Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We observed a translocation (2;22)(p23;q11.2) in the bone marrow cells of a patient with multiple subcutaneous nodules. Tumor histology and immunohistochemical staining demonstrated a malignant lymphoma, diffuse large cell type, displaying a CD30 negative B cell immunophenotype. To our knowledge, this is the first report of this specific translocation in lymphoma, which may join the site of the anaplastic lymphoma kinase (ALK) gene at 2p23 to the region of the immunoglobulin lambda light chain gene at 22q11.2. The ALK gene was initially identified through its involvement in the t(2;5)(p23;q35) found most commonly in anaplastic large cell lymphoma. This observation in a CD30 negative large cell lymphoma of B cell lineage further extends the relationship of anaplastic large cell morphology, ALK activation, lymphoid lineage, and expression of the CD30 antigen.
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PMID:Diffuse large cell, B-cell type lymphoma with a novel translocation (2;22)(p23;q11.2). 921 18

The revised European-American Classification of Lymphoid Neoplasms (REAL), proposed by the International Lymphoma Study Group, contains molecular genetic data which may characterize a given lymphoma entity. In this recent review, the molecular genetic alterations integrated into the diagnostic procedure of lymphomas are discussed. Based on our recent knowledge the rearrangements of bcl-1, bcl-2, bcl-6, anaplastic lymphoma kinase and c-myc genes are associated with mantle cell, diffuse large B-cell, anaplastic large cell and Burkitt's lymphomas, respectively. The integration of the relevant molecular data in the evaluation of objective diagnoses and therefore specific and successful therapies. Furthermore, the knowledge of the molecular event associated with lymphomas helps to better understand tumor development and biology.
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PMID:[The role of genetic studies in the diagnosis and classification of non-Hodgkin lymphoma]. 929 69

The myeloid cell nuclear differentiation antigen (MNDA) is a nuclear protein expressed specifically in developing cells of the human myelomonocytic lineage, including the end-stage monocytes/macrophages and granulocytes. Nuclear localization, lineage- and stage-specific expression, association with chromatin, and regulation by interferon alpha indicate that this protein is involved in regulating gene expression uniquely associated with the differentiation process and/or function of the monocyte/macrophage. MNDA does not bind specific DNA sequences, but rather a set of nuclear proteins that includes nucleolin (C23). Both in vitro binding assays and co-immunoprecipitation were used to demonstrate that MNDA also binds protein B23 (nucleophosmin/NPM). Three reciprocal chromosome translocations found in certain cases of leukemia/lymphoma involve fusions with the NPM/B23 gene, t(5;17) NPM-RARalpha, t(2;5) NPM-ALK, and the t(3;5) NPM-MLF1. In the current study, MNDA was not able to bind the NPM-ALK chimera originating from the t(2;5) and containing residues 1-117 of NPM. However, MNDA did bind the NPM-MLF1 product of the t(3;5) that contains the N-terminal 175 residues of NPM. The additional 58 amino acids (amino acids 117-175) of the NPM sequence that are contained in the product of the NPM-MLF1 fusion gene relative to the product of the NPM-ALK fusion appear responsible for MNDA binding. This additional NPM sequence contains a nuclear localization signal and clusters of acidic residues believed to bind nuclear localization signals of other proteins. Whereas NPM and nucleolin are primarily localized within the nucleolus, MNDA is distributed throughout the nucleus including the nucleolus, suggesting that additional interactions define overall MNDA localization.
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PMID:MNDA binds NPM/B23 and the NPM-MLF1 chimera generated by the t(3;5) associated with myelodysplastic syndrome and acute myeloid leukemia. 932 47

Non-Hodgkin's lymphoma (NHL) occasionally involves the placenta, and information of such occurrence should be useful for management of the mother and fetus. We report the first case of anaplastic large cell lymphoma (ALCL) disseminated to the placenta. The diagnosis was made via excisional biopsy of cervical lymphadenopathy in a 20-year-old woman at 27 weeks' gestation. Involvement of the placenta was noted on gross examination after cesarean section delivery of a girl at 30 weeks' gestation. The ALCL was microscopically confined to intervillous spaces in a manner similar to previous reports of other NHLs. The immunophenotype was characteristic (CD30+, EMA+, BNH9+), and the now frequently associated t(2;5)(p23;q35) translocation with this lymphoma was detected by the recently produced monoclonal antibody ALK1 against the nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) chimeric protein. Complete remission was induced in the mother after delivery. Both mother and child are healthy at 10 years' follow-up. The case is reported in light of the sparse literature on lymphomatous involvement of the placenta.
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PMID:Anaplastic large cell lymphoma of maternal origin involving the placenta: case report and literature survey. 933 Dec 98

