Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite a normal development of all major lymphoid subsets, with time, interleukin-2 (IL-2)-deficient mice develop a fatal immunopathology. The disease phenotype is characterized by lymphoadenopathy, splenomegaly, T cell infiltration of various organs, overproduction of a number of cytokines and autoantibody formation. Phenotypically, CD4+ and CD8+ T cells exhibit features characteristic of antigenically experienced cells. The accumulation of cells with a memory phenotype together with the previous suggestion of an involvement of IL-2 in the termination phase of immune responses prompted us to study the fate of superantigen-reactive T cells in IL-2-deficient mice in comparison to their IL-2-producing littermates. We show that expansion in vivo of CD4+ and, to a lesser extent, CD8+ T cells reactive to the superantigens staphylococcal enterotoxin A and B (SEA and SEB) proceeds normally in the absence of IL-2, but that fewer CD4+ cells are subsequently deleted. The residual superantigen-reactive cells fail to become anergic as measured by proliferation in vitro in response to the same superantigen. T cell blasts generated in vitro from lymph node cells of IL-2-deficient mice by superantigen stimulation in the absence of exogenous IL-2 also fail to become anergic. In contrast to cells from IL-2-producing littermates, they do not exhibit Fas-induced apoptosis when cultured on anti-Fas antibody-coated plates, although Fas expression by IL-2-deficient cells is normal or even elevated compared to the IL-2-producing control cells. The data suggest that activation of T cells in the absence of IL-2 fails to generate a signal which is necessary to activate the apoptotic pathway and thus leads to an accumulation of antigen-experienced cells and the chronic inflammatory responses observed in IL-2-deficient mice.
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PMID:Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice. 758 28

Ligation of major histocompatibility complex (MHC) class II antigens expressed on antigen-activated human CD4+ T-lymphocytes induces early signal transduction events including the activation of tyrosine kinases, the tyrosine phosphorylation of phospholipase-C gamma 1 and the mobilization of intracellular calcium. Similar responses have been observed in B-cells following stimulation of MHC class II molecules, including the increased production of intracellular cAMP. In this report, we demonstrate that the ZAP-70 tyrosine kinase is a responsive signaling element following cross-linking of HLA-DR in class II+ T-cells, and that the homologous tyrosine kinase p72syk is stimulated in B-cells following ligation of class II antigens. Antibody mediated co-ligation of the T-cell antigen receptor (TCR/CD3) with class II molecules resulted in augmented tyrosine phosphorylation of ZAP-70. Comparable to antibody induced receptor ligation, bacterial superantigen (SEA and SEB) treatment of HLA-DR+ T-cells stimulated ZAP-70 tyrosine phosphorylation, consistent with class II transmembrane signaling by ligation of HLA-DR and V beta in cis. Modulation of the TCR/CD3 led to abrogation of class II induced ZAP-70 tyrosine phosphorylation, but did not result in sequestering of ZAP-70 from the cellular cytoplasm. Hyperphosphorylated ZAP-70 was associated with TCR/CD3 zeta-chain following cross-linking of HLA-DR, suggesting a mechanism for the TCR/CD3-dependence of class II induced signals in alloantigen-activated human T-cells. In both tonsillar B-lymphocytes and B-cell leukemia lines, p72syk was rapidly phosphorylated on tyrosine residues following HLA-DR cross-linking. Tyrosine phosphorylation of p72syk induced through ligation of either the B-cell antigen receptor or class II molecules was potently inhibited by herbimycin A. MHC class II ligation on B-lymphocytes resulted in cell death, which was both qualitatively distinct from Fas-induced apoptosis and partially protected by herbimycin A pretreatment. Thus, ligation of MHC class II molecules expressed on human lymphocytes stimulates the ZAP-70/p72syk family of tyrosine kinases, leading functionally to a tyrosine kinase-dependent pathway of receptor-induced cell death.
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PMID:ZAP-70 and p72syk are signaling response elements through MHC class II molecules. 852 73

