Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated B cells express Fas (CD95) and are targets for apoptosis induced by CD4+ Th1 effector cells that kill in a Fas-dependent fashion. We report here that IL-4 reverses the susceptibility to Fas-mediated apoptosis that characterizes CD40-stimulated primary B cells. IL-4-induced Fas resistance is not associated with an alteration in the elevated level of Fas expression produced by CD40 ligand and does not depend on additional receptor-mediated signals. However, IL-4-induced resistance to Th1 cell-mediated cytotoxicity (Th1-CMC) develops more slowly than resistance mediated by surface Ig and is not affected by protein kinase C depletion, unlike anti-Ig-induced Fas resistance. By these two criteria, IL-4-and anti-Ig-induced resistance to Th1-CMC appear to be driven through distinct mechanisms; in keeping with this, suboptimal doses of IL-4 and anti-Ig act in synergy to induce marked protection against Th1-CMC. An important role for IL-4-induced Fas resistance is suggested by the observation that sera from IL-4-overexpressing transgenic mice contain autoreactive Abs.
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PMID:IL-4 induces Fas resistance in B cells. 881 75

The Apo-1/Fas (CD95) antigen is known to be involved in the process of T cell-mediated target cell killing and has recently been shown to be expressed on myeloma cell lines and native malignant plasma cells. Several cytokines have been reported to interfere with spontaneous and even Apo-1/Fas-induced apoptosis, but no attempt has been made yet to investigate these interactions and the possible underlying mechanisms in myeloma cells. Since in myeloma patients Interferon (IFN)-alpha2 displays a profound therapeutic effect in vivo, which is usually attributed to its growth inhibitory and/or immunomodulatory capacity, we set out to study the potential interference of IFN-alpha2 with Apo-1/Fas-induced apoptosis. Contrary to expectations, IFN-alpha2 reduced the degree of apoptosis caused by the treatment of five Apo-1/Fas-sensitive myeloma cell lines with a Fas monoclonal antibody (mAb). Simultaneous application of IFN-alpha2 and Fas mAb was superior to the prolonged (i.e. >8 h) preincubation with the cytokine as far as inhibition of Apo-1/Fas-induced apoptosis was concerned. This effect of IFN-alpha2 was neither explained by a down-regulation of the Apo-1/Fas receptor nor caused by modulation of the expression levels of c-myc, bcl-2-, bcl-xL, bax- or p53 genes. IFN-alpha2 did not alter the Apo-1/Fas-induced activity of Mitogen-activated protein kinase (MAPK) 1 and did not inhibit the Apo-1/Fas-mediated proteolytic cleavage of ADP-ribosyltransferase, a substrate of Interleukin-beta1 converting enzyme (ICE) and homologues. However, activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) mimicked the effects of IFN-alpha2. Furthermore, the bis-indolylmaleimide GF 109203X, a specific inhibitor of PKC, inhibited the effect of PMA as well as that of IFN-alpha2 on Apo-1/Fas-induced apoptosis. These results point to a PKC-dependent mechanism of transient interaction between the intracellular signaling along the IFN-alpha2 and the Apo-1/Fas pathway (downstream of MAPK signaling as well as of ICE homologues), which becomes exhausted by prolonged stimulation with the cytokine. According to our data IFN-alpha2, applied continuously and in high doses resembling the therapeutic situation in vivo, inhibits myeloma growth. However, based on the observed inhibitory effect of IFN-alpha2 on Apo-1/Fas-induced apoptosis, a partial inhibition of the natural immune surveillance on myeloma cells by endogenous IFN-alpha2 present in the bone marrow microenvironment of this malignancy should be investigated.
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PMID:Modulation of Apo-1/Fas (CD95)-induced programmed cell death in myeloma cells by interferon-alpha 2. 897 13

