous cell lines L428 or L540, which had been loaded with the Ki-1 or the Ki-1-analogous antibodies Ber-H2, HSR-1, -2 and -3 (method 1). These other antibodies reacted with the Ki-1/120, but not with the Ki-1/57 antigen. The latter, devoid of the Ki-1/120, was isolated from L540 cells after removal of the membrane form by method 1 or from U266/Bl myeloma or Raji Burkitt lymphoma cells which only contain the smaller form. Effects of non-specific adsorption were eliminated by various control precipitates. The Ki-1/57 intracellular antigen showed autophosphorylation and could phosphorylate histones as well. In contrast, a protein kinase activity of the membrane-associated Ki-1/120 could not be demonstrated.
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PMID:Protein kinase activity of the intracellular but not of the membrane-associated form of the Ki-1 antigen (CD30). 216 Nov 15

The Hodgkin-associated Ki-1 antigen occurs in two different molecular forms. The 120-kDa membrane-associated form is a phosphorylated glycoprotein, which is derived from a non-phosphorylated intracellular 84-kDa apoprotein that is co-translationally N-glycosylated with a carbohydrate portion of 6 kDa. The other form of the Ki-1 antigen is a non-glycosylated phosphoprotein of 57 kDa which only occurs intracellularly. Both forms of the antigen are phosphorylated at serine residues. Enzymatic cleavage with sialidase reduced the 120-kDa membrane antigen by about 15 kDa, while its 90-kDa precursor and the 57-kDa intracellular form of the Ki-1 antigen remained unaltered. Pulse-chase experiments revealed that the 57-kDa and 90/120-kDa molecules are synthesized independently of each other. Four to eight hours after synthesis, the degradation of the 120-kDa molecule to a 105-kDa membrane-associated intermediate begins. This is further processed and appears in the cell supernate as a 90-kDa molecule. Hodgkin's disease-derived, Epstein-Barr virus-transformed cell lines and the acute T cell leukemia line MOLT-4 contain both forms of the Ki-1 antigen, whereas only the 57-kDa intracellular antigen is expressed in U266/B1 myeloma cells, in the Burkitt lymphoma cell lines Raji and Daudi and in acute promyelocytic HL-60 leukemia cells.
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PMID:The Hodgkin-associated Ki-1 antigen exists in an intracellular and a membrane-bound form. 254 29

The HeFi-1 mAb recognizes a membrane protein on Hodgkin's disease cells and on a limited number of other human cells that are either tumorigenically transformed or virally activated. Herein biochemical and structural analyses of the HeFi-1 reactive membrane protein (HRMP) were done to identify its potential importance in cellular transformation in the Hodgkin's disease cell line L428, in the T cell lymphoma line HuT 78, and in several EBV-transformed lymphoblastoid cell lines. Immunoprecipitation studies demonstrated that the mature form of the HRMP had an apparent Mr of 120 kDa in tumor cells and 116 kDa in the EBV-transformed cell lines and that it was phosphorylated at both serine and tyrosine residues in all cell lines tested. The precursor to the HRMP is an 86-kDa core protein that, after processing by high mannose N-linked glycosylation, migrates with an apparent Mr of 90 kDa. This protein is then further processed to the mature 120-kDa HRMP in part by O-linked glycosylation, the addition of sialic acid residues, and by the conversion of N-linked oligosaccharides from the high mannose to the complex type. Detectable amounts of the 90-kDa molecule can be found in the membrane and, although this protein can be phosphorylated in vitro, it is not phosphorylated in intact cells. The combined results of this study suggest that the HRMP is involved in cellular metabolism and show that an unusual amount of post-translational processing of the 90-kDa precursor results in the formation, and perhaps phosphorylation, of the mature 120-kDa HRMP.
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PMID:Biochemical and structural properties of a Hodgkin's disease-related membrane protein. 338 12

