Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The long terminal repeat from a thymotropic mouse mammary tumor virus variant, DMBA-LV, was used to drive the expression of two reporter genes, murine c-myc and human CD4, in transgenic mice. Expression was observed specifically in thymic immature cells. Expression of c-myc in these cells induced oligoclonal CD4+ CD8+ T-cell thymomas. Expression of human CD4 was restricted to thymic progenitor CD4- CD8- and CD4+ CD8+ T cells and was shut off in mature CD4+ CD8- and CD4- CD8+ T cells, known to be derived from the progenitor double-positive T cells. These results suggest the existence of similar and common factors in CD4+ CD8- and CD4- CD8+ T cells and support a model of differentiation of CD4+ CD8+ T cells through common signal(s) involved in turning off the expression of the CD4 or CD8 gene.
Mol Cell Biol 1992 Aug
PMID:A viral long terminal repeat expressed in CD4+CD8+ precursors is downregulated in mature peripheral CD4-CD8+ or CD4+CD8- T cells. 132 39

The S49 cell lines are a unique series of tumor sublines isolated from a single BALB/c thymoma. Several different sublines were previously isolated from non-mutagenized cells using pharmacologic agents that would select for different stages of thymic development. In this report we show that all seven of the sublines studied express TL class I Ag confirming their derivation from immature thymocytes. This uniform TL expression is in contrast to the previously characterized locus-specific shut off of Kd,Dd, and/or LdAg by various S49 sublines. Furthermore, S49 sublines were found to display disparate CD4/CD8 expression. Whereas the unselected subline is a CD4+/CD8+ double positive, each of the selected sublines is singly positive for either CD4 or CD8. All seven sublines were found to be CD3+ and express alpha beta TCR heterodimers. To establish whether the S49 sublines have a monoclonal or polyclonal origin, their TCR rearrangements were compared. Based on the detection of identical but unusual TCR gamma rearrangements and similarity of the alpha and beta rearrangements, we propose that the S49 sublines probably had a monoclonal origin. However, significant differences between the TCR alpha and beta gene rearrangement were observed, suggesting that these sublines have undergone further differentiation at TCR loci in addition to CD4/CD8 and MHC loci. Evidence is presented that much of this phenotypic diversity preceded their in vitro selection.
Mol Immunol 1992 Nov
PMID:T cell receptor rearrangements in various S49 lymphoma sublines. 132 77

We have analyzed the control of developmental expression of the CD4 gene, which encodes an important recognition molecule and differentiation antigen on T cells. We have determined that the CD4 promoter alone functions at high levels in the CD4+ CD8- mature T cell but not at the early CD4+ CD8+ stage of T-cell development. In addition, the CD4 promoter functions only in T lymphocytes; thus, the stage and tissue specificity of the CD4 gene is mediated in part by its promoter. We have determined that a Myb transcription factor binds to the CD4 promoter and is critical for full promoter function. Thus, Myb plays an important role in the expression of T-cell-specific developmentally regulated genes.
Mol Cell Biol 1992 Apr
PMID:Expression of the CD4 gene requires a Myb transcription factor. 134 6

The streptokinase molecule (415 AA) was cleaved at methionine 237, 347 and 370 yielding four polypeptide fragments. Human HLA-class II restricted streptokinase-specific T cell clones and cell lines (CD2+, CD3+, CD4+, CD8-, TCR alpha beta+, TCR gamma delta-) recognized antigenic epitopes on all four fragments AA 1-236, AA 238-346, AA 348-369 and AA 371-415. T cell clones recognizing fragment AA 1-236 were restricted by at least two different HLA-class II elements, this indicating that more than one antigenic epitope can be recognized on this fragment. In addition, two streptokinase-specific T cell clones recognized only the intact molecule and none of the molecular fragments. These two clones probably recognized an antigenic epitope including one of the methionine residues used for molecular cleavage. We conclude that T cell proliferative responses to streptokinase are determined by recognition of at least five different antigenic epitopes distributed along the entire streptokinase polypeptide chain.
Mol Immunol 1992 Sep
PMID:At least five antigenic epitopes on the streptokinase molecule are recognized by human CD4+ TCR alpha beta+ T cells. 137 78