CD95 (Fas/APO-1)-mediated apoptosis appears to be regulated by positive and negative signaling molecules. A human CD40/CD95 chimeric receptor was stably transfected into CD95-expressing human Jurkat T cells, and signaling through native and chimeric CD95 was compared in the same cell type to assess contributions of the CD95 extracellular and intracellular domains. Apoptosis was induced in these transfectants by soluble CD40 ligand and also by the anti-CD40 monoclonal antibodies (mAb) M2 and M3. The M2 mAb was more effective than M3 in these transfectants. In contrast to apoptosis mediated through native CD95, CD40/CD95-mediated apoptosis was not inhibited by phorbol-12-myristate-13-acetate (PMA). The apoptotic response to the anti-CD40 mAb M3, but not M2, was enhanced by PMA and dibutyryl cyclic adenosine monophosphate (db-cAMP), which also increased mRNA levels and surface expression of CD40/CD95. The enhancing effects of PMA, but not those of db-cAMP, were sensitive to cycloheximide. The M2 and M3 mAbs appeared to have virtually identical binding affinities but, when added to cells together, M3 inhibited M2-induced apoptosis. These mAbs may bind neighboring epitopes, but M2 induces a more effective signaling-competent conformation upon the chimeric receptor. These data suggest that dimerization, however only in a signaling-competent conformation, was sufficient to induce apoptosis. When expressed as a chimera with the CD40 extracellular domain, the CD95 intracellular domain was not inhibited by protein kinase C (PKC)-dependent pathways, suggesting that the CD95 extracellular domain is required for association with a molecule that inhibits the apoptotic signal.
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PMID:Apoptosis through CD95 (Fas/APO-1), but not a CD40/CD95 chimeric receptor, is inhibited by phorbol-12-myristate-13-acetate. 905 40

Activation of protein kinase C (PKC) has been reported to inhibit Fas (APO-1, CD95)-mediated apoptosis in different cellular systems. Human Jurkat leukemic T cells express the Fas antigen in the cell membrane and undergo apoptosis upon cross-linking by anti-Fas monoclonal antibodies (mAb). Cleavage of the apoptosis-associated protease CPP32 and its substrate poly(ADP-ribose)polymerase are observed after the engagement of Fas antigen with mAb. In this report, we show that all these effects are substantially inhibited by the activation of PKC with a phorbol ester. Bisindolylmaleimide, an inhibitor of PKC, prevents phorbol ester-induced down-regulation of Fas signaling. Inhibition of Fas-mediated cell death by phorbol ester is also observed in other human leukemic T cell lines. Cross-linking of Fas antigen by mAb results in the rapid increase in tyrosine phosphorylation of several protein substrates which is further elevated in the presence of the protein tyrosine phosphatase inhibitor, orthovanadate. Furthermore, orthovanadate markedly enhances the cell death response to Fas mAb in different human leukemic T cell lines and human T cell blasts. These effects of orthovanadate on early tyrosine phosphorylation and cell death are clearly diminished by PKC activation. These results strongly suggest that tyrosine phosphorylation is involved in Fas signaling in apoptosis and that PKC plays a negative role in Fas-mediated apoptosis by counteracting at a very early stage the signals generated following cross-linking of this receptor.
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PMID:Activation of protein kinase C attenuates early signals in Fas-mediated apoptosis. 920 97

Apoptosis induced by ligation of either the tumor necrosis factor (TNF) p55 receptor or the Fas/APO-1/CD95 receptor has been suggested to require ceramide as a signaling molecule. Ceramide is formed as a result of sphingomyelinase (SMase) activation in the sphingomyelin cycle, and ligation of TNF and Fas receptors has been reported to stimulate SMase activity. We have studied the effects of D609, a xanthogenate compound with antitumoral properties, on TNF- or Fas-induced apoptosis of monocytic U937 cells. First, the effects of D609 on SMase activity were assessed using in vitro assays for neutral and acidic SMase, and the results suggested that D609 caused a modest stimulation of the activity of both SMases in U937 cells. Exposure of U937 cells for 6 h to TNF or anti-Fas mAb induced apoptosis in 40-45% of the cells, as measured by fluorescent staining of nuclear chromatin. Cotreatment with D609 potentiated TNF- as well as Fas-mediated apoptosis up to 70 and 90%, respectively. Furthermore, in incubations with D609 alone, 60% of the cells became apoptotic within 16 h. Since D609 has been reported to inhibit protein kinase C (PKC) activity, the effect of phorbol 12-myristate 13-acetate (PMA) on D609-induced apoptosis was investigated. PMA was found to inhibit D609-induced apoptosis in U937 cells as well as cell death induced by TNF and anti-Fas mAb. Thus, PKC inactivation may play an important role in the regulation of apoptosis in U937 cells. In summary, the present results show that D609 stimulates SMase activity, potentiates TNF- and Fas-induced apoptosis, and induces apoptosis on its own in U937 cells.
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PMID:Induction of apoptosis and potentiation of TNF- and Fas-mediated apoptosis in U937 cells by the xanthogenate compound D609. 928 51

