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)

The aim of the present study was to (1) evaluate the responsiveness of human mononuclear cells to lipoprotein lipase (LPL), as assessed by tumor necrosis factor-alpha (TNFalpha) production, during the process of differentiation of monocytes to macrophages, and (2) determine the mechanisms by which LPL exerts its effect on these cells. Treatment of human monocytes with purified endotoxin-free bovine LPL (1 microgram/mL) resulted in a 161+/-15% increase in TNFalpha production over control values (P<0.01). A further increase in TNFalpha production was observed after treatment of monocyte-derived macrophages (MDMs) with LPL (490+/-81% over control values, P<0.01). Increased TNFalpha mRNA expression and protein kinase C activity were also observed in LPL-treated human monocytes and MDMs. These LPL effects were abrogated by the specific protein kinase C inhibitor calphostin C (1 micromol/L). Although heparinase totally abolished LPL-induced TNFalpha production in human monocytes, this agent did not significantly inhibit LPL effect in human MDMs. In contrast, treatment of MDMs with chondroitinase suppressed LPL-induced TNFalpha production. Taken together, these data suggest that (1) differentiation of human monocytes to MDMs is associated with increased LPL-induced TNFalpha mRNA expression and production, (2) a protein kinase C-dependent pathway is involved in the induction of TNFalpha by LPL in these cells, and (3) LPL effect is mediated by cell surface proteoglycans. As MDMs secrete LPL in the vascular wall, we propose that LPL, by acting as an autocrine activator of MDM function, may contribute to the high level of TNFalpha found in the atheromatous lesion.
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PMID:Differentiation of human monocytes to monocyte-derived macrophages is associated with increased lipoprotein lipase-induced tumor necrosis factor-alpha expression and production: a process involving cell surface proteoglycans and protein kinase C. 1036 70

Glycoprotein showing inhibitory activity against mast cell degranulation and hyaluronidase activity was purified from the hot water extract of mint plant (Perilla frutescens Britton). The purified inhibitor gave a single band detected with Coomassie brilliant blue staining and periodic acid-Schiff staining on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The molecular mass was estimated to be 6.0 kDa on SDS-PAGE. The inhibitor did not become inactivated when boiled for 30 min or digested with trypsin, V8 protease, or proteinase K but was inactivated by NaIO(4) oxidation. The inhibitor prevented mast cell degranulation and hyaluronidase activity (IC(50) = 0.42 mg/mL) in a dose-dependent manner. The inhibitor also inhibited the protein kinase C activity. It is possible to purify and characterize a glycoprotein with putative pharmacological properties from mint plants.
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PMID:Glycoprotein derived from the hot water extract of mint plant, Perilla frutescens britton. 1056 18

Angiotensin II (Ang II)-induced apoptosis was demonstrated for the first time in cultured adult rat ventricular myocytes (ARVMs) isolated by retrograde heart perfusion with Krebs-Henseleit bicarbonate (KHB) buffer containing collagenase and hyaluronidase. ARVMs incubated with 10 mumol/L Ang II for 48 h showed morphological features of apoptosis (cellular shrinkage, condensation of cytoplasm) and a characteristic "ladder" of DNA bands representing integer multiples of the internucleosomal DNA length about 180-200 bp, which became more evident with further incubation up to 72 h. With shorter incubation time (< or = 24 h) or at a lower Ang II concentration (< 10 mumol/L), such changes failed to occur. This effect of Ang II could be abolished by losartan (10 mumol/L), verapamil (1 mumol/L) or staurosporine (10 nmol/L). The above results indicate that Ang II-induced apoptosis in ARVMs may be mainly mediated by Ang II type I (AT1) receptors with [Ca2+]i and protein kinase C (PKC) playing a critical role.
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PMID:Angiotensin II-induced apoptosis in cultured adult rat ventricular myocytes. 1132 51

Midkine, a heparin-binding growth factor, plays a critical role in cell migration causing suppression of neointima formation in midkine-deficient mice. Here we have determined the molecules essential for midkine-induced migration. Midkine induced haptotaxis of osteoblast-like cells, which was abrogated by the soluble form of midkine or pleiotrophin, a midkine-homologous protein. Chondroitin sulfate B, E, chondroitinase ABC, B, and orthovanadate, an inhibitor of protein-tyrosine phosphatase, suppressed the migration. Supporting these data, the cells examined expressed PTPzeta, a receptor-type protein-tyrosine phosphatase that exhibits high affinity to both midkine and pleiotrophin and harbors chondroitin sulfate chains. Furthermore, strong synergism between midkine and platelet-derived growth factor in migration was detected. The use of specific inhibitors demonstrated that mitogen-activated protein (MAP) kinase and protein-tyrosine phosphatase were involved in midkine-induced haptotaxis but not PDGF-induced chemotaxis, whereas phosphatidylinositol 3 (PI3)-kinase and protein kinase C were involved in both functions. Midkine activated both PI3-kinase and MAP kinases, the latter activation was blocked by a PI3-kinase inhibitor. Midkine further recruited PTPzeta and PI3-kinase. These results indicate that PTPzeta and concerted signaling involving PI3-kinase and MAP kinase are required for midkine-induced migration and demonstrate for the first time the synergism between midkine and platelet-derived growth factor in cell migration.
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PMID:Haptotactic migration induced by midkine. Involvement of protein-tyrosine phosphatase zeta. Mitogen-activated protein kinase, and phosphatidylinositol 3-kinase. 1134 82

