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)

Crosslinking of the CD4 coreceptor can inhibit subsequent T-cell activation via the T-cell antigen receptor (TCR)/CD3 complex. The ability of the human immunodeficiency virus (HIV) envelope protein, gp 120, to cause similar inhibition has implicated this inhibitory signal in the induction of T-cell anergy and apoptosis observed in the acquired immunodeficiency syndrome (AIDS). In order to clarify the biochemical basis of this inhibition, we analyzed the effect of CD4 ligation on early signaling events induced by subsequent CD3xCD4 co-crosslinking. By comparison with CD3 crosslinking alone, CD3xCD4 co-crosslinking of a CD3+CD4+ human T-cell leukemia line (SupT1) resulted in an enhanced increase in free intracellular calcium concentration and tyrosine phosphorylation of several cellular substrates, including the prominent phosphorylation of an unidentified 120-kDa protein (p120). Prior CD4 ligation inhibited these responses. Similar results were obtained with A3.01, another CD3+CD4+ T leukemic line. However, P120 was only minor phosphorylated on tyrosine upon receptor crosslinking in A2.01/CD4(-cyt401), a derivative line expressing a truncated CD4 coreceptor lacking its cytoplasmic domain which binds the p56lck protein tyrosine kinase (PTK). Furthermore, prior CD4 ligation failed to inhibit in this line the increased tyrosine phosphorylation induced by subsequent CD3xCD4 co-crosslinking. Thus, prior CD4 crosslinking, or expression of truncated CD4, are both associated with reduced p120 phosphorylation. These results suggest that p120 is a p56lck substrate playing an important role during T-cell activation.
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PMID:The role of p56lck in CD4-mediated suppression of CD3-induced early signaling events in T lymphocytes. 861 46

Engagement of the T cell antigen receptor results in both its phosphorylation and its ubiquitination. T cell antigen receptor ubiquitination was evaluated in Jurkat, a well characterized human T leukemia cell line. Treatment of cells with the tyrosine kinase inhibitor herbimycin A resulted in an inhibition of receptor ubiquitination. Consistent with this, pervanadate, which increases cellular tyrosine phosphorylation, enhanced receptor ubiquitination. A requirement for receptor-mediated tyrosine kinase activity for ubiquitination was confirmed in cells lacking the tyrosine kinase p56lck and also in cells that are defective in expression of CD45, a tyrosine phosphatase that regulates the activity of p56lck. The need for tyrosine kinase activation for ubiquitination was not bypassed by directly activating protein kinase C and stimulating endocytosis of receptors. These observations establish ubiquitination of the T cell antigen receptor as a tyrosine kinase-dependent manifestation of transmembrane signaling and suggest a role for tyrosine phosphorylation in the ligand-dependent ubiquitination of mammalian transmembrane receptors.
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PMID:T cell antigen receptor ubiquitination is a consequence of receptor-mediated tyrosine kinase activation. 862 3

CD28/B7 interactions have been demonstrated to provide a co-stimulatory signal for the generation of CD8+ cytotoxic T lymphocytes in the absence of CD4+ T helper cells. The CD28 signals required for induction of cytotoxicity have yet to be described. To investigate further the biochemical signaling pathways associated with CD28-dependent cytotoxicity, we have studied the human thymic leukemia cell line, YT. YT cells kill B7+ targets in a non-major histocompatibility complex (MHC)-restricted, CD28-dependent manner. CD28 ligation on the surface of YT cells caused a rapid increase in the tyrosine phosphorylation of four major cellular substrates with masses estimated to be 110, 95, 85, and 44 kDa. The 110 and 85 kDa substrates were identified as the catalytic and regulatory subunits, respectively, of phosphatidylinositol 3-kinase (PI3-K). Engagement of CD28 caused the rapid receptor association and activation of PI3-K but did not activate phospholipase C gamma. CD28-induced tyrosine phosphorylation and PI3-K activation was independent of p56lck protein tyrosine kinase (PTK) activity (previously reported to be associated with CD28) and was insensitive to inhibition by the PTK inhibitor herbimycin A. Two structurally and mechanistically dissimilar inhibitors of PI3-K, wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) also failed to block CD28-dependent tyrosine phosphorylation events or the association of PI3-K with the CD28 receptor. However, both drugs inhibited CD28-dependent cytotoxicity and CD28 receptor associated PI3-K activity with IC50 values similar to the reported IC50 values for PI3-K inhibition. Although herbimycin A did not significantly block the observed CD28-dependent tyrosine phosphorylation or PI3-K activation, herbimycin did block CD28-dependent cytotoxicity in a dose-dependent manner. These data support a role for PI3-K activation in the CD28-dependent initiation of cytotoxic effector function and suggest that a herbimycin sensitive step(s) is either CD28-independent, resides within a PI3-K-independent CD28 signaling pathway, or is downstream of CD28-dependent PI3-K activation.
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PMID:CD28-dependent killing by human YT cells requires phosphatidylinositol 3-kinase activation. 864 5