The interleukin-3 (IL-3)-dependent murine bone marrow-derived cell line FDC-P2/185-4 (185-4) undergoes apoptosis when IL-3 is withdrawn from culture medium. Previous results from our studies indicated that a high concentration of aggregated mouse IgG prevented apoptosis of 185-4 cells through Fc gammaRIII by an autocrine mechanism, producing IL-3. But after 24 hours, 185-4 cells expressed CD95 (Fas/Apo-1) on their surfaces on stimulation via Fc gammaRIII. In addition, this CD95 was functional and apoptosis was induced by anti-CD95 monoclonal antibody (MoAb). We investigated how these conflicting effects were induced by Fc gammaRIII stimulation within the context of cell survival and death. The results showed that IL-3 was induced by calcium ionophore and that the IL-3 induced by Fc gammaRIII stimulation was blocked by EGTA or FK506, but not by staurosporine (protein kinase C [PKC] inhibitor), indicating the important role of calcium-calcineurin in this system. On the other hand, the CD95 expression induced by Fc gammaRIII stimulation was blocked by staurosporine, but not by EGTA or FK506, and phorbol myristate acetate (PMA) induced CD95 expression in the same manner as Fc gammaRIII, indicating the involvement of PKC in the CD95 expression induced by Fc gammaRIII stimulation. Thus, Fc gammaRIII-mediated stimulation even while promoting immediate survival of the bone marrow cells, also triggers mechanisms that will facilitate their eventual deletion at the end of the response. These results suggest that a balance between cell survival and death is maintained to avoid unlimited cell growth caused by Fc gammaRIII-ligand interaction in hematopoiesis during inflammation.
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PMID:Fc gammaRIII-mediated regulation of hematopoiesis in murine bone marrow cells by interleukin-3 and CD95 (Fas/Apo-1). 929 24

Fas(CD95) and its ligand (FasL) interaction plays a pivotal role in T cell receptor (TCR)-mediated apoptosis. However, the susceptibility of T cells to Fas-mediated apoptosis is tightly regulated during immune responses, a regulation which is thought to maintain the antigen-specificity of T cell apoptosis. Here we show that TCR stimulation enhances the induction of Fas-mediated apoptosis. In addition, using a mutant T cell hybridoma with impaired FasL expression, we show that the synergy provided by TCR stimulation can be mimicked by activators of PKC but not calcium influx. This effect cannot be inhibited by actinomycin D, suggesting that TCR stimulation leads to the alteration in preexisting signaling molecules to enhance Fas-mediated apoptosis. Our results therefore provide a mechanism of how Fas-FasL interactions lead to T cell death in an antigen-specific manner via repetitive antigen stimulation.
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PMID:T cell receptor signals enhance susceptibility to Fas-mediated apoptosis. 938 92

CD95(APO-1/Fas) is a cell surface receptor that, when oligomerized by natural ligand, CD95L, or antibody, confers an apoptotic signal to apoptosis-sensitive cells. Whereas CD95 is expressed in every colonocyte of normal colon mucosa, CD95 is down-regulated or lost in the majority of colon carcinomas. To investigate the sensitivity to CD95-mediated apoptosis of normal and neoplastic colonocytes, we applied cross-linking CD95(anti-APO-1) monoclonal antibody to freshly isolated colon crypts and colon carcinoma cell lines and monitored apoptosis by DNA fragmentation and morphology. Normal colonocytes were constitutively sensitive to CD95-mediated apoptosis. All carcinoma lines were constitutively resistant but were sensitized upon pretreatment with IFN-gamma. Transcription blocking, protein synthesis, and export in carcinoma cells indicated that even low surface levels of CD95 were sufficient to efficiently transmit the signal. Despite low CD95 surface levels of non-IFNgamma-treated cells, actinomycin D, cycloheximide, and brefeldin A each sensitized all cell lines, but at different rates and kinetics. In this context, it was observed that a greatly delayed apoptotic response of SW620 cells was associated with the absence of antibody-induced CD95 capping. Phorbol 12-myristate 13-acetate inhibited CD95-mediated apoptosis by counteracting the IFNgamma-, actinomycin D-, and cycloheximide-mediated but not the brefeldin A-mediated sensitization. This phorbol 12-myristate 13-acetate-induced protection against apoptosis was completely abolished by staurosporine and by a selective protein kinase C inhibitor, Goe 6983. We conclude that, during malignant transformation, colonocytes acquire different mechanisms to escape CD95-mediated apoptosis. These include abrogation of CD95, inhibition of CD95 capping, and activation of antiapoptotic programs, both governed by and independent of protein kinase C.
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PMID:Colon carcinoma cells use different mechanisms to escape CD95-mediated apoptosis. 945 1