Antithrombin inhibits chemokine-induced migration of neutrophils by activating heparan sulfate proteoglycan-dependent signaling. Whether antithrombin affects migration of other types of leukocytes is not known. We investigated the effects of antithrombin on spontaneous and chemokine-triggered migration of lymphocytes and monocytes from human peripheral blood in modified Boyden chamber micropore filter assays. Lymphocyte and monocyte populations from human peripheral blood were purified using magnetic antibody cell sorting. The signaling mechanisms required for antithrombin-dependent migration were studied using signaling enzyme blockers. Expression of heparan sulfate proteoglycan core protein was studied by RT-PCR and flow cytometry. The antithrombins used were Kybernin P from human plasma and a monoclonal-antibody-purified preparation from this plasma. Pretreatment of lymphocytes and monocytes with antithrombin inhibited chemotaxis toward optimal concentrations of interleukin-8 or Rantes (regulated upon activation normal T-cell expressed and activated) at concentrations of antithrombin as low as 10 nU/ml. In the absence of the chemokines, direct exposure of cells to gradients of antithrombin stimulated migration. Effects of antithrombin were abolished by pretreating cells with heparinase-1, chondroitinase, sodium chlorate and anti-syndecan-4 antibodies. Expression of syndecan-4 mRNA and protein in monocytes and lymphocytes was demonstrated in RT-PCR and anti-syndecan-4 immunoreactivity assays, respectively. In the presence of pentasaccharide, antithrombin lost its effect on cells. Data indicate that antithrombin directly inhibits chemokine-stimulated migration of monocytes and lymphocytes via the effects of its heparin-binding site on cell surface syndecan-4 by activation of protein kinase C and Rho signaling.
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PMID:Syndecan-4 mediates antithrombin-induced chemotaxis of human peripheral blood lymphocytes and monocytes. 1180 40

Multicellular resistance, a subtype of therapeutic resistance manifested in cancer cells grown as three-dimensional multicellular masses, such as spheroids in vitro and solid tumors in vivo, occurs with respect to a variety of anticancer treatment strategies including chemotherapy, ionizing radiation, and even host-mediated antibody-dependent cellular cytotoxicity. Previous studies from our laboratory have shown that multicellular resistance to chemotherapy demonstrated by aggregates of EMT-6 murine mammary carcinoma cells can be overcome by using hyaluronidase to disrupt intercellular adhesive interactions and associated patterns of protein expression. In this proof of principle study, we explored the concept of antiadhesive chemosensitization in the context of human cancer cells by using a monoclonal antibody to disrupt E-cadherin-mediated cell-cell interactions in multicellular spheroids of HT29 human colorectal adenocarcinoma. In so doing, we found that disruption of E-cadherin-mediated adhesion sensitizes multicellular spheroids of HT29 in vitro to treatment with 5-fluorouracil, paclitaxel, vinblastine, and etoposide but not cisplatin. Furthermore, we have found that antibody-mediated blockage of E-cadherin function leads to decreased expression and activity of protein kinase C alpha and beta1, both of which have previously been implicated in chemoresistance exhibited by HT29 cells; however, we have found that the chemosensitization effects of the anti-E-cadherin antibody are independent of its influence on protein kinase C beta1.
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PMID:Antiadhesive antibodies targeting E-cadherin sensitize multicellular tumor spheroids to chemotherapy in vitro. 1498 55