The activation marker CD30 is expressed on the cell surface of the malignant cells in Hodgkin's disease and a few non-Hodgkin lymphomas. We have analyzed the regulation of membrane-bound CD30 and found that the binding of a variety of anti-CD30 antibodies induced down-regulation of CD30 on cell lines. In addition, such down-modulation was also observed after treatment of the cell surface proteins with the sulfhydryl reagent iodoacetamide or after stimulation of the second messenger pathway with phorbol ester or calcium ionophore. This modulation was abolished at 4 degrees C and strongly inhibited by chelators like EDTA or 1,10-phenanthroline, whereas EGTA, a selective inhibitor of Ca(2+)-dependent proteinases and other inhibitors of serine, thiol and acid proteinases, showed no effect. The down-modulation was strengthened by Zn2+ or Cd2+, but not by other divalent cations such as Fe2+, Mn2+, Mg2+, Ca2+ or Co2+, thus indicating the involvement of a zinc metalloproteinase in CD30 modulation which can be activated by protein kinase C and by alkylation of sulfhydryl groups. Pulse-chase experiments, analysis of the CD30 glycosylation and specific measurement of the 90-kDa soluble form of CD30 (sCD30) with a sandwich radioimmunoassay revealed that CD30 down-modulation results from enhanced release of 90-kDa sCD30 by the site-specific cleavage of CD30 accomplished by a zinc metalloproteinase. This release occurs at the cell membrane without prior endocytosis.
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PMID:A zinc metalloproteinase is responsible for the release of CD30 on human tumor cell lines. 759 Dec 96

LMP-1 is the only Epstein-Barr virus-encoded latent protein known to have the properties of a transforming oncogene in rodent fibroblasts and the only latent protein, besides EBNA-1, detected in nasopharyngeal carcinoma and Hodgkin's lymphoma biopsies. LMP-1 is characterized by serine/threonine phosphorylation and rapid turnover (half-life, 2 to 3 h) due to specific proteolytic cleavage, which causes release of a phosphorylated C-terminal fragment (p25) into the cytoplasm. We used biochemical, functional, and mutational analyses to identify sites of phosphorylation. All of the phosphorylation sites detected lie in the C-terminal domain. In particular, we identified S-313 and T-324 as functionally important sites. Prevention of phosphorylation at S-313, by altering it to a glycine, prevented detectable phosphorylation of both LMP-1 and p25, indicating that it is a major site on both forms of the molecule. However, lack of detectable phosphorylation had no effect on p25 cleavage or on the ability of LMP-1 to transform Rat-1 fibroblasts. Alteration of S-313 to an aspartate resulted in a form of LMP-1 that was toxic to Rat-1 cells. Alteration of T-324 to a glycine residue had no detectable effect on the ability of LMP-1 to become serine phosphorylated or transform Rat-1 cells. Alteration of T-324 to a glutamate, however, inhibited all detectable phosphorylation and resulted in a form of LMP-1 that was unable to transform Rat-1 fibroblasts. These results are discussed in the context of a model in which LMP-1 function is modulated by phosphorylation and dephosphorylation at S-313 and T-324.
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PMID:Biochemical, genetic, and functional analyses of the phosphorylation sites on the Epstein-Barr virus-encoded oncogenic latent membrane protein LMP-1. 838 69

Chromosome 12q24.1 is a recurrent breakpoint in high-grade B-cell non-Hodgkin lymphoma (B-NHL). To identify the genes involved at 12q24.1, molecular cloning of a three-way translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line (Wien 133) was performed; all four translocation breakpoints were cloned and sequenced. Analysis of clones encompassing the der(12)(12;14)(q24.1;q32.3) breakpoint showed a CpG island from chromosome 12q24.1 juxtaposed in a tail-to-tail configuration with a productively rearranged Ig VH4-DH-JH5 gene. A total of 4.5 kb of genomic DNA including the CpG island was sequenced and analyzed using gene-identification programs; all three programs identified a potential 92-bp exon within the centromeric boundary of the CpG island. Using this as a probe, an RNA transcript of 3.8 kb, expressed at low levels in a wide variety of normal tissues, was detected. Overlapping cDNA clones were isolated and sequenced. The longest open-reading frame predicted a serine-rich protein of 231 amino acids. This protein, termed BCL7A, exhibited no recognizable protein motifs but showed homology with the actin-binding protein, caldesmon. In Wien 133, the BCL7A breakpoint occurred within the first intron and resulted in a MYC-BCL7A fusion transcript, with exon I of BCL7A being replaced by MYC exon I. The normal, untranslocated allele of BCL7A was also expressed without mutation. One of the 11 other B-NHL cell lines examined with 12q24.1 cytogenetic abnormalities, a mediastinal B-NHL cell line (Karpas 1106), showed biallelic rearrangement within the first intron of BCL7A, which was adjacent to the breakpoint observed in Wien 133. Disruption of the amino-terminus of BCL7A defines a new mechanism in the pathogenesis of a subset of high-grade B-NHL.
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PMID:Molecular cloning of complex chromosomal translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line defines a new gene (BCL7A) with homology to caldesmon. 860 26