Jurkat T cells undergo rapid apoptosis upon stimulation of the Fas/APO-1 (CD95) receptor. We examined the role of the mitogen-activated protein kinase (MAPK) cascade as a negative regulator of Fas-mediated apoptosis. To this end, we used both physiologic and artificial activators of MAPK, all of which activate MAPK by distinct routes. MAPK activity could be efficiently elevated by two T cell mitogens, the lectin PHA and an agonistic Ab to the T cell receptor complex as well as by the type 1 and 2A phosphatase inhibitor, calyculin A, and the protein kinase C-activating phorbol ester, tetradecanoyl phorbol acetate. All these treatments were effective in preventing the characteristic early and late features of Fas-mediated apoptosis, including activation of caspases. Our results indicate that the elevated MAPK activities intervene upstream of caspase activation. The degree of MAPK activation by the different stimuli used in our study corresponds well to their potency to inhibit apoptosis, indicating that MAPK activation serves as an efficient modulator of Fas-mediated apoptosis. The role of MAPK in modulation of Fas-mediated apoptosis was further corroborated by transient transfection with constitutively active MAPK kinase, resulting in complete inhibition of the Fas response, whereas transfection with a dominant negative form of MAPK kinase had no effect. Furthermore, the apoptosis inhibitory effect of the MAPK activators could be abolished by the specific MAPK kinase inhibitor PD 098059. Modulation of Fas responses by MAPK signaling may determine the persistence of an immune response and may explain the insensitivity of recently activated T cells to Fas receptor stimulation.
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PMID:Suppression of Fas/APO-1-mediated apoptosis by mitogen-activated kinase signaling. 951 Jan 60

The role of the basal activity of the serine/threonine protein kinase, protein kinase C (PKC) in the regulation of anti-CD95-induced apoptosis in Jurkat T cells was investigated. The PKC-specific inhibitor GF 109203X and the proposed cPKC-specific inhibitor Go 6976, in a concentration-dependent manner, increased the percentage of cells undergoing apoptosis induced by anti-CD95 mAb as demonstrated by propidium iodide (PI) staining, TUNEL assay and DNA fragmentation by gel electrophoresis. Furthermore, Go 6976 and GF 109203X abrogated phorbol myristate acetate-induced inhibition of anti-CD95-induced apoptosis. To examine the molecular mechanism by which PKC modulates anti-CD95-induced apoptosis, the effects of Go 6976 on known effector and regulatory molecules of cell death were studied. Increased recruitment of cells undergoing apoptosis was associated with enhanced anti-CD95-induced proteolytic cleavage of the most receptor-proximal cysteine protease caspase-8, subsequent cleavage and activation of the machinery protease caspase-3, and cleavage of the caspase substrates DNA-dependent protein kinase catalytic subunit, poly-(ADP-ribose) polymerase and lamin B1. CD95 and FADD protein levels in Jurkat T cells were not altered by Go 6976 treatment. In addition, Go 6976 did not alter protein levels and subcellular distribution of the anti-apoptotic molecules Bcl-2 and Bcl-xL. These data suggest indirectly that basal PKC activity acts at an early stage in the anti-CD95-induced caspase pathway to attenuate subsequent activation of downstream effector molecules and associated apoptosis in Jurkat T cells.
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PMID:Inhibition of the protein kinase C pathway promotes anti-CD95-induced apoptosis in Jurkat T cells. 970 Oct 26


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