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 used the U937 cell line to analyze CD14, CD11/CD18, HLA class-I and DR antigen expression during PMA-induced differentiation. Treatment of U937 cells with PMA markedly increased CD14, CD11a, CD11b and CD18 antigen expression, and slightly increased CD11c expression. Protein kinase C may play a major role in regulating the expression of these antigens. The protein kinase inhibitor H7 abrogated the inductive effect of PMA. Calcium ionophore, when added alone or in the presence of PMA, had no effect. The inhibitory effect of the calcium antagonist verapamil, EGTA, and of chlorpromazine, an antagonist of calcium-binding proteins, supports a role for calcium-dependent protein kinase C in the up-regulation of CD14 and CD11/CD18 surface expression. The specific calmodulin inhibitors R24571 and W7 had no effect on antigen expression. Our findings suggest that protein kinase C activation is an important step in the PMA-induced differentiation of U937 cells.
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PMID:Protein kinase C-mediated regulation of the expression of CD14 and CD11/CD18 in U937 cells. 168 74

The administration of 150 nM etoposide, an inhibitor of DNA topoisomerase II activity, decreased the proliferation and induced the differentiation of U937 human promonocytic cells, as determined by nitroblue tetrazolium reduction, surface accumulation of CD11b/CD18 and CD11c/CD18 integrins, and c-fms protooncogene expression. The expression of these differentiation markers started to be detected at 24 h of treatment. Etoposide caused little cell damage, as determined by trypan blue exclusion and by apoptotic-like DNA degradation, which was slightly initiated at 48 h. The treatment induced a transient increase in c-fos, c-jun, and jun B mRNA levels, with maximum values at 12 h, a transient increase in collagenase mRNA level, with maximum value at 48 h, and a progressive increase in vimentin and lamin A and C mRNAs. These changes were qualitatively similar to those produced by 12-O-tetradecanoylphorbol-13-acetate. Etoposide also caused a transient increase of total AP-1 binding activity, with maximum value at 12 h of treatment, as determined by gel retardation assays. The drug produced an early transient activation (3-6 h) of membrane-bound protein kinase C, followed by the later activation (48 h) of both the membrane and cytosolic enzyme. The protein kinase C inhibitors, sphinganine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), attenuated the induction of differentiation markers by etoposide. These results suggest that protein kinase C and AP-1-dependent gene expression could be involved in myeloid cell differentiation by DNA topoisomerase II inhibitors.
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PMID:Etoposide-induced differentiation of U937 promonocytic cells: AP-1-dependent gene expression and protein kinase C activation. 781 32

We have raised a monoclonal antibody (mAb), NG2B12, directed against rat CD18, capable of inducing lymphocyte homotypic adhesion and granulocyte adherence to plastic. NG2B12-induced aggregation is temperature sensitive and requires metabolic energy, an intact cytoskeleton and the presence of Mg2+, but is independent of protein synthesis. Ca2+ is not only dispensable but exerts a suppressive effect on the NG2B12-induced adhesion. The adhesion is readily observed in thymocytes and concanavalin A blasts of thymocytes and splenocytes but is very weak in resting spleen and lymph node cells. NG2B12 also enhances phorbol 12-myristate 13-acetate (PMA)-induced aggregation in an additive fashion. The NG2B12-induced homotypic adhesion is mediated by LFA-1. mAb against ICAM-1 completely inhibited the induced adhesion of activated cells but inhibited only partially and in a time-dependent manner the adhesion of resting thymocytes. The activation of protein phosphatases 1 and 2A (as assessed by the use of okadaic acid) is necessary for the NG2B12-induced adhesion of both resting and activated thymocytes. In contrast, H-7 (an inhibitor of protein kinase C and A), substantially suppressed the adhesion of resting thymocytes, whereas W-7 (an inhibitor of calmodulin-dependent protein kinase) inhibited the adhesion of activated thymocytes. NG2B12 induces both adherence to plastic and homotypic aggregation of granulocytes; the events being blocked by anti-CD18 (WT.3) and anti-CD11b/CD11c (OX-42) mAb, augmented by okadaic acid and not modified by H-7 and W-7. Additionally, we have demonstrated that NG2B12 and PMA employ distinct intracellular signaling pathways in inducing adhesion of both thymocytes and granulocytes.
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PMID:A novel anti-rat CD18 monoclonal antibody triggers lymphocyte homotypic aggregation and granulocyte adhesion to plastic: different intracellular signaling pathways in resting versus activated thymocytes. 791 39