Recent evidence indicates that death of uninfected lymphocytes by apoptosis plays an important role in the immunopathogenesis of HIV infection. We have previously demonstrated that CD4 cross-linking (CD4XL) performed in PBMC results in induction of T cell apoptosis in an accessory cell-dependent manner. In this study, we have investigated the roles of Fas interaction with its ligand (FasL) and of accessory cells in the CD4XL model of T cell apoptosis mediated by the anti-CD4 mAb Leu3a- or HIV-1 envelope protein g120. Here, we provide evidence that CD4XL-induced CD4+ T cell apoptosis is Fas-FasL interaction dependent and that monocytes play a critical role in inducing T cell apoptosis. We show that CD4XL-induced T cell apoptosis is blocked by the addition of soluble Fas or by anti-FasL mAb NOK-1; depletion of monocytes from PBMC, but not of CD19+ cells or CD8+ cells, abrogates CD4XL-induced T cell apoptosis. Conversely, addition of monocytes to purified CD4+ T cells augments CD4XL-induced apoptosis. In purified monocytes, CD4XL results in FasL expression; in purified CD4+ T cells, however, CD4XL upregulates Fas but not FasL expression. These findings underscore the important role of monocytes in HIV disease pathogenesis and firmly support the notion of CD4XL as a potent mechanism for inducing bystander cell death.
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PMID:Monocytes express Fas ligand upon CD4 cross-linking and induce CD4+ T cells apoptosis: a possible mechanism of bystander cell death in HIV infection. 903 97

The granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R induces apoptosis of hemopoietic cells. We examined the GM-CSF receptor subunit requirements and the signaling molecules involved. Using Jurkat T cells transfected with the GM-CSF receptor we found that both receptor subunits were necessary for E21R-induced apoptosis. Specifically, the 16 membrane-proximal residues of the alpha subunit were sufficient for apoptosis. This sequence could be replaced by the corresponding sequence from the interleukin-2 receptor common gamma subunit, identifying this as a conserved cytokine motif necessary for E21R-induced apoptosis. Cells expressing the alpha subunit and truncated betac mutants showed that the 96 membrane-proximal residues of betac were sufficient for apoptosis. E21R, in contrast to GM-CSF, did not alter tyrosine phosphorylation of betac, suggesting that receptor-associated tyrosine kinases were not activated. Consistent with this, E21R decreased the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase). E21R-induced apoptosis was independent of Fas/APO-1 (CD95) and required interleukin-1beta-converting enzyme (ICE)-like proteases. In contrast, Bcl-2, which protects cells from growth factor deprivation-induced cell death, did not prevent this apoptosis. These findings demonstrate the GM-CSF receptor and ICE-like protease requirements for E21R-induced apoptosis.
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PMID:The apoptosis-inducing granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R functions through specific regions of the heterodimeric GM-CSF receptor and requires interleukin-1beta-converting enzyme-like proteases. 909 24

Morphology and immunohistochemical features of the developmental process of the human intrahepatic biliary system (IBS) are reviewed. Human IBS arises from the ductal plate, a double-layered cylindrical structure located at the interface between portal mesenchyme and primitive hepatocytes. The ductal plate first appears from primitive hepatocytes (hepatoblasts) around 8 gestational weeks (GW), and its formation proceeds from the hepatic hilum to the periphery. The ductal plate gradually undergoes remodeling from 12 GW; some parts of the ductal plate disappear and other parts migrate into the portal mesenchyme. Around 20 GW, the migrated duct cells transform into immature bile ducts and peribiliary glands. Some immature peribiliary glands transform into pancreatic acinar cells around postnatal 3 months. The immature biliary elements express cytokeratins no. 7, 8, 18 and 19. Several growth factors (TGF-alpha, HGF) and their receptors (EGFR, MET, ERBB2) were expressed in the primitive IBS cells. Some extracellular matrix proteins including type IV collagen, laminin and tenascin are expressed in the mesenchyme around the primitive IBS. During IBS remodeling, apoptosis and cell proliferation occur with appropriate expression of apoptosis-related proteins (bcl-2, Fas, c-myc, Lewis(y)). Some pancreatic digestive enzymes (alpha-amylase, trypsinogen, lipase), cathepsin B, and matrix metalloproteinases (MMP-1, 2, 3, 9) and their inhibitors (TIMP-1, 2) are expressed in the remodeling IBS cells. Glycoconjugate residues of glycoproteins gradually appear during IBS development. The appropriate expression of these immunophenotypes may play an important role in the normal development of IBS.
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PMID:Normal and abnormal development of the human intrahepatic biliary system: a review. 914 36

