Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cells of autoimmune-prone mice homozygous for the lpr mutation respond poorly to mitogens in terms of proliferation and of IL-2 production. In a previous study, we have correlated this deficient activation with the inability of mitogens to stimulate hydrolysis of phosphatidylinositol 4,5-bisphosphate in lpr T cells, although these cells bind mitogen and express the TCR/CD3 complex. In order to determine whether activation-deficient lpr T cells contain functional GTP-binding (G) protein(s) and phospholipase C, we examined the effects of the G protein activating agent sodium fluoride plus Al+3 (AlF-4). AlF-4 stimulated phosphatidylinositol turnover, a response characteristic of TCR/CD3 occupancy, in mature L3T4+ and Ly2+ T cells. Second, and more important, AlF-4 stimulated the same biochemical events in L3T4-, Ly2- (double-negative) T cells from the normal thymus or from the enlarged lymph nodes of autoimmune-prone mice homozygous for the lpr mutation. However, these double-negative T cells were unresponsive to receptor-active ligands such as T cell mitogens or anti-CD3-epsilon mAb, despite their ability to bind these ligands. These findings suggest that activation-deficient double negative T cells express the receptors, G protein(s) and effector enzymes necessary for second messenger formation and further suggest that the failure of these cells to generate the relevant second messengers in response to mitogens or anti-CD3-epsilon antibody may be due to inefficient coupling of the TCR/CD3 complex to G proteins.
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PMID:Stimulation of PIP2 hydrolysis by aluminum fluoride in resting T cell subsets of normal and autoimmune-prone lpr mice. 254 77

The proliferative capacity of T cells infiltrating human tumors is known to be impaired, possibly through their interaction with tumor. Here we demonstrate that soluble products derived from renal cell carcinoma (RCC-S) explants but not normal kidney can inhibit an IL-2-dependent signaling pathway that is critical to T cell proliferation. A major target of the immunosuppression was the IL-2R-associated protein tyrosine kinase, Janus kinase 3 (Jak3). RCC-S suppressed basal expression of Jak3 and its increase following stimulation with anti-CD3/IL-2. Jak3 was most sensitive to suppression by RCC-S; however, reduction in expression of p56(lck), p59(fyn), and ZAP-70 was observed in some experiments. Expression of other signaling elements linked to the IL-2R (Jak1) and the TCR (TCR-zeta, CD3-epsilon, and phospholipase C-gamma) were minimally affected. In naive T cells, RCC-S also partially blocked induction of IL-2R alpha-, beta- and gamma-chain expression when stimulating via the TCR/CD3 complex with anti-CD3 Ab. To determine whether RCC-S suppressed IL-2-dependent signaling, primed T cells were employed since RCC-S had no effect on IL-2R expression but did down-regulate Jak3 expression and, to a lesser degree, p56(lck) and p59(fyn). Reduction in Jak3 correlated with impaired IL-2-dependent proliferation and signal transduction. This included loss of Jak1 kinase tyrosine phosphorylation and no induction of the proto-oncogene, c-Myc. These findings suggest that soluble products from tumors may suppress T cell proliferation through a mechanism that involves down-regulation of Jak3 expression and inhibition of IL-2-dependent signaling pathways.
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PMID:Tumor-induced suppression of T lymphocyte proliferation coincides with inhibition of Jak3 expression and IL-2 receptor signaling: role of soluble products from human renal cell carcinomas. 930 Jul 31

Tumor-associated lymphocytes (TALs) freshly isolated from patients with cancer usually manifest reduced proliferative and cytolytic functions. To determine whether alterations in signal transduction contribute to functional impairments seen in TALs, we purified populations of T and natural killer (NK) cells by negative selection from ascites of seven patients with ovarian carcinoma. The average purity was 84 +/- 5% for CD3(+) TALs and 77 +/- 10% for CD3(-)CD56(+)CD16(+) TALs. Expression of several signal transduction molecules, including the CD3-epsilon, CD3-zeta, and FcepsilonRI-gamma chains, p56(lck) protein tyrosine kinase, and phospholipase C-gamma1, was studied in these cells using Western blotting. A marked decrease in expression of zeta and FcepsilonRI-gamma associated with CD3 or FcgammaRIIIA was observed in T or NK cells obtained from TALs, as compared to T or NK cells purified from normal peripheral blood. Expression of CD3-epsilon, as assessed using flow cytometry, Western blotting, or ELISA was also reduced in purified TAL-T cells relative to that in normal peripheral blood T cells. Surface expression of CD3 on T cells and FcgammaRIIIA on NK cells obtained from TALs was significantly decreased in comparison to normal peripheral blood lymphocytes (PBLs): the mean fluorescence intensity of CD3 was 277 +/- 18 for TAL-T (n = 7) versus 349 +/- 13 for PBL-T (n = 9) and that of CD16 was 58 +/- 1 for TAL-NK (n = 7) versus 385 +/- 55 for PBL-NK (n = 23) cells. These observations suggest a defect in assembly of T cell receptor and FcgammaRIIIA multicomponent transmembrane receptors, which are zeta and gamma dependent. In addition to alterations in expression, the function of these receptors was also modified, since cross-linking of CD3 on TAL-T and CD16 on TAL-NK cells with the respective monoclonal antibodies resulted in a pattern of protein phosphorylation that was distinct from that observed in normal PBLs. Expression of tyrosine kinase p56(lck) and its kinase activity were also depressed, while expression of phospholipase C-gamma1 appeared to be normal in most preparations of the TALs tested. In vitro proliferation of TAL-T in response to anti-CD3 monoclonal antibody and TAL-NK cells to interleukin 2 were significantly depressed as was the ability to produce IFN-gamma. In contrast, TAL-T cells were able to produce interleukin 10 at levels similar to those secreted by normal PBLs. Thus, in TALs obtained from patients with advanced ovarian cancer, alterations in expression and activity of signaling molecules were associated with reduced cellular functions such as proliferation and production of certain cytokines.
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PMID:Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. 981 3