Integrins are a family of cell surface heterodimers which mediate both cell-cell and cell-extracellular matrix interactions and affect cellular differentiation through their signal transduction capacity. Integrin expression is regulated during differentiation as well as by numerous growth factors and cytokines. We have analyzed the changes in p150,95 (CD11c/CD18 or alpha X/beta 2) and VLA-4 (CD49d/CD29 or alpha 4/beta 1) integrin subunits mRNA levels that take place during the myeloid differentiation of HL60 and U937 cells, and compared them to other integrins with similar functional activities. Northern blot analysis revealed that the monocytic differentiation of U937 and HL60 cells alters the alpha X and alpha 4 mRNA steady-state levels: alpha X mRNA is induced de novo whereas alpha 4 mRNA decreases to undetectable levels. Both changes were dependent on the activity of protein kinase C and were also observed upon granulocytic differentiation of HL60 cells. Parallel analysis of other integrin subunits mRNA (beta 1, alpha 5, beta 7) demonstrated that the mRNA levels for the alpha subunits of the fibronectin receptors alpha 4/beta 1 (VLA-4) and alpha 5/beta 1 (VLA-5) are differentially regulated during the monocytic differentiation of myeloid cell lines, and suggested that myeloid cells express a heterodimer formed by the association of beta 7 with an integrin alpha subunit distinct from alpha 4. Nuclear transcription assays and functional analysis of the alpha X and alpha 4 promoter regions demonstrated that the transcription rate of the alpha X gene is considerably elevated after phorbol 12-myristate 13-acetate treatment of U937 cells, while that of alpha 4 is almost unaffected, suggesting that post-transcriptional mechanisms are causing the extremely low alpha 4 mRNA levels observed in differentiated U937 cells.
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PMID:Regulated expression of p150,95 (CD11c/CD18; alpha X/beta 2) and VLA-4 (CD49d/CD29; alpha 4/beta 1) integrins during myeloid cell differentiation. 802 May 69

The phorbol esters induce differentiation of chronic lymphocytic leukemia (CLL) cells. Clinical use of this observation has been hampered by the fact that phorbol esters are also tumor promoters. In this study we demonstrate that another protein kinase C activator, without tumor promoting activity, has similar effects on CLL cells. Fresh leukemic cells from the peripheral blood of 13 patients with CLL were isolated and cultured in the absence (control) or presence of Bryostatin 1 or 12-0-tetradecanoylphorbol 13-acetate (TPA). Aliquots of cells were then analyzed after 24, 72 and 120 hours for morphological changes, acid phosphatase (ACP) and the co-expression of two hairy cell-associated surface antigens, CD22 and CD11c, by flow cytometry. Bryostatin 1 induced changes in shape and morphology similar to TPA, with adherence and increase in cell size, abundant cytoplasm and irregular cytoplasmic membrane. Both agents induced a statistically significant increase in the expression of CD22 and CD11c compared with control (p < 0.0008). There was no significant difference between the two agents in the degree of expression of these two markers. Both agents also induced ACP that was tartrate resistant (TRAP). These changes indicate that Bryostatin is as effective as TPA in inducing further differentiation of CLL cells to a hairy cell stage.
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PMID:Bryostatin 1-induced hairy cell features on chronic lymphocytic leukemia cells in vitro. 809 52

Previous studies have suggested that gangliosides have an important role in cell signaling and recognition. However, their specific function in these processes has not been clearly defined. A mAb, R24, that reacts specifically with a cell surface ganglioside (GD3) has been demonstrated to stimulate proliferation of T cells derived from human peripheral blood. In this study, we have investigated the mechanisms by which the R24 mAb affects T cell functions. We have observed that the R24 mAb stimulates GD3+ T cell proliferation, cytotoxicity, and surface marker expression of IL-2R alpha-chain, IL-2R beta-chain, HLA-DR, CD11a, and CD11c. Additionally, IFN-gamma activity but not IL-1, IL-2, or IL-4 activity was present in culture supernatants 72 h after R24 stimulation. In some donors, increased IL-6 and TNF-alpha activity also was detected after R24 treatment. Furthermore, R24 treatment resulted in translocation of c-rel, but little or no NF kappa B p50 or p65, from the cytoplasm to the nucleus and an increase of NF kappa B binding complexes containing c-rel and p50. This treatment also caused increased tyrosine phosphorylation of specific protein substrates. R24-stimulated increases in proliferation, cytotoxicity, and cell surface protein expression could be blocked by cyclosporin and staurosporin, indicating that cyclophilin/calcineurin and protein kinase C may be involved in the R24 signaling pathway. Additionally, herbimycin A, a tyrosine kinase inhibitor, blocked the R24-stimulated increase in proliferation but not cytotoxicity at concentrations consistent with specificity for tyrosine kinases. These results suggest that multiple biochemical pathways are involved in the activation of human T cells by R24.
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PMID:Increased proliferation, cytotoxicity, and gene expression after stimulation of human peripheral blood T lymphocytes through a surface ganglioside (GD3) 828 32

