Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p56lck is a new member of the src family of cellular tyrosine protein kinases. It is expressed constitutively at a low level in normal T cells and at an elevated level in the LSTRA and Thy19 Moloney murine leukemia virus-induced thymoma cell lines. It is possible that the expression of p56lck at an elevated level contributes to the transformation of these thymoma cells. The structure of the mRNAs encoding p56lck was examined by using an RNase protection assay. Both a chimeric lck mRNA containing the 5' untranslated region of Moloney virus mRNA and a normal lck mRNA were found in Thy19 and LSTRA cells. The chimeric lck transcript was 4- to 10-fold more abundant than the normal transcript. Transcription arising from a viral promoter is therefore responsible for the elevated levels of lck mRNA in these two cell lines. Surprisingly, uninfected murine T cells were also found to contain lck transcripts with differing 5' untranslated regions. One species of mRNA was colinear with the region of the chromosome just upstream of the initiation codon for p56lck. The other appeared to arise through splicing of an unidentified 5' untranslated exon to a sometimes cryptic splice acceptor just upstream of the region encoding p56lck. These data suggest that lck is expressed through the use of at least two different promoters. The promoters could be subject to different forms of regulation.
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PMID:Two lck transcripts containing different 5' untranslated regions are present in T cells. 350 24

T cell activation via CD3/Ti linked pathways results in the polymerization and reorganization of actin. However, little is known about the morphology and temporal appearance of filamentous actin (F-actin) after activation. Similarly, little is known about the relationship between F-actin and changes in cell shape or other parameters of activation, such as the appearance of proteins newly phosphorylated on tyrosine, that occur after stimulation via the CD3/Ti complex. Accordingly, we have characterized changes in cell shape and F-actin morphology occurring in the Jurkat T cell leukemia attached to the surface of culture vessels by immobilized anti-CD3 antibodies (OKT3, UCHT-1, SPV-T3b). These antibodies induced activation within 30 min as measured by increased protein tyrosine kinase activity and conversion of the proto-oncogene product, lck, from 56 kDa to 60 kDa (p56lck conversion), and after 12 to 96 h as measured by growth arrest and, in some experiments, IL-2 production. Activation was not seen when cells were attached to the substrates using antibodies directed to other cell surface proteins including CD71 (transferrin receptor), CD7, and CD11a (LFA-1), demonstrating the specificity of activation for immobilized anti-CD3 antibodies. Temporal changes in cell shape and F-actin morphology were characterized in Jurkat cells attached by immobilized anti-CD3 antibodies (stimulatory antibodies) and compared with the patterns obtained obtained in Jurkat cells attached by antibodies specific for the other markers (nonstimulatory antibodies). In these experiments, Jurkat cells were incubated with antibody-coated substrates for 1 to 30 min at 37 degrees C and actin rearrangements were visualized on fixed, detergent-permeabilized cells using rhodamine-conjugated phalloidin. Analysis of cell shape and F-actin morphology during the first 30 min of activation revealed a unique pattern that was observed only when cells were stimulated with anti-CD3 antibodies. Jurkat cells attached by either stimulatory or nonstimulatory antibodies reorganized their actin similarly after the first minute of culture, as characterized by the formation of small, F-actin rich pseudopods at the sites of attachment. After 5 min of culture in cells attached by stimulatory antibodies, the actin was polymerized into a dense collar rimming the inner edge of the cell. From 15 to 60 min, this collar was replaced by numerous F-actin rich, branched pseudopods. These branched pseudopods were larger and had longer microfilament bundles than their earlier counterparts. By contrast, in cells attached by nonstimulatory antibodies, the initial configuration was maintained for at least 60 min, except that a decrease in microfilament bundle length was noted.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Actin polymerization and pseudopod reorganization accompany anti-CD3-induced growth arrest in Jurkat T cells. 768 89

Human T-cell leukemia virus type I (HTLV-I) gives rise to a neurologic disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the pathogenesis of the disease is unknown, the presence of a remarkably high frequency of Tax-specific, cytotoxic CD8 T cells may suggest a role of these cells in the development of HAM/TSP. Antigen-mediated signaling in a CD8 T-cell clone specific for the Tax(11-19) peptide of HTLV-I was studied using analog peptides substituted in their T-cell receptor contact residues defined by x-ray crystallographic data of the Tax(11-19) peptide in the groove of HLA-A2. CD8 T-cell stimulation with the wild-type peptide antigen led to activation of p56lck kinase activity, interleukin 2 secretion, cytotoxicity, and clonal expansion. A Tax analog peptide with an alanine substitution of the T-cell receptor contact residue tyrosine-15 induced T-cell-mediated cytolysis without activation of interleukin 2 secretion or proliferation. Induction of p56lck kinase activity correlated with T-cell-mediated cytotoxicity, whereas interleukin 2 secretion correlated with [3H]thymidine incorporation and proliferation. Moreover, Tax peptide analogs that activated the tyrosine kinase activity of p56lck could induce unresponsiveness to secondary stimulation with the wild-type peptide. These observations show that a single amino acid substitution in a T-cell receptor contact residue of Tax can differentially signal CD8 T cells and further demonstrate that primary activation has functional consequences for the secondary response of at least some Tax-specific CD8 T cells to HTLV-I-infected target cells.
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PMID:Differential activation of proliferation and cytotoxicity in human T-cell lymphotropic virus type I Tax-specific CD8 T cells by an altered peptide ligand. 773 26