Fas is expressed constitutively in colonic epithelial cells and is also expressed in colon carcinomas and in cultured colon carcinoma cell lines. However, the potential role of Fas signaling in mediating apoptosis in cells of this type remains unknown. We have developed human colon carcinoma cell models deficient in thymidylate synthase that demonstrate acute (TS- cells) or delayed (Thy4 cells) apoptosis following DNA damage induced by thymineless stress. Complete protection of cells from acute apoptosis and prolongation of delayed apoptosis was obtained following exposure to the NOK-1 monoclonal antibody (inhibitory to Fas signaling) during the period of dThd deprivation. These results suggested that apoptosis induced by thymineless stress was regulated by autocrine signaling via Fas-FasL interactions. Fas expression was high in both TS- and Thy4 cells. However, FasL, undetectable in synchronous cultures, was up-regulated in TS- cells at 48 hr, when cells were undergoing acute apoptosis, and in Thy4 cells at 96 hr, correlating with the delayed onset of thymineless death. FasL expression also correlated with acute apoptosis induced in parental GC3/cl cells, commencing at 48 hr, following thymidylate synthase inhibition by 5-fluorouracil/leucovorin exposure. Fas-mediated apoptosis induced by the cytotoxic anti-Fas monoclonal antibody CH-11 was inhibited following adenoviral delivery of a Bcl-2 cDNA, and Bcl-2 also protected cells from acute apoptosis induced by dThd deprivation. Taken together, these data demonstrate a functional Fas system in these cultured colon carcinoma cell models, and they demonstrate that Fas-FasL interactions can link DNA damage induced by thymineless stress to the apoptotic machinery of colon carcinoma cells.
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PMID:Thymineless death in colon carcinoma cells is mediated via fas signaling. 922 29

The Fas receptor rapidly induces apoptosis when activated by ligand binding or by cross-linking with anti-Fas antibody. The Fas ligand (FasL), a member of the tumor necrosis factor family of ligands, is a 40-kilodalton type II transmembrane protein which is cleaved to produce soluble ligand. Although the Fas-FasL interaction plays a critical role in peripheral T cell homeostasis and cytotoxic T lymphocyte-mediated target cell killing, the requirements for human FasL receptor binding and oligomerization have not been defined. Here we report two distinct domains of the ligand which are responsible for self-association and binding to the Fas receptor. A COOH-terminal sequence of the FasL was found to be required for binding and biological activity, as verified by deletion mutagenesis, use of the NOK-1 blocking antibody and the humanized gld FasL mutation. N-Linked glycosylation of the FasL was not required for biological activity. However, the FasL expression level was dependent upon the three N-linked glycosylation sites. Moreover, the ability of the FasL to self-associate was not dependent upon transmembrane or cytoplasmic sequences, but was localized to a 47-amino acid region in its extracellular domain. These results indicate that the FasL-Fas receptor complex depends upon independent motifs located within the extracellular domain of the FasL.
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PMID:Separate domains of the human fas ligand dictate self-association and receptor binding. 940 25