More than 60% of anaplastic large-cell lymphomas (Ki-1 lymphoma) are associated with a t(2;5)(p23;q35) translocation that produces an 80 kDa hyperphosphorylated chimeric protein (p80) derived from the fusion of the anaplastic lymphoma kinase (ALK) with nucleophosmin (NPM). The NPM-ALK chimeric gene is an activated tyrosine kinase that has been shown to be a potent oncogene. We have developed a cellular model for the study of p80 action in rat 1a fibroblasts. Expression of cDNA's encoding NPM-ALK (p80) in rat 1a fibroblasts induces anchorage-independent growth in soft agar and promotes foci formation in culture. Cells expressing exogenous p80 showed significantly increased proliferation characterized by accelerated cell cycle entry into S-phase. Consistent with increased G0/G1 to S-phase transition, there is also marked up-regulation of cyclin A and cyclin D1 expression. In addition, p80 transformed cells showed elevated expression of several immediate early genes involved in cellular proliferation, including fos, jun, and c-myc. DNA binding analysis of nuclear extracts prepared from p80 transformed cells reveal marked up-regulation of AP-1 DNA binding activity. Functional AP-1-specific transfection assays also show up-regulation of AP-1-dependent transcriptional activation. These finding demonstrate that p80 transformed rat 1a fibroblast can be a highly useful model system for the molecular and biochemical characterization of the mechanisms of action of this interesting new oncogene.
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PMID:The activated anaplastic lymphoma kinase increases cellular proliferation and oncogene up-regulation in rat 1a fibroblasts. 933 49

Approximately 5% to 10% of all non-Hodgkin's lymphomas contain a t(2;5)(p23;q35) chromosomal rearrangement, which we have previously shown results in the generation of the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). To assess the transforming potential of NPM-ALK in an animal model, we infected 5-fluorouracil-treated murine bone marrow using retroviral stocks and transplanted this infected marrow into lethally irradiated BALB/cByJ mice. Male mice were transplanted with bone marrow from female donors at 10 weeks of age, with 7 of the animals receiving marrow infected with a retroviral construct, pSR alphaMSVtkneo-NPM-ALK, that contains the human NPM-ALK cDNA, and 4 serving as a control group, receiving "empty" pSR alphaMSVtkneo-infected marrow. Whereas all mice in the control group were alive and well up to 11 months after transplantation, 4 of the 7 mice transplanted with marrow containing the NPM-ALK construct developed lymphoma within 4 to 6 months. Tumors arose in the mesenteric lymph nodes, with metastases to the lungs, kidneys, liver, spleen, and the paraspinal area. When cells from the tumors and bone marrow were transplanted into sublethally irradiated secondary recipients, 10 of these 13 mice developed tumors within 9 months. Immunoblot analysis of cell lysates using an ALK polyclonal antibody showed NPM-ALK expression in all tumors examined. Histologically, the tumors were composed of a uniform population of large immunoblastic cells with basophilic cytoplasm, centrally placed nuclei, and distinct nucleoli. Genotypic analysis showed that the tumors were B-lineage and clonal, with rearrangements of the Ig heavy- and kappa light-chain loci and no rearrangements of the T-cell receptor beta locus. Immunocytochemical studies confirmed the presence of IgM heavy chains and kappa light chains within the tumor cells. Thus, in this retroviral gene transfer model, NPM-ALK expression in mice causes B-lineage large-cell lymphoma, suggesting a direct causative role for this activated fusion tyrosine kinase in human lymphoma.
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PMID:Retrovirus-mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice. 937 69

