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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The signaling messengers for the regulation of intracellular calcium-dependent functions involve a phospholipid-sensitive protein kinase (protein kinase C) modulated by diacylglycerol, which is a product of phosphoinositide degradation. We found that protein kinase C activity is two times higher in the epithelium than in the stroma-endothelial layers of the rabbit cornea. 12-0-tetradecanoylphorbol-13-acetate (TPA) and phosphatidylserine stimulate protein kinase C at low Ca2+ concentrations. The TPA-phosphatidylserine stimulated activity of corneal epithelium was recovered in the soluble fraction; in the membrane-bound fraction, a very active phosphatidylinositol kinase accounted for half the basal phosphorylation of the corneal epithelium.
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PMID:Calcium- and phospholipid-dependent protein kinase C and phosphatidylinositol kinase: two major phosphorylation systems in the cornea. 303 19

The transneuronal spread of a virulent wild-type herpes simplex virus type 2 (HSV-2) and its US3 protein kinase-deficient (US3 PK-) mutant was immunohistochemically studied in mice after inoculations into the cornea, anterior chamber, tongue, and masseter muscle. After corneal inoculation, the wild-type virus was demonstrated in various brain stem areas including the trigeminal tract and nucleus, the reticular formation, and cerebellar nucleus group. Viral antigen-positive neurons were strictly confined to the ipsilateral spinal trigeminal nucleus in mice corneally infected with the US3 PK- mutant. No viral antigens were detected in the central nervous system (CNS) after inoculation with the mutant into the tongue and masseter muscle. However, when mice were immunosuppressed by treatment with cyclophosphamide, both the corneally infected mutant and wild-type virus could invade the CNS. The results suggest that the US3 PK- mutant principally retains the capacity to spread in the CNS.
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PMID:Immunohistochemical studies on the transneuronal spread of virulent herpes simplex virus type 2 and its US3 protein kinase-deficient mutant after ocular inoculation. 870 64

Keratinocyte growth factor (KGF), also called fibroblast growth factor-7, is widely known as a paracrine growth and differentiation factor that is produced by mesenchymal cells and has been thought to act specifically on epithelial cells. Here it is shown to affect a new cell type, the microvascular endothelial cell. At subnanomolar concentrations KGF induced in vivo neovascularization in the rat