The expression of CD45 RA/RO antigen was investigated in neoplasms including cases expressing CD7 antigen as the sole pan-T antigen (n = 8), T-lineage acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) at various stages of differentiation (n = 32), peripheral stage T-lineage leukemia (n = 10) and adult T-cell leukemia (ATL) (n = 14). The p56lck gene expression was also investigated in selected cases. The expression pattern of CD45 RA/RO antigen was defined as of RA, mixed, or RO type. All but one CD7+ CD5- CD2- case were of the RA type. The CD7+ CD5+ CD2- prothymic stage included seven RA and one mixed type cases. One CD7+ CD5- CD2+ case was of the RA type, but the other was of the RO type. The CD7+ CD5+ CD2+ prothymic stage included three RA and four mixed type cases. All seven CD3- CD4+ CD8+ (double-positive) thymic cases were of the RO type. The CD3+ CD4+ CD8+ (triple-positive) stage included two RO and three mixed-type cases. One CD3+ CD4+ CD8- late thymic case was of the mixed type. The peripheral stage cases included five RA, three RO, and two mixed type cases. All ATL cases were of the RO type. The expression of p56lck gene in the prothymic stage was less marked than that in the thymic stage. On the basis of these results, the following sequence of pattern of the CD45 RA/RO antigen expression along with T-lineage differentiation was reconstructed: prothymic stage [RA and mixed type]-->double-positive thymic stage [RO type]-->triple-positive thymic stage [RO and mixed type]-->peripheral stage [RA, mixed, and RO type]. While one RO-type CD7+ CD5- CD2- and one RO-type CD7+ CD5- CD2+ cases were not in accord with this sequence, the pattern of CD45 RA/RO antigen expression in most of T-lineage neoplasms could be determined by the respective stage of differentiation. The poor expression of the p56lck gene by the prothymic blasts compared with the thymic blasts may be related to the expression pattern of the CD45 RA/RO molecules, which exhibits phosphatase activity. The consistent RO-type expression in the ATL cases may reflect the activated status of the neoplastic T cells due to the presence of the HTLV-I gene. Alternatively, the target cells for HTLV-I-induced neoplastic transformation may possible be of the RO type.
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PMID:Expression pattern of CD45 RA/RO isoformic antigens in T-lineage neoplasms. 774 Nov 40

The lck gene, which encodes a lymphoid-specific Src family tyrosine kinase, is transcribed from two promoters that are differentially utilized during T cell development. We have shown previously that the human lck type I promoter, which is preferentially expressed in immature thymocytes, requires a binding site (-97 to -90) for the Ets family of transcription factors for its activity in Jurkat T leukemia cells. Three putative Myb binding sites (-86 to -82, -77 to -72 and -59 to -54) were analysed for their ability to activate the lck type I promoter. In vitro assays demonstrated specific binding of purified, bacterially expressed c-Myb DNA binding domain to the Myb (-59 to -54) site. Transient transfection assays using the site-directed mutants of the lck type I promoter in Jurkat cells revealed that mutation of the Myb (-59 to -54) site abolished transcriptional activity. In transiently transfected HeLa cells, the lck type I promoter was activated by co-transfection with a vector that expresses c-Myb. This c-Myb dependent activation required the presence of intact Myb and Ets binding sites, indicating that the expressed c-Myb functions with endogenous Ets related transcription factors to activate the lck type I promoter. This effect was further enhanced by co-transfection with vectors that express either Ets1 or Ets2. These results demonstrate that Myb and Ets related transcription factors synergistically activate the human lck type I promoter.
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PMID:Myb and Ets related transcription factors are required for activity of the human lck type I promoter. 797 Jul 21

The T cell protein tyrosine kinase p56lck is implicated in thymic development and mitogenic activation of T lymphocytes, and is itself regulated by reversible tyrosine phosphorylation. When phenylarsine oxide (PAO), a membrane-permeable inhibitor of phosphotyrosine phosphatases, was added to Jurkat T leukemia or LSTRA thymoma cells, the phosphate content of p56lck increased rapidly. The sites of increased phosphorylation were mapped to Tyr-192, Tyr-394 and Tyr-505. Hyperphosphorylated p56lck displayed retarded mobility on SDS gels, unaltered or marginally increased cytoskeletal association, and its catalytic activity changed in a biphasic manner; during the first 10-20 min of PAO-treatment the activity increased and then it declined to very low values within 1-2 hr. Our data suggest that p56lck contains both positive and negative regulatory sites which are constantly dephosphorylated at an unexpectedly high rate by cellular phosphotyrosine phosphatases.
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PMID:Induction of hyperphosphorylation and activation of the p56lck protein tyrosine kinase by phenylarsine oxide, a phosphotyrosine phosphatase inhibitor. 799 41

