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)

We have previously reported that the phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA) induces further differentiation of the human acute lymphoblastic leukemia cell line Reh to a monocytoid B lymphocyte stage. In the present study, we investigated the differentiating capacity of another protein kinase C (PKC) activator, bryostatin 1 (bryo). Reh cells were treated in vitro with TPA, bryo, or interferon-alpha (IFN-alpha) for a period of 5 days during which cells were analyzed for changes in growth patterns, morphology, cytochemistry, and surface phenotype. Bryo caused a dose-dependent growth inhibition of Reh cells. Morphologically, the treated cells expressed monocytoid features with development of filopodia and numerous vacuoles indicating phagocytic activity. Bryo induced similar phenotypic changes to TPA, including induction of CD11c, increased expression of CD22 and down-regulation of CD10 and CD19. Enzymatically, bryo, like TPA, induced tartrate-sensitive acid phosphatase expression but failed to induce periodic acid Schiff (PAS) and nonspecific esterase (NSE). Bryo inhibited the TPA action on NSE and CD10. IFN-alpha showed additive growth inhibitory and phenotypic effects to bryo. Collectively, our findings indicate that bryo is capable of inducing further differentiation of the Reh cells along the B cell lineage similar to those of TPA.
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PMID:Bryostatin 1-induced modulation of the acute lymphoblastic leukemia cell line Reh. 839 68

IFN-alpha influences the recirculation and growth of normal and malignant B lymphocytes, although the mechanisms involved are not currently known. Lymphocyte recirculation is fundamentally dependent on cell-to-cell interactions that are mediated by cell surface adhesion molecules. In this report, we examined the relationship between the effect of IFN-alpha on cell-to-cell adhesion processes and induction of the Leu-13 cell surface protein in established human Daudi B lymphoid cell lines that are either sensitive or resistant to the antiproliferative activity of IFN-alpha. IFN-alpha directly triggered homotypic adhesion of IFN-sensitive Daudi B cells in a time- and dose-dependent manner. In contrast, IFN-alpha had no effect on the cell-to-cell adhesion of IFN-resistant Daudi B cells. The capacity of IFN-alpha to trigger homotypic aggregation correlated directly with the level of induction of the cell surface protein Leu-13 and could be potentiated by anti-Leu-13 mAb. Other cytokines also known to influence the proliferation, differentiation, or recirculation of B lymphocytes such as IFN-gamma, IL-2, IL-4, IL-6, TNF-alpha, and low molecular weight B cell growth factor did not induce either Leu-13 expression or homotypic aggregation of Daudi B cells. The adhesion pathway triggered by the IFN-inducible protein Leu-13 required metabolic energy and an intact cytoskeleton but was not dependent on: 1) new protein synthesis; 2) protein kinase C, protein kinase A, or tyrosine kinase activities; or 3) the function of known adhesion molecules including LFA-1, ICAM-1, CD44, or VLA-4. Taken together, these studies demonstrate a fundamental role for IFN-alpha and the IFN-inducible protein Leu-13 in regulating a novel homotypic adhesion pathway in B lymphocytes, and provide insight into the possible mechanisms by which IFN-alpha regulates biologic processes including recirculation.
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PMID:IFN-alpha induces homotypic adhesion and Leu-13 expression in human B lymphoid cells. 842 37

Interferon-alpha (IFN-alpha) regulates the growth, differentiation, and recirculation of normal and malignant B lymphocytes. In this report we examine the effects of IFN-alpha on the distribution of the cytoskeletal protein spectrin in peripheral blood B lymphocytes from normal donors and patients diagnosed with chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL). Exposure of normal and leukemic B cells to IFN-alpha in vitro was shown by immunofluorescence microscopy to cause a dose-dependent increase in the percentage of cells containing discrete focal accumulations of spectrin, ie, a single large aggregate or cap-like structure near the plasma membrane. Although the magnitude of this effect was variable among individual patient samples, in some experiments IFN-alpha induced a fourfold increase in the percentage of leukemic B cells exhibiting focal accumulations of spectrin. Spectrin reorganization induced by IFN-alpha was abrogated by the protein synthesis inhibitor cycloheximide. In addition, IFN-alpha increased the total cellular content of spectrin in B-CLL cells by approximately twofold to fourfold. Finally, a role for protein kinase C in mediating the effects of IFN-alpha on spectrin's organization is implicated by studies in which calphostin C inhibited the IFN-induced focal accumulation of spectrin. Taken together, these studies suggest that the immunomodulatory activities of IFN-alpha in normal and malignant B cells involve a change in the organization of the spectrin-based cytoskeleton.
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PMID:Interferon-alpha alters spectrin organization in normal and leukemic human B lymphocytes. 842 67