p21 is induced by and mediates the effects of p53 in response to DNA damage arresting the cell in G1 or G2, by inhibiting multiple cyclin-cyclin-dependent kinases (CDK) or binding to proliferating-cell nuclear antigen (PCNA), respectively. To determine whether p21 mutants occur in tumors we examined DNA from 188 primary non-Hodgkin's B-cell lymphoma (NHL) tumors and 84 chronic myelogenous leukemia samples for mutational changes in the coding region of p21 by single-strand conformation polymorphism (SSCP) analysis and direct sequencing of polymerase chain reaction (PCR)-amplified DNA. We did not find mutations in the coding region in these two tumor types. We identified a polymorphic nucleotide change in codon 31 in which a transversion from C to A substituted amino acid arginine for serine. Three of 188 NHL tumors were homozygous for this change, but they were not identified in 84 CMLs or in 97 normal controls. On the other hand, in one CML case a transition from G to A in codon 64 substituted amino acid threonine for alanine. These data do not indicate that derangements in the coding region of p21 contribute to the initiation and/or progression of these tumors.
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PMID:Absence of somatic changes in p21 gene in non-Hodgkin's lymphoma and chronic myelogenous leukemia. 865 61

A novel protein, named NNX3, was molecularly characterized by cloning its cDNA, and its gene was mapped to chromosome 19q12. The equivalent mouse cDNA and gene were also cloned to allow us to analyze expression in murine in addition to human cells and tissues. Human and mouse NNX3 genes are composed of nine exons coding for proteins that are unrelated to any known protein. Signal peptides and hydrophobic domains are absent, corroborating their localization in the cytoplasm in transfected Cos cells. In Western blotting and immunoprecipitation, human NNX3 appeared as a doublet of Mr 64K-66K, while mouse NNX3 was a 70-kDa protein, both apparently much larger than the predicted 50 kDa, due in part to a stretch of 16-18 acidic residues hinging two nearly equally sized domains. In addition, phosphorylation of serine residues was demonstrated. Putative nuclear targeting signals were predicted, but NNX3 protein and two truncated versions remained localized in the cytoplasm of transfected Cos cells. NNX3 was expressed in embryonic and adult mouse tissues, particularly in brain, muscle, and lung. The expression of human NNX3 was most notable in human skeletal muscle and in ganglion cells and was also evident in human tumors and derived cell lines. This was confirmed by entries appearing in the GenBank EST database during the later phase of this study, representing partial NNX3 cDNA isolated from diverse neoplastic and developing tissues. Surprisingly, NNX3 was immunochemically detected in Reed-Sternberg cells of Hodgkin disease, in parallel with restin, a cytoplasmic protein we previously characterized (J. Delabie et al., 1993, Leuk. Lymphoma 12, 21-26). The cloning and comprehensive molecular analysis of NNX3 as presented will form the basis for elucidating its function and, conversely, will constitute a marker for Reed-Sternberg cells in Hodgkin disease.
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PMID:Molecular cloning of a gene on chromosome 19q12 coding for a novel intracellular protein: analysis of expression in human and mouse tissues and in human tumor cells, particularly Reed-Sternberg cells in Hodgkin disease. 987 55

Bispecific monoclonal antibodies (Bi-mAbs) specific for a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes represent one of the most successful experimental strategies for the immunotherapy of cancer. We report that the in vivo administration of both alpha-CD3/CD30 and alpha-CD28/CD30 Bi-mAbs results in the specific activation of xenotransplanted, resting human T cells infiltrating the CD30-positive Hodgkin's tumor. Bi-mAb treatment resulted in enhanced expression of cytokines such as interleukin 1beta, interleukin 2, tumor necrosis factor type alpha, and activation markers including Ki-67, CD25, and CD45RO in tumor-infiltrating lymphocytes. This antigen-dependent, local T-cell stimulation led to the activation of the cytolytic machinery in T lymphocytes, determined by the up-regulation of mRNA-encoding perforin and the cytotoxic serine-esterases granzymes A and B. The Bi-mAb-induced generation of CTLs depended on the presence of the CD30 antigen and the combined application of both Bi-mAbs. Our findings suggest that the combined application of T-cell-activating Bi-mAbs is able to achieve a tumor site-specific activation of the T-cell cytolytic machinery in vivo. The fact that these cytotoxic cells do not home in tumor-associated antigen-negative tissue and do not enter circulation might explain our previous observations (C. Renner et al., Blood, 87: 2930-2937, 1996) of a high cure rate in preclinical models even at an advanced stage of disease.
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PMID:Immunotherapy of human tumors with T-cell-activating bispecific antibodies: stimulation of cytotoxic pathways in vivo. 1021 7


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