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL). The virus-encoded p40tax-1, a nuclear oncoprotein, is known to promote transcription of its own as well as a variety of cellular genes. However, the mechanism by which p40tax-1 promotes lymphocyte transformation is not fully understood. In the present study, we examined whether p40tax-1 can induce hematopoietic cell proliferation by cooperating with the products of cellular proto-oncogenes; i.e. an activated form of the src-family protein tyrosine kinase p56lck (lck F505), c-Myc or Bcl-2. These oncoproteins are critical mediators of interleukin 2 (IL-2)-induced proliferative signals. We show that p40tax-1 alone cannot render the hematopoietic cell line, BAF-B03, able to proliferate in the absence of cytokines, but it can do so in cooperation with lckF505, or c-Myc but not with Bcl-2.
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PMID:Selective cooperation of HTLV-1-encoded p40tax-1 with cellular oncoproteins in the induction of hematopoietic cell proliferation. 864 81

The oncogene product from the avian reticuloendotheliosis virus strain T, v-Rel, is a member of the Rel/ NF-kappa B family of transcription factors. The mechanism by which v-Rel induces oncogenic transformation remains unclear. Several attempts to transform mammalian cells with v-Rel have failed, suggesting that v-Rel transformation may be a species-specific event. However, here we demonstrate that v-Rel, but not a truncated c-Rel, expressed under the control of the lck promoter, efficiently induced malignancies in transgenic mice. Most of the animals died before 10 months of age and developed immature, multicentric aggressive T-cell leukemia/lymphomas. Most tumors contain CD4+CD8+ cells or CD4-CD8+ cells, which have an immature rather than a mature peripheral phenotype. No tumor development was observed in control littermates and transgenic mice expressing a truncated form of c-Rel. Tumor formation was correlated with the presence of constitutive p50/v-Rel DNA binding activity and overexpression of several kappa B-regulated genes in v-rel transgenic thymocytes. However, v-Rel is also transforming in transgenic thymocytes lacking p50, indicating that p50/v-Rel heterodimer formation is not essential for the transforming activity of v-Rel. The transforming activity of v-Rel in p50 null mice has been identified as v-Rel/v-Rel homodimers. Since tumors represent immature T-lymphocytes, constitutive v-Rel expression appears to be leukemogenic at earlier stages of T-cell development. These v-Rel mice should aid in the study of lymphoma development, T-cell development and NF-kappa B regulation.
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PMID:The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice. 867 Aug 67

Previous studies have demonstrated that the active metabolite of leflunomide, A77 1726 [N-(4-trifluoromethylphenyl-2-cyano-3-hydroxycrotoamide)], is capable of inhibiting the activities of tyrosine kinases and dihydroorotate dehydrogenase (DHO-DHase). In the present study, we define the relative contribution of these activities to the ability of A77 1726 to inhibit proliferation of the murine leukemia cell line LSTRA. A77 1726 inhibited LSTRA cell growth and proliferation (IC50 = 10-30 microM); this inhibition, however, could be reversed by the addition of exogenous uridine, suggesting that the anti-proliferative activity of A77 1726 may be due to inhibition of de novo pyrimidine nucleotide synthesis. Quantitation of nucleotide levels revealed that A77 1726, at an IC50 of about 10 microM, selectively inhibited pyrimidine nucleotide but not purine nucleotide synthesis. In vitro enzyme assays confirmed that A77 1726 directly inhibited the activity of DHO-DHase, the fourth enzyme in the de novo pathway of pyrimidine nucleotide synthesis (IC50 = 220 nM). LSTRA cells overexpress p56lck and have elevated levels of tyrosine phosphorylated intracellular proteins. A77 1726 reduced the intracellular levels of tyrosine phosphorylated proteins with relatively high IC50 values ranging from 50 to 100 microM. A77 1726 also inhibited p56lck activity in LSTRA membrane preparation and immunoprecipitates; the IC50 values for inhibition of immunoprecipitated p56lck autophosphorylation and exogenous substrate histone 2B were 80 and 40 microM, respectively. The anti-tyrosine phosphorylation activity of A77 1726 was not affected by uridine. These studies therefore demonstrate the two activities of A77 1726: inhibition of pyrimidine nucleotide synthesis and interference with tyrosine phosphorylation.
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PMID:Two activities of the immunosuppressive metabolite of leflunomide, A77 1726. Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation. 875 24