Human peripheral blood natural killer (NK) cells (CD56+, CD16+, CD3 epsilon- lymphocytes) express CD69 after their stimulation by interleukin-2 (IL-2) or interferon-alpha (IFN-alpha). This activation antigen represents a triggering surface molecule in NK cell clones as its stimulation triggers the cytolytic machinery of these cells. However, the mechanisms regulating the expression of CD69 in NK cells are unknown despite the functional relevance of CD69 in NK cell activation. Thus, we have analyzed the role of protein kinase C (PKC) and protein tyrosine kinases (PTK) in the expression of CD69 on purified NK cells activated by IL-2, IFN-alpha, anti Fc gamma RIII (CD16) monoclonal antibodies or by K562 target cells. We found that CD69 is induced on NK cells not only by IL-2 and IFN-alpha but also by activation of the CD16 pathway, the interaction with NK target cells and the direct activation of PKC by phorbol 12-myristate 13-acetate (PMA), indicating that CD69 induction is associated to different NK activation pathways. The treatment with the PKC inhibitor staurosporine abolished the induction of CD69 induced by PMA or K562. However, it did not significantly affect CD69 induction by IL-2, IFN-alpha or CD16 cross-linking. This demonstrates that whereas PKC can play a central role in the regulation of CD69 expression in some instances (response to K562 cells or PMA), it does not participate in others (response to IL-2, IFN-alpha or anti CD16 monoclonal antibodies). On the other hand genistein, a competitive inhibitor of PTK enzymes, blocked the expression of CD69 induced by activation of NK cells via IL-2 or IFN-alpha receptors, CD16 and K562 receptor(s), indicating that stimulation of PTK is a common step in the signal transduction events leading to the induction of CD69 antigens after the activation of NK cells via these receptors.
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PMID:Regulation of CD69 expression on human natural killer cells: differential involvement of protein kinase C and protein tyrosine kinases. 847

Adult rat ventricular myocytes and cardiac microvascular endothelial cells (CMEC) both express an inducible nitric oxide synthase (iNOS or NOS2) following exposure to soluble inflammatory mediators. However, NOS2 gene expression is regulated differently in response to specific cytokines in each cell type. Interleukin-1 beta (IL-1 beta) induces NOS2 in both, whereas interferon gamma (IFN gamma) induces NOS2 expression in myocytes but not in CMEC. Therefore, we examined the specific signal transduction pathways that could regulate NOS2 mRNA levels, including activation of 44- and 42-kDa mitogenactivated protein kinases (MAPKs; ERK1/ERK2) and STAT1 alpha, a transcriptional regulatory protein linked to cell membrane receptors. Although IL-1 beta treatment increased ERK1/ERK2 activities in both cell types, IFN gamma activated these MAPKs only in myocytes. STAT1 alpha phosphorylation, consistent with IFN gamma-induced signaling, was readily apparent in both cell types, and binding of activated STAT1 alpha from cytoplasmic or nuclear fractions from IFN gamma-treated adult myocytes to a sis-inducible element could be demonstrated by gel-shift assay. The farnesyl transferase inhibitor BZA-5B blocked activation of ERK1/ERK2 and induction of NOS2 by IFN gamma and IL-1 beta in myocytes. IL-1 beta and IFN gamma-induced NOS2 gene expression in myocytes was also down-regulated by both protein kinase C (PKC) desensitization and by the PKC inhibitor bisindolylmaleimide, implicating PKC-linked activation of Ras or Raf in the induction of NOS2 by IL-1 beta and IFN gamma in cardiac muscle cells. In CMEC, the MAPK kinase inhibitor PD 98059 blocked activation of ERK1/ERK2 and down-regulated IL-1 beta-mediated NOS2 induction, whereas activation of ERK2 in the absence of cytokines by okadaic acid, an inhibitor of phosphoserine protein phosphatases, also induced NOS2 mRNA. These data demonstrate that ERK1/ERK2 activation appears to be necessary for the induction of NOS2 by IL-1 beta and IFN gamma in cardiac myocytes and CMEC. In the absence of ERK1/ERK2 activation by IFN gamma in CMEC, phosphorylation of STAT1 alpha is not sufficient for NOS2 gene expression. These overlapping yet distinct cellular responses to specific cytokines may serve to target NOS2 gene expression to specific cells or regions within the heart and also provide for rapid escalation of NO production if required for host defense.
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PMID:Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha. 855 38