p56lck, a member of the src family of cytoplasmic tyrosine kinases, is expressed predominantly in T cells where it associates with the T-cell surface molecules CD4 and CD8. Mutants of CD4 and CD8 that have lost the ability to associate with p56lck no longer enhance antigen-induced T-cell activation. This suggests that p56lck plays an important role during T-cell activation. In an effort to understand the function of p56lck in T cells, a constitutively activated lck gene (F505lck) was introduced into T-helper hybridoma cell lines by retroviral infection. In four T-cell lines we examined, the activated lck protein stimulated interleukin-2 (IL-2) production, a hallmark of T-cell activation, in the absence of antigenic stimulation. In addition, a marked increase in antigen-independent IL-2 production was apparent when T cells infected with a temperature-sensitive F505lck were shifted to the permissive temperature. Only one cell line expressing F505lck exhibited increased sensitivity to antigenic stimulation. The SH3 domain of p56lck was dispensable for the induction of antigen-independent IL-2 production. In contrast, deletion of the majority of the SH2 domain of p56F505lck reduced its ability to induce spontaneous IL-2 production markedly. Activated p60c-src also induced antigen-independent IL-2 production, whereas two other tyrosine kinases, v-abl and the platelet-derived growth factor receptor, did not. Tyrosine phosphorylation of a 70-kDa cellular protein was observed after cross-linking of CD4 in T cells expressing F505lck but not in cells expressing F527src.
Mol Cell Biol 1992 Oct
PMID:Activated lck tyrosine protein kinase stimulates antigen-independent interleukin-2 production in T cells. 138 89

Guanethidine sulphate causes destruction of peripheral sympathetic neurons and infiltration of mononuclear inflammatory cells in the sympathetic ganglia of both athymic nude (rnu/rnu) and euthymic LEW/Mol rats. The effect of guanethidine is believed to be an autoimmune reaction. To determine the effect of immunosuppressive drugs concurrently with guanethidine treatment both athymic and euthymic rats were treated with guanethidine 40 mg/kg i.p. daily for 14 days, cyclophosphamide 100 mg/kg i.p. on days 1 and 8, methylprednisolone 10 mg/kg and cyclosporin A 10 mg/kg daily from days 1 to 7, and then every other day from days 8 to 14. The number of neurons in the sympathetic ganglia was counted and four subpopulations of mononuclear inflammatory cells were identified by monoclonal antibodies MHC II, CD8 T-cells/NK-cells, CD5 T-cells, CD4 T-cells/macrophages. Our results show that the immunosuppressive drugs used were unable to prevent the guanethidine-induced reduction of sympathetic neurons, although the number, of neurons following guanethidine-methylprednisolone treatment was significantly higher compared with guanethidine alone in both athymic and euthymic rats. The identification of mononuclear cells in the sympathetic ganglia showed that the CD8/NK and CD5 populations were the populations primarily responding to guanethidine treatment. Both CD8/NK and CD5 populations were absent without guanethidine, but increased significantly following guanethidine in both athymic and euthymic animals. None of the immunosuppressive drugs used could prevent the guanethidine-induced rise in the CD8/NK population in neither athymic nor in euthymic rats. The rise in the CD5 population was suppressed following treatment with all immunosuppressive drugs in athymic rats, but only following methylprednisolone in euthymic animals. These results indicate that guanethidine induces proliferation of T-cells in euthymic rats and non-functional CD5 positive pre T-cells in athymic animals. The CD5 population in both athymic and euthymic animals appears relatively more sensitive to immunosuppressive drugs than the NK-cell population also activated by guanethidine. This relatively resistant NK-cell population seems to play an important role in the guanethidine-induced destruction of sympathetic neurons and can explain why the guanethidine-induced immunological reaction could not be fully prevented by the immunosuppressive drugs used. The conclusion is that guanethidine induces destruction of sympathetic neurons by a NK-cell-mediated reaction.
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PMID:Effect of immunosuppressive agents on the guanethidine-induced sympathectomy in athymic and euthymic rats. 138 39

During T cell development in the mammalian thymus, immature T cells are observed that lack the cell surface markers CD4, CD8, and CD3. A subtracted cDNA library was constructed to isolate cDNAs that are specific for these immature T cells. Tissue-specific expression of 97 individual cDNAs were examined using different cell types by Northern blot analysis, and six cDNAs were analyzed by reverse transcriptase (RT) polymerase chain reaction (PCR) detection of RNA. Approximately 50% of the clones could not be detected on Northern blots, and 40% of the clones were expressed by at least one other cell-type including monocytes, mature T cells, and B cells. Eight cDNA clones appear to be specific for the CD4-, CD8-, CD3- T cell line, used to construct the library, as determined by Northern blot analysis. In addition, 330 cDNA clones were subjected to partial automated DNA sequence determination. Database searches, with both nucleotide and protein translations, revealed cDNAs that exhibit interesting similarities to human cell-cycle gene 1, platelet-derived growth factor receptor, c-fms oncogene (CSF-1) receptor, and members of the immunoglobulin gene superfamily. This approach of employing subtraction coupled with large scale partial cDNA sequence determination can be useful to identify genes that may be involved in early T cell growth, cellular recognition or differentiation.
Mol Biol Cell 1992 Jul
PMID:A new approach to understanding T cell development: the isolation and characterization of immature CD4-, CD8-, CD3- T cell cDNAs by subtraction cloning. 138 65