The prevalence of the t(2;5)(p23;q35) and/or anaplastic lymphoma kinase (ALK) gene products in cutaneous anaplastic large cell (ALC) lymphomas and a potential precursor lesion, lymphomatoid papulosis (LyP), is controversial. ALK gene products, which are absent from normal lymphohaematopoietic cells, are a phenotypic marker of lymphomas carrying the t(2;5). We used in situ hybridization and immunohistology to screen 14 cutaneous ALC lymphomas, 21 cases of LyP, and one nodal ALC lymphoma associated with LyP for ALK gene products. ALK gene products were not detectable in these cases. In contrast, ALK gene products were found in a lymphonodal ALC lymphoma with subsequent extension to the skin and in t(2;5)-positive cell lines. Detection of the Epstein-Barr virus (EBV)-encoded small nuclear transcripts (EBER), and of immunoglobulin light chain transcripts served to check for the presence of cellular RNA in the tissue sections. EBER transcripts were found in scattered reactive lymphoid cells, but not in atypical or tumour cells. ALK gene expression and EBV infection seem to be a rare finding in cutaneous ALC lymphomas and LyP. This points to a molecular aetiology of primary cutaneous ALC lymphomas and LyP distinct from that of extracutaneous CD30+ lymphoproliferative disease. Detection of the t(2;5) or ALK gene products in cutaneous lymphoproliferative lesions therefore requires exclusion of extracutaneous ALC lymphoma in such patients.
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PMID:Absence of anaplastic lymphoma kinase (ALK) and Epstein-Barr virus gene products in primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis. 941 24

The tumor-specific increased minimal requirement for methionine has been shown to be a highly promising therapeutic target. To attack this target we have previously cloned the methioninase gene from Pseudomonas putida and produced recombinant methioninase (rMETase). A pilot Phase I clinical trial has been carried out to determine rMETase toxicity, rMETase pharmacokinetics, and serum MET-depletion in cancer patients. Patients with advanced breast cancer, lung cancer, renal cancer and lymphoma were given a single rMETase treatment at doses ranging from 5,000 to 20,000 units by i.v. infusion over 6-24 hours. No clinical toxicity was observed in any patient after rMETase treatment. rMETase levels reached 0.1 to 0.4 units per ml of serum in the patients which correspond to therapeutic levels in vitro. The lowest serum methionine levels in rMETase-treated patients were 0.1% of the pre-treatment levels corresponding to approximately 0.1 microM, which also correlates to therapeutic levels in vitro. The results of the rMETase pilot Phase I clinical trial therefore indicate that i.v. infusion of rMETase is safe and effectively depletes its biochemical target of serum methionine suggesting potential efficacy in future clinical trials.
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PMID:Recombinant methioninase infusion reduces the biochemical endpoint of serum methionine with minimal toxicity in high-stage cancer patients. 942 92

Successful treatment of melanoma and lymphoma may result from the induction of specific antitumor immunity. Dendritic cells (DCs) are powerful antigen-presenting cells and show a remarkable capacity to stimulate antigen-specific T-cell responses. Administration of FLT3 ligand (FL) results in a reversible accumulation of functionally active DCs in both lymphoid and nonlymphoid tissues. Therefore, we evaluated the possible antitumor effect of FL in murine melanoma (B16 and CL8-1) and lymphoma (EL-4) models. In all experiments, tumor growth was significantly inhibited by FL administration. Analysis by immunohistochemistry revealed an increase in the DC accumulation within B16 and EL-4 tumors after treatment with FL. No change was observed for CL8-1 melanoma. These data suggest a potential role for FL in the immunotherapy of malignant skin tumors and possible DC involvement in this effect.
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PMID:FLT3 ligand administration inhibits tumor growth in murine melanoma and lymphoma. 945 75

Binding of fibroblast growth factors (FGFs) to receptor tyrosine kinases (FGFRs) and signaling is facilitated by binding of FGF to heparan sulfate proteoglycans (HSPGs). There are multiple families of HSPGs, including extracellular and cell surface forms. An important and potentially controversial question is whether cell surface forms of HSPGs act as positive or negative regulators of FGF signaling. This study examines the ability of the cell surface HSPG syndecan-1 to regulate FGF binding and signaling. HSPG-deficient Raji lymphoma cells, expressing a transfected syndecan-1 cDNA (Raji S1 cells), were used as HSPG "donor" cells. BaF3 cells, expressing an FGFR1 cDNA (FR1C-11 cells), were used as FGFR "reporter" cells. Using Raji S1 cells preincubated with FGF, it was found that they formed heterotypic aggregates with FR1C-11 cells in the presence of FGF-2, but not FGF-1. In addition, the FR1C-11 cells demonstrated FGF-2, but not FGF-1, dependent survival when cultured on fixed Raji S1 cells. Thus, Raji syndecan-1 1) differentially regulates the binding and signaling of FGFs 1 and 2 and 2) acts as a positive regulator of FGF-2 signaling.
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PMID:The cell surface proteoglycan syndecan-1 mediates fibroblast growth factor-2 binding and activity. 946 93


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