Epidermal growth factor is a potential mitogen for many different human tumours. Its effect is mediated via a bispecific receptor (EGFR), the expression of which correlates well with invasive disease. We investigated the modulation of EGFR by cytokines produced following bacillus Calmette Guerin (BCG)-immunotherapy. Our data demonstrate the IFN gamma, TNF alpha and IL-1 alpha can decrease the expression of EGFR on some bladder tumour cell lines. IFN gamma reduced EGFR expression on two of eight cell lines (RT4, SD). However, IL-1 and TNF did not share this activity. When cells were treated with a combination of all three cytokines, EGFR was decreased on three cell lines (RT4, RT112, SD) and furthermore, the change in the receptor expression was even more marked. Treatment with phorbol ester (thereby activating protein kinase C) resulted in rapid disappearance of the receptor from the cell surface. Interestingly, the decrease of EGFR expression did not require protein synthesis. Although the cytokines studied could down modulate EGFR, this only occurred on three out of eight cell lines; therefore, it is unlikely that the suppression of proliferative activity caused by cytokine-induced decrease of EGFR expression is central to the antitumour action of BCG therapy, but in a proportion of tumours this mechanism may be involved.
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PMID:Cytokine modulation of epidermal growth factor receptor expression on bladder cancer cells is not a major contributor to the antitumour activity of cytokines. 856 66

We have recently shown that interleukin 2 (IL-2) can increase the contractile strength or rat atrial muscle through the activation of phospholipases and protein kinase C. The results of this study confirm that the reaction of IL-2 with rat atria involves protein kinase C and not the Ca(++)-calmodulin dependent kinases. Phorbol 12-myristate 13-acetate (PMA), a tumor promoter that activates protein kinase C directly (bypassing the phosphoinositide turnover step), has effects that are similar to those of IL-2 on atrial contractility. Furthermore, preincubation of the tissue with PMA prevents the IL-2 effect, suggesting that the kinases activated by the tumor promoter and IL-2 share a common substrate. This effect of IL-2 on atrial contractility opposes the cholinomimetic inhibitory action of IFN gamma. Thus, preincubation of cardiac tissue with IL-2 or PMA eliminates the effects of IFN gamma and viceversa. Apparently, the inhibitory action of IL-2 on IFN gamma involves an impaired response or atria to cholinergic activation, as IL-2 shifts to the right the dose response curve of the tissue to the cholinergic muscarinic agonist carbachol. Protein kinase C is also necessary for the occurrence of the IL-2-IFN gamma interference. The results of this study suggest that, during an inflammatory reaction in the heart, the balance of the two lymphokines can determine changes in the response of the tissue to autonomous nervous system agonists or to the cytokines that mimic the effects of these neurotransmitters.
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PMID:Opposite effects of interleukin-2 (IL-2) and interferon gamma (IFN gamma) on rat atria contractility. 858 May 31