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

Bryostatin 1 (Bryo1), a macrocyclic lactone and a protein kinase C activator, is extracted and purified from the marine bryozoan Bugula neritina. In this study we describe its effect on morphology, surface immunophenotype, acid phosphatase (AcP), tartrate-resistant acid phosphatase (TRAP), proliferation and cell cycle of non-Hodgkin's B-lymphoma cell lines representing four differentiation stages. Except for the WSU-BL, a high-grade SCNCL, all other cell lines showed obvious changes in their morphology when treated with 200 nM Bryo1. Phenotypically, a dramatic decrease of CD10 and induction of CD11c and BL7 on some cell lines consistent with further B-cell differentiation was seen. The lines in control cultures showed variable expression of AcP and TRAP. Following treatment with Bryo1, there was a general increase in AcP expression except in WSU-BL line. WSU-FSCCL and WSU-DLCL were TRAP-negative but became TRAP-positive when treated with Bryo1. Cell growth and cycle analysis during treatment of different cell lines revealed evidence of strong, moderate, or no growth inhibition by Bryo1 compared with control cultures. Our results indicate that Bryo1 shows differentiation effects on low-grade FSCCL, intermediate-grade FLCL and high-grade DLCL, and stimulatory or no effect on high-grade SCNCL. Since Bryo1 does not have tumor-promoting activity, it has a potential therapeutic role as a B-cell differentiating agent.
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PMID:Differential effects of bryostatin 1 on human non-Hodgkin's B-lymphoma cell lines. 842 74

Administration of 0.3 microM mitomycin C (MMC) or 2.0 microM cis-diamminedichloroplatinum II (CDDP) decreased the growth activity and induced the differentiation of U-937 human promonocytic cells, as shown by nitroblue tetrazolium reduction and an increase in surface expression of the leukocyte integrins CD11b/CD18 and CD11c/CD18. Expression of these differentiation markers started to be significant at 48 hr of treatment. These concentrations resulted in little cell damage (determined by Trypan blue exclusion) and slightly induced apoptosis (determined by DNA degradation and changes in nuclear morphology). The treatments induced a transient increase in c-fos and c-jun mRNA levels, with maximum values at 1-6 hr; a transient increase in collagenase mRNA level, with a maximum value at 48 hr; and a progressive increase in vimentin and lamin A and C mRNA levels. These changes were qualitatively similar to those produced by 12-0-tetradecanoylphorbol 13-acetate. CDDP and MMC also caused a transient increase of total AP-1 binding activity, as determined by gel retardation assays. The drugs produced an early transient activation (3-6 hr) of membrane-bound protein kinase C, followed by a later activation (48 hr) of both the membrane and the cytosolic enzyme. These results suggest that protein kinase C and AP-1-dependent gene expression could be involved in myeloid cell differentiation by alkylating agents.
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PMID:Differentiation of U-937 promonocytic cells with mitomycin C or cis-diamminedichloroplatinum II. 863 94

Bistratene A (BisA) induced growth arrest in G2/M in HL60 cells. In addition, BisA-treated cells (50 nM for 48 h) became adherent and expressed the adhesion molecule CD11c, but did not express the monocyte enzyme alpha-napthyl acetate esterase or phagocytose complement coated yeasts. BisA activated protein kinase C (PKC)-delta and induced translocation of PKC-delta to the nucleus. This suggests that activation of PKC-delta can induce growth arrest and cell adhesion, but is insufficient to mediate full differentiation of HL60 cells. BisA has potential as a new probe for determining the function of PKC isoenzymes, specifically PKC-delta.
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PMID:The polyether bistratene A activates protein kinase C-delta and induces growth arrest in HL60 cells. 865 26


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