The CD4 and CD8 antigens on T cells have been shown to associate with the Src family member p56lck and a GTP-binding protein, p32. The identification of receptor interactions with intracellular mediators is essential in the elucidation of downstream signals mediated by engagement of these receptor complexes. In this study, we report the detection of an additional 110-kDa polypeptide (p110) associated with the CD4-p56lck complex in human peripheral blood T lymphocytes and leukemic T-cell lines. p110 bound preferentially to CD4-p56lck as an assembled complex and poorly, if at all, to the individual components. p110 was recognized directly by an antiserum to the C-terminal region of the serine/threonine kinase Raf-1 and is related to a p110 polypeptide detected in anti-Raf-1 immunoprecipitates. Despite its association with the CD4-p56lck complex, p110 was found to be phosphorylated predominantly on serine residues. Furthermore, phorbol ester treatment of cells resulted in a transient increase in the detection of p110 associated with CD4-p56lck, concomitant with the modulation of CD4-p56lck from the cell surface. This Raf-1-related p110 is therefore likely to play a role in signals generated from the CD4-p56lck complex. p110 may serve as a bridge between the CD4-p56lck complex and the serine/threonine kinase pathways of T-cell activation.
Mol Cell Biol 1992 Nov
PMID:A Raf-1-related p110 polypeptide associates with the CD4-p56lck complex in T cells. 140 95

It is well known that oxazaphosphorines [e.g., cyclophosphamide and 4-hydroperoxycyclophosphamide (mafosfamide)] are potent immunosuppressive agents. Under the proper conditions, they can potentiate immune responses as well. Immunomodulation represents a major breakthrough in the management of chemotherapy-resistant tumors. Thus, we evaluated the clinical and laboratory sequelae of low to intermediate doses (100-1000 mg/m2) of mafosfamide administered to 16 patients. Four weeks after therapy, one patient had a complete remission, eight patients presented with stable disease, and seven patients did not respond. Clinical and laboratory toxicity was mild and totally reversible, and therapy was well tolerated in all patients. Analyses of phenotypic cell surface antigens on circulating peripheral blood mononuclear cells showed inconsistent alterations of the CD4/CD8 ratio, initial depletion with later rebound of CD8+ cells, increase of CD20+ cells, and a mafosfamide dose-dependent regulation of natural killer-like cells as characterized by CD16 and CD56 positivity. Cell-mediated cytotoxicity against K562 target cells peaked 1 day after therapy and was most pronounced in patients who had received 300 mg/m2 mafosfamide, whereas cytotoxicity against Daudi targets was essentially unchanged, consistent with an increase in natural killing activity without augmentation of lymphokine activated killing. We conclude that mafosfamide administration at low to intermediate doses can be performed with good safety and tolerance; immunophenotypic analyses and cytotoxicity assays showed most pronounced alterations in patients receiving low doses of mafosfamide. These observations support the use of mafosfamide in the attempt to augment antitumor immune responses.
Mol Biother 1992 Jun
PMID:Biologic and therapeutic efficacy of mafosfamide in patients with metastatic renal cell carcinoma. 151 95

The TcR-alpha chain is the last subunit of the TcR/CD3 complex to be expressed during thymic ontogeny. Since the presence of all subunits are required for efficient expression of this complex on the cell surface, this has lead to the hypothesis that the TcR-alpha chain is the limiting subunit which controls cell surface TcR/CD3 expression during thymocyte differentiation. We have examined this issue using a T-lymphoma cell clone, RS4.2, which has a CD4- CD8- Thyl+ J11d+ IL2R+ phenotype, identical with immature thymocytes which have the capacity to generate all major T cell subsets. The RS4.2 cell clone accumulates abundant amounts of TcR-beta, CD3-gamma, -delta, -epsilon and -zeta transcripts, but expresses trace levels of TcR-alpha transcripts and cell surface TcR/CD3. TcR-alpha mRNA levels can be dramatically augmented in RS4.2 cells by three distinct mechanisms: in response to treatment with either phorbol myristate acetate (PMA), calcium ionophore (A23187), or cycloheximide (CHX). However, the expression of TcR/CD3 on the cell surface fails to be increased by any of these agents. In fact, PMA induces a rapid down-regulation of cell surface TcR/CD3 expression. In contrast, these agents trigger an increase in cell surface IL2R expression which coincides with augmented IL2R-alpha mRNA levels. Thus, in RS4.2 cells, IL2R surface expression is controlled by transcript levels, while TcR/CD3 surface expression is regulated by post-transcriptional events, independent of TcR-alpha mRNA accumulation.
Mol Immunol 1992 Apr
PMID:TcR-alpha mRNA accumulation does not dictate cell surface TcR/CD3 expression. 153 11


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