To understand the mechanism of p56lck protein downregulation observed in human T cells infected by human T-cell leukemia virus type 1 (HTLV-1), we have investigated the ability of the 3' end of the HTLV-1 genome as well as that of the tax and rex genes to modulate p56lck protein expression and p56lck mRNA synthesis. By using Jurkat T cells stably transfected with constructs that expressed either the 3' end of the HTLV-1 genome (JK C11-pMTEX), the tax gene (JK52-Tax) or the rex gene (JK9-Rex), we found that the expression of p40tax (Tax) was sufficient to modulate p56lck protein expression. Similarly, we found that the expression of the mRNA which encoded p56lck was repressed in Jurkat T cells which expressed Tax. This downregulation was shown to be proportional to the amount of tax mRNA found in the transfected cells, as evidenced by experiments that used cells (JPX-9) stably transfected with a tax gene driven by a cadmium-inducible promoter. Furthermore, cadmium induction of Tax in JPX-9 cells transiently transfected with a construct containing the chloramphenicol acetyltransferase (CAT) gene under control of the lck distal promoter (lck DP-CAT) resulted in the downregulation of CAT gene expression. In contrast, cadmium induction of Tax in JPX-9 cells transiently transfected with a CAT construct driven by a lck DP with a deletion extending from position -259 to -253 (a sequence corresponding to a putative E-Box) did not modulate CAT gene expression, suggesting that the effect of Tax on p56lck is mediated through an E-Box binding protein.
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PMID:Transrepression of lck gene expression by human T-cell leukemia virus type 1-encoded p40tax. 903 29

The lymphoid-specific protein tyrosine kinase, p56lck which is essential for both T cell development and function, is aberrantly expressed in colon and small lung carcinoma lines. In this paper, we demonstrate p56lck is also expressed in colon tumour biopsies due predominantly or exclusively to the use of the lck type I promoter. In T leukaemia lines, the lck type I promoter requires binding sites for both Ets- and Myb-related transcription factors. In contrast, in colon tumour lines the activation of the lck type I promoter requires the Ets but not the Myb binding site. In these lines, a consensus binding site for HMG-related transcription factors, AACAAAG, is required for efficient lck type I promoter activity. Sox-4 is a candidate transcription factor for binding and activating the lck type l promoter in colon carcinoma cells. Co-expression of Ets-1 and Sox-4, but neither protein alone, was sufficient to activate the lck type l promoter in HeLa cells which do not normally express lck transcripts. These results suggest that aberrant expression of p56lck from the lck type l promoter in colon carcinoma arises from transcriptional activation mediated by Ets- and HMG-related transcription factors.
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PMID:An alternative pathway for expression of p56lck from type I promoter transcripts in colon carcinoma. 941 36

The TCL1 oncogene on human chromosome 14q32.1 is involved in the development of T cell leukemia in humans. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. The TCL1 oncogene is activated in these leukemias by juxtaposition to the alpha or beta locus of the T cell receptor, caused by chromosomal translocations t(14:14)(q11:q32), t(7:14)(q35:q32), or by inversions inv(14)(q11:q32). To show that transcriptional alteration of TCL1 is causally involved in the generation of T cell neoplasia we have generated transgenic mice that carry the TCL1 gene under the transcriptional control of the p56(lck) promoter element. The lck-TCL1 transgenic mice developed mature T cell leukemias after a long latency period. Younger mice presented preleukemic T cell expansions expressing TCL1, and leukemias developed only at an older age. The phenotype of the murine leukemias is CD4-CD8+, in contrast to human leukemias, which are predominantly CD4+CD8-. These studies demonstrate that transcriptional activation of the TCL1 protooncogene can cause malignant transformation of T lymphocytes, indicating the role of TCL1 in the initiation of malignant transformation in T prolymphocytic leukemias and T chronic lymphocytic leukemias.
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PMID:Deregulated expression of TCL1 causes T cell leukemia in mice. 952 Apr 62

In myeloid malignancies, T-cell and NK function has been shown to deteriorate with transformation from pre-leukaemia to advanced disease. Immune dysfunction in solid tumours has been attributed to abnormal signal transduction, possibly through altered expression of intracellular components of the TCR/CD3 complex (e.g. CD3-zeta), receptors on NK cells and their associated protein tyrosine kinases (PTKs; p56lck, p59fyn and ZAP-70). Using a flow cytometric method to detect dual-expression of surface proteins and intracellular components of the TCR/CD3 complex, we have studied 46 patients with myeloid malignancies. CD3-zeta expression was abnormal in 64% of patients, and was more prominent in those with advanced disease. Three patients with reduced CD3-zeta were analysed both pre- and post-treatment, and recovery of CD3-zeta expression was associated with successful remission induction (expression of PTKs was variable and reduced levels were seen all disease stages). The results of this study suggest that loss of signalling proteins is not a result of direct contact of leukaemic cells with lymphocytes per se or the extent of the leukaemia burden, but to a specific property of some myeloid malignancies, which is more frequently acquired with greater malignant transformation.
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PMID:Variable expression of CD3-zeta and associated protein tyrosine kinases in lymphocytes from patients with myeloid malignancies. 953 50


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