Chronic inflammation is characterized by tissue infiltration with monocytes/macrophages, which possess broad proinflammatory, destructive, and remodeling capacities. Elevated levels of osteoprotegerin, an important regulator of differentiation and activation of osteoclasts that also affects different cells of the immune system, were found in the serum of patients with chronic inflammatory diseases. The study of whether osteoprotegerin affects monocyte locomotion in vitro and the possible mechanisms and pathways involved was investigated using Boyden microchemotaxis chambers and Western blot analyses. Osteoprotegerin significantly stimulated monocyte chemotaxis, whereas preincubation of monocytes with osteoprotegerin inhibited monocyte migration toward optimal concentrations of regulated upon activation normal T cell expressed and secreted, monocyte chemotactic protein -1, and procalcitonin. The effects of osteoprotegerin were abolished by pretreating cells with heparinase I and chondroitinase or antibodies against the ectodomain of syndecan-1. Osteoprotegerin signaling was shown to involve protein kinase C, phosphatidylinositol 3-kinase/Akt, and tyrosine kinase. Data suggest that osteoprotegerin affects monocyte mi-gration and protein kinase C and phosphatidylinositol 3-kinase/Akt activation via syndecan-1. Osteoprotegerin-induced deactivation of monocyte chemotaxis toward different chemokines is due to interaction of osteoprotegerin with heparan sulfate and chondroitin sulfate.
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PMID:Syndecan-1 is involved in osteoprotegerin-induced chemotaxis in human peripheral blood monocytes. 1572 9

In dopaminergic neurons, chondroitin sulfate (CS) proteoglycans play important roles in neuronal development and regeneration. However, due to the complexity and heterogeneity of CS, the precise structure of CS with biological activity and the molecular mechanisms underlying its influence on dopaminergic neurons are poorly understood. In this study, we investigated the ability of synthetic CS oligosaccharides and natural polysaccharides to promote the neurite outgrowth of mesencephalic dopaminergic neurons and the signaling pathways activated by CS. CS-E polysaccharide, but not CS-A, -C or -D polysaccharide, facilitated the neurite outgrowth of dopaminergic neurons at CS concentrations within the physiological range. The stimulatory effect of CS-E polysaccharide on neurite outgrowth was completely abolished by its digestion into disaccharide units with chondroitinase ABC. Similarly to CS-E polysaccharide, a synthetic tetrasaccharide displaying only the CS-E sulfation motif stimulated the neurite outgrowth of dopaminergic neurons, whereas a CS-E disaccharide or unsulfated tetrasaccharide had no effect. Analysis of the molecular mechanisms revealed that the action of the CS-E tetrasaccharide was mediated through midkine-pleiotrophin/protein tyrosine phosphatase zeta and brain-derived neurotrophic factor/tyrosine kinase B receptor pathways, followed by activation of the two intracellular phospholipase C (PLC) signaling cascades: PLC/protein kinase C and PLC/inositol 1,4,5-triphosphate/inositol 1,4,5-triphosphate receptor signaling leading to intracellular Ca(2+) concentration-dependent activation of Ca(2+)/calmodulin-dependent kinase II and calcineurin. These results indicate that a specific sulfation motif, in particular the CS-E tetrasaccharide unit, represents a key structural determinant for activation of midkine, pleiotrophin and brain-derived neurotrophic factor-mediated signaling, and is required for the neuritogenic activity of CS in dopaminergic neurons.
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PMID:Activation of phospholipase C pathways by a synthetic chondroitin sulfate-E tetrasaccharide promotes neurite outgrowth of dopaminergic neurons. 1768 Sep 89

We propose that the extracellular matrix (ECM) signals CD44, a hyaluronan receptor, to increase the responsiveness to mechanical stimulation in the rat hind paw. We report that intradermal injection of hyaluronidase induces mechanical hyperalgesia, that is inhibited by co-administration of a CD44 receptor antagonist, A5G27. The intradermal injection of low (LMWH) but not high (HMWH) molecular weight hyaluronan also induces mechanical hyperalgesia, an effect that was attenuated by pretreatment with HMWH or A5G27. Pretreatment with HMWH also attenuated the hyperalgesia induced by hyaluronidase. Similarly, intradermal injection of A6, a CD44 receptor agonist, produced hyperalgesia that was inhibited by HMWH and A5G27. Inhibitors of protein kinase A (PKA) and Src, but not protein kinase C (PKC), significantly attenuated the hyperalgesia induced by both A6 and LMWH. Finally, to determine if CD44 receptor signaling is involved in a preclinical model of inflammatory pain, we evaluated the effect of A5G27 and HMWH on the mechanical hyperalgesia associated with the inflammation induced by carrageenan. Both A5G27 and HMWH attenuated carrageenan-induced mechanical hyperalgesia. Thus, while LMWH acts at its cognate receptor, CD44, to induce mechanical hyperalgesia, HMWH acts at the same receptor as an antagonist. That the local administration of HMWH or A5G27 inhibits carrageenan-induced hyperalgesia supports the suggestion that carrageenan produces changes in the ECM that contributes to inflammatory pain. These studies define a clinically relevant role for signaling by the hyaluronan receptor, CD44, in increased responsiveness to mechanical stimulation.
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PMID:Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation. 2699 9