Activation of resting T lymphocytes by ligands to the T cell receptor (TcR)/CD3 complex is initiated by phosphorylation of a number of key regulatory proteins on specific tyrosine residues. One such protein is the heterodimeric enzyme phosphatidylinositol-3-kinase (PI3K). We recently found that this enzyme is also rapidly activated following TcR/CD3 triggering and that immunoprecipitated PI3K was activated in vitro by direct tyrosine phosphorylation. Here we show that TcR/CD3-induced tyrosine phosphorylation and activation of PI3K in Jurkat T leukemia cells depend on the presence of the p56lck tyrosine kinase: in a variant of the Jurkat T cell line lacking p56lck, JCaM1, these responses were absent. We also show that p56lck directly activates PI3K purified from transfected COS-1 cells, indicating that other T cell-specific proteins are not required for the process. Finally, tryptic peptide maps show that p56lck phosphorylates three tyrosine residues in the p85 alpha subunit of PI3K and two in p110 of PI3K. Our results suggest that p56lck is required for activation of PI3K in Jurkat T cells and can itself directly activate it by phosphorylating one or several stimulatory sites.
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PMID:Activation of phosphatidylinositol-3-kinase in Jurkat T cells depends on the presence of the p56lck tyrosine kinase. 802 May 61

A newly isolated T-cell line (CB1) derived from a T-acute lymphoblastic leukaemia (T-ALL) patient contained cells (40% of total) which did not express the CD45 phosphotyrosine phosphatase. The cells were sorted into CD45- and CD45+ populations and shown to be clonal in origin. T-cell receptor (TCR) cross-linking or coligation of the TCR with its CD4/CD8 co-receptors induced tyrosine phosphorylation and calcium signals in CD45+ but not in CD45- cells. Unexpectedly, whole cell p56lck and p59fyn tyrosine kinase activities were not reduced in CD45- compared to CD45+ cells. A novel technique was therefore developed to isolated specific pools of aggregated receptors expressed at the cell surface, together with their associated tyrosine kinases. Using this technique it was shown that cell surface CD4-p56lck kinase activity was 78% lower in CD45- than in CD45+ cells. Phosphorylation of TCR zeta- and gamma-chains occurred in TCR immunocomplexes from CD45+ but not CD45- cells, despite comparable levels of p59fyn and TCR proteins. Furthermore, TCR-associated tyrosine kinase activity towards an exogenous substrate was 84% lower in CD45- than in CD45+ cells. Addition of recombinant p59fyn to TCR immunocomplexes isolated from CD45-cells restored the phosphorylation of the TCR zeta- and gamma-chains. Our results demonstrate that CD45 selectively regulates the pools of p59fyn and p56lck kinases which are associated with the TCR and CD4 at the cell surface. Activation by CD45 of these receptor-associated kinase pools correlates with the ability of the TCR and its coreceptors to couple to intracellular signalling pathways.
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PMID:The CD45 tyrosine phosphatase regulates specific pools of antigen receptor-associated p59fyn and CD4-associated p56lck tyrosine in human T-cells. 816 90

We have analysed DNA and RNA from 36 T-cell lymphomas induced in Fischer rats by Moloney murine leukemia virus for alterations affecting the structure or expression of the lck gene. At least five primary tumors (14%) have a proviral insertion upstream of lck. In at least four of the tumors, proviral insertion increases lck mRNA levels an average of eight-fold. Overexpression of lck results from transcription initiating in the viral promoter and extending into lck sequences. Three different structures of hybrid transcript were detected. In all three, the hybrid RNAs are spliced to a normal lck splice acceptor in the first exon of lck, resulting in removal of three out of frame ATG codons which would be expected to increase the translation efficiency of the hybrid message. In one tumor, the viral splice donor is used, in one tumor, proviral insertion generates a splice donor sequence one base pair downstream of the long terminal repeat boundary, and in two tumors, a cryptic splice donor in the upstream lck sequences is used. The significance of these unusual splicing patterns and of the higher frequency of proviral insertions adjacent to lck in rats relative to mice is discussed.
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PMID:Frequent activation of the lck gene by promoter insertion and aberrant splicing in murine leukemia virus-induced rat lymphomas. 842 92

Screening by Northern blot for lck expression in 51 patients with diverse hematologic diseases has shown, for four of them, a 3 to 15-fold increase in the level of lck mRNA when compared with expression in healthy donors. These patients suffered from diverse malignancies: one Burkitt lymphoma, one T-cell lymphoma and two non-Hodgkin B-cell lymphoma. Specific analysis of the different lck transcripts in these patients by polymerase chain reaction and their relative quantitation demonstrate a significant increase of only the type IB and the type IC lck transcripts arising from the proximal promotor. Our study shows: (a) a high lck expression may occur in diverse hematologic diseases, (b) whatever the type of malignancy, this high expression results in a specific increase of the spliced transcripts arising only from the proximal promotor, and (c) in these four patients without any rearrangement or amplification, the high lck expression probably results from the specific activation of the proximal promotor.
Leukemia 1993 Feb
PMID:Selective increase of alternatively spliced Lck transcripts from the proximal promotor in hematopoietic malignancies. 842 78


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