Interferon gamma (IFNgamma) inhibits the growth and differentiation of highly purified human erythroid colony-forming cells (ECFCs) and induces erythroblast apoptosis. These effects are dose- and time-dependent. Because the cell surface receptor known as Fas (APO-1; CD95) triggers programmed cell death after activation by its ligand and because incubation of human ECFCs with IFNgamma produces apoptosis, we have investigated the expression and function of Fas and Fas ligand (FasL) in highly purified human ECFCs before and after incubation with IFNgamma in vitro. Only a small percentage of normal human ECFCs express Fas and this is present at a low level as detected by Northern blotting for the Fas mRNA and flow cytometric analysis of Fas protein using a specific mouse monoclonal antibody. The addition of IFNgamma markedly increased the percentage of cells expressing Fas on the surface of the ECFCs as well as the intensity of Fas expression. Fas mRNA was increased by 6 hours, whereas Fas antigen on the cell surface increased by 24 hours, with a plateau at 72 hours. This increase correlated with the inhibitory effect of IFNgamma on ECFC proliferation. CH-11 anti-Fas antibody, which mimics the action of the natural FasL, greatly enhanced IFNgamma-mediated suppression of cell growth and production of apoptosis, indicating that Fas is functional. Expression of FasL was also demonstrated in normal ECFCs by reverse transcriptase-polymerase chain reaction and flow cytometric analysis with specific monoclonal antibody. FasL was constitutively expressed among erythroid progenitors as they matured from day 5 to day 8 and IFNgamma treatment did not change this expression. Apoptosis induced by IFNgamma was greatly reduced by the NOK-2 antihuman FasL antibody and an engineered soluble FasL receptor, Fas-Fc, suggesting that Fas-FasL interactions among the ECFCs produce the erythroid inhibitory effects and apoptosis initiated by IFNgamma.
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PMID:Fas ligand is present in human erythroid colony-forming cells and interacts with Fas induced by interferon gamma to produce erythroid cell apoptosis. 945 53

Ceramide has been suggested as the secondary messenger mediating the apoptotic signal for Fas engagement. By using different inhibitors, we demonstrated here that ceramide is unlikely a mediator of Fas-initiated apoptosis. First, cAMP prevented cell death induced by ceramide but not by Fas. Second, ceramide-triggered, but not Fas-triggered, apoptosis was antagonized by the free radical scavenger C60. Third, the metal chelator pyrrolidinedithiocarbamate suppressed ceramide-initiated DNA fragmentation but had no effect on the Fas-induced cell death. Fourth, the SAPK/ERK kinase dominant negative mutant, which attenuated ceramide-induced cell death, did not prevent Fas-induced apoptosis. Finally, activation of NF-kappaB inhibited ceramide-induced but not Fas-initiated apoptosis. The fact that many antagonists of ceramide-induced apoptosis could not suppress Fas-mediated cell death clearly indicates that ceramide is not the mediator for Fas-initiated apoptotic signal.
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PMID:Apoptotic signal of Fas is not mediated by ceramide. 953 73

B-chronic lymphocytic leukemia (B-CLL) is characterized by cellular and humoral immune defects resulting in increased rates of infection and disturbed immune surveillance against cancer cells as well as by the expansion of slowly proliferating tumor cells. We found increased Fas receptor (FasR) expression in peripheral blood CD4+ and CD8+ cells of B-CLL patients compared with the equivalent cells of healthy donors. Although increased Fas receptor expression was significant in both T-lymphocytic subsets, only CD4+ cells from B-CLL patients underwent apoptosis after treatment with the agonistic Fas antibody CH11. In CD4+ cells of B-CLL patients, the Fas-sensitivity also correlated with a CD4+/CD8+ ratio below the lower threshold of healthy individuals (<1.0). By contrast, FasR expression in the CD19(+) fraction of B-CLL patients was downregulated compared with normal controls, and this was associated with an insensitivity to CH11-induced apoptosis. The B-CLL cell line EHEB as well as CD19(+) cells from B-CLL patients constitutively expressed Fas ligand (FasL). The FasL was functionally active, as the B-CLL cell line as well as T-cell-depleted CD19+ B-CLL fractions were able to kill target T-acute lymphatic leukemia (T-ALL) cells in vitro. This effect was inhibited by the antagonistic FasR-antibody ZB4, the neutralizing anti-FasL monoclonal antibody (MoAb) NOK-2 or by transfection of the caspase inhibitor crmA. These data point to the fact that expression of FasL on CD19(+) B-CLL cells, together with enhanced susceptibility of CD4+ T cells toward FasL-bearing effector cells, are causally linked to the relative reduction of CD4+ cells occurring during B-CLL progression. These findings could explain the inversion of the ratio of CD4+/CD8+ cell numbers, which may be causally linked to the immune deficiency observed in these patients and to the expansion of the neoplastic clone in B-CLL.
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PMID:Differential sensitivity of CD4+ and CD8+ T lymphocytes to the killing efficacy of Fas (Apo-1/CD95) ligand+ tumor cells in B chronic lymphocytic leukemia. 959 76


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