The signal transducer and activator of transcription (STAT) family of transcription factors is triggered by cytokine and growth factor receptors in a number of cell types, and binds to a consensus sequence defined in part by the IFN-gamma activation site (GAS). It is not known whether these transcription factors respond to other kinds of growth stimuli, and, with particular relevance to lymphocytes, it is not known whether STAT proteins participate in Ag-specific responses. To determine the role of STAT proteins, coupling between Ag-receptor cross-linking and nuclear expression of DNA-binding protein complexes that recognize GAS sequences was evaluated. Ag-receptor triggering in primary B lymphocytes stimulated nuclear expression of a complex that specifically binds the IFN response factor-1 (IRF-1) GAS sequence, and is distinguished by electrophoretic mobility and GAS preference from IRF-1 GAS-binding complexes induced by IFN-gamma. Activation of nuclear IRF-1 GAS-binding activity by sIg was inhibited by the tyrosine kinase inhibitor, herbimycin A, and binding activity was eliminated by tyrosine phosphatase treatment. Activation of IRF-1 GAS-binding activity was blocked by depletion of protein kinase C. The IRF-1 GAS-binding activity induced by sIg engagement in B cells was transcriptionally active, and was found to consist of immunoreactive STAT5 and STAT6 proteins. This work demonstrates that the STAT signaling pathway previously associated with cytokine signaling is triggered in B lymphocytes through Ag-receptor engagement in a protein kinase C-dependent fashion. This heretofore described cytokine signaling pathway may play a role in bringing about Ag-specific proliferative and differentiative responses.
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PMID:Antigen-receptor engagement in B cells induces nuclear expression of STAT5 and STAT6 proteins that bind and transactivate an IFN-gamma activation site. 868 42

The sheep endometrial oxytocin receptor plays a central role in determining the time at which luteolysis occurs during the oestrous cycle, and in the events leading to the establishment of pregnancy (the maternal recognition of pregnancy). Expression of the receptor in the uterus is controlled by ovarian steroid hormones, and by trophoblast interferon (IFN-tau). We report here studies on the second messengers involved in the effect of IFN-tau, and on the structure and expression of the oxytocin receptor. The receptor is expressed in ovine endometrial explants during culture, when the explants are taken during the luteal phase of the cycle; this process is partially blocked by inhibitors of protein kinase C, or by down-regulation of protein kinase C. Therefore it is suggested that protein kinase C, rather than tyrosine kinases, is involved in the effect of IFN-tau on oxytocin receptor expression. Northern blotting shows that in common with uterine oxytocin receptor mRNA in other species, the message is heterogeneous. cDNA sequencing indicates the sheep uterine oxytocin receptor is at least 2 amino acids longer than those of other species, and expression of the receptor in Cos-7 cells induces oxytocin responsiveness in terms of phosphoinositide turnover.
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PMID:The sheep endometrial oxytocin receptor. 871 78

Herpes simplex virus 1 (HSV-1) is able to induce interferon-alpha production by natural IFN-alpha-producing cells. In this study, signal transduction in this process was examined. It was found that sequestering of calcium by EGTA abolished IFN-alpha induction by HSV-infected cells. Stimulation of human PBMC by HSV-1-infected fibroblasts resulted in the production of inositol triphosphate (InsP3) and tyrosine phosphorylation of cellular proteins. The protein kinase C inhibitor, H7, and the tyrosine kinase inhibitor, herbimycin A, were able to suppress IFN-alpha gene expression as determined by IFN bioassay and RT-PCR. An IFN-alpha-specific ELISpot assay revealed that herbimycin A and H7 remarkably decreased the number of IFN-alpha-producing cells. PMA or calcium ionophore A23187 alone did not increase IFN-alpha production. However, PMA in conjugation with ionophores increased IFN-alpha production as early as 2 h. HA1004 and 2',5'-dideoxyadenosine, which are potent inhibitors of PKA pathway, had no effect on IFN-alpha production. In contrast, BrcAMP, a specific PKA activator, inhibited the IFN-alpha secretion and number of IFN-alpha-producing cells and to a lesser extent reduced the level of IFN-alpha mRNA. Our results indicate that protein kinase C, tyrosine kinases, and protein kinase A are involved in the regulation of IFN-alpha production in response to HSV-1.
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PMID:Role of tyrosine kinases, protein kinase C, and protein kinase A in the regulation of interferon-alpha production induced by herpes simplex virus type 1. 874 63


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