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)

Our laboratory has previously demonstrated that natural killer (NK) cell-mediated cytotoxicity is protein kinase C (PKC)-dependent and that PKC is translocated from the cytoplasm to the plasma membrane during NK cell activation. Furthermore, exposuring NK cells to a sensitive target cell for 4-6 hr at 37 degrees C rendered NK cells functionally inactive and these inactivated effector cells (i) do not turn over PI in response to K562 stimulation and (ii) lose mRNA for perforin and granzyme A and B less than 30 min after contact with K562. In this study, we first confirmed earlier findings that the interaction of sensitive target cells with human NK cells triggers an influx of extracellular calcium into NK cells. In addition, using flow cytometry we demonstrated that there was a delayed maximum uptake of extracellular calcium into functionally inactive NK cells when these cells were reexposed to fresh K562. Finally, we demonstrated that exposuring NK cells to K562 for 4 hr leads to a loss of NK cytotoxic activity and to the maximal expression of CD69.
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PMID:Signal transduction in cytotoxic lymphocytes: decreased calcium influx in NK cell inactivated with sensitive target cells. 845 73

The present study has examined the role of IL-2 and IL-4 in the regulation of different kinase pathways for the generation of alphaCD3-induced activated killer cells, CD3-AK. It has previously been shown that the IL-2 promoted CD3-AK cell response is mediated through a PKC (protein kinase C)-dependent pathway, which is susceptible to PKC inhibitors and resistant to inhibitors of PTK (protein tyrosine kinase), and that IL-4 synergized with IL-2 to induce CD3-AK cells. However, the IL-4-promoted CD3-AK cell response was PKC-independent as assessed by its resistance to PKC inhibitors. These findings suggest a dichotomy in the pathways leading to CD3-AK cell generation. To further determine whether IL-4 mediated a different kinase pathway to activate the T cells, we studied its effect on protein tyrosine phosphorylation. IL-4 up-regulated protein tyrosine phosphorylation in CD3-AK cells in a dose-dependent fashion, and resulted in increased levels of a number of phosphorylated proteins. Of particular note was the increase of tyrosine phosphorylated p56(lck) and p59(fyn) in CD3-AK cells. The changes in global protein tyrosine phosphorylation were correlated with the up-regulation by IL-4 of CD3-AK cell cytolytic activity, and the production of granzyme A. alphaIL-4 specifically blocked all the effects which were induced by IL-4. The PTK inhibitor genistein inhibited the IL-4-augmented cytolytic activity of CD3-AK cells as well as the IL-4-induced augmentation of protein tyrosine phosphorylation to the basal level of CD3-AK cells cultured in IL-2 alone. Consistent with a dichotomy in pathways for IL-2- and IL-4-mediated CD3-AK generation, genistein had no effect on the generation of CD3-AK cells cultured in IL-2 alone. Thus while PKC is primarily involved in the generation of IL-2-promoted CD3-AK cells, PTK appears to be required for the regulation of IL-4-promoted CD3-AK response.
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PMID:IL-2 and IL-4 mediate through two distinct kinase pathways for the activation of alphaCD3-induced activated killer cells. 895 13

The activation of latent transforming growth factor beta (L-TGFbeta) is essential for the action of TGFbeta, which, in turn, is involved in the regulation of expression of some progesterone-responsive genes. One mechanism by which TGFbeta is activated involves thrombospondin (TSP), a protein that binds extracellular proteins. Immunoreactive TSP (irTSP) protein and TSP-1 mRNA in myometrial tissues of ovulatory and pregnant women were localized by immunohistochemistry and in situ hybridization. IrTSP and TSP-1 mRNA were randomly distributed in myometrial smooth muscle cells of some, but not all, tissues of pregnant women at term before labor; but in some areas of most of these tissues, irTSP was intense and commonly localized extracellularly. Intense irTSP and TSP-1 mRNA in myocytes were more common in myometrium during labor. In myometrium from ovulatory women (n = 26), irTSP was localized primarily in vascular smooth muscle cells and was detected occasionally in scattered myocytes. Little TSP-1 mRNA was demonstrable by in situ hybridization in vessels or myocytes of myometrial tissue from ovulatory women (n = 7). By Northern analysis of total RNA, TSP-1 mRNA was detected in myometrial tissue of pregnant women and in human myometrial smooth muscle cells in culture. The levels of TSP-1 mRNA in myometrial tissues of pregnant women during labor (n = 18) were greater than those in myometrium at > 37 wk gestation before labor began (n = 25, p < 0.001). The ratios of TSP-1 to glyceraldehyde 3-phosphate dehydrogenase mRNAs in 3 myometrial tissues during oxytocin-induced labor were not statistically different from those in myometrium during spontaneous labor but were greater than those in myometrium before labor (p < 0.05). The level of TSP-1 mRNA in confluent human myometrial cells in culture was relatively high, was increased by treatment with fetal bovine serum, and was decreased by treatment with platelet-derived growth factor or activators of adenylyl cyclase or protein kinase C. Myometrial cells in culture constitute a useful model for studying the regulation of TSP-1 gene expression in human myometrium.
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PMID:Thrombospondin-1 expression in human myometrium before and during pregnancy, before and during labor, and in human myometrial cells in culture. 974 36

The release of granzyme A and B through granule exocytosis by CD8+ CTL clone OE4 upon T cell receptor (TCR) activation was blocked by FK506 in a dose-dependent manner (IC50 = 3 nM), whereas a significant granzyme release was still detectable even in the presence of excess FK506. In contrast, the production of IFN-gamma was highly sensitive to FK506 (IC50 = 0.01 nM) and could be completely blocked by FK506. Both FK506-sensitive and insensitive granule exocytosis pathways were involved in the actual perforin-dependent killing toward different target cells. The combination of ionomycin and phorbol ester was able to mimic TCR stimulation to induce IFN-gamma production, although the same treatment triggered granule exocytosis inefficiently. Granule exocytosis and IFN-gamma production following TCR activation were profoundly prevented by calphostin C. Thus, these results demonstrate that the granule exocytosis pathway in this CD8+ CTL clone depends on the activation of protein kinase C, and requires either calcineurin-dependent or independent additional signals downstream of TCR activation.
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PMID:Involvement of FK506-sensitive and insensitive granule exocytosis pathways in perforin-dependent target cell lysis mediated by a CD8+ CTL clone. 1078 81

Thrombospondins (TSPs) have been implicated as antitumor and antimetastasis factors in breast cancer. Although this effect has been attributed to the antiangiogenic activity of TSPs, recent observations suggest other mechanisms may be at work. The TSP receptor CD47 (integrin-associated protein) has recently been reported to mediate a novel form of apoptosis. Here, we have studied the response of breast cancer cells to CD47 ligands TSP-1, the CD47 agonist peptide 4N1K derived from TSP-1, and the anti-CD47 monoclonal antibody 1F7. All of these ligands killed four different breast cancer cell lines. This CD47-mediated cell death did not require active caspases or Bcl-2 degradation and did not cause DNA laddering or cytochrome c release. Pertussis toxin (PTX) prevented CD47-mediated death, indicating the involvement of Gi alpha. 4N1K dramatically reduced intracellular cAMP levels, an effect reversed with PTX. Forskolin, 8-bromo cAMP, and isobutylmethylxanthine (IBMX) all prevented CD47-mediated apoptosis, indicating the involvement of cAMP. H89 and protein kinase A (PKA) inhibitor peptide prevented rescue of breast cancer cells by PTX, 8-Br-cAMP, and forskolin, suggesting that the effects of cAMP are mediated via PKA-dependent phosphorylation events. Epidermal growth factor also inhibited CD47-induced apoptosis via a PKC-dependent but ERK-independent pathway. Thus, CD47-mediated killing of breast cancer cells occurs by a novel pathway involving regulation of cAMP levels by heterotrimeric Gi with subsequent effects mediated by PKA.
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PMID:CD47 mediates killing of breast tumor cells via Gi-dependent inhibition of protein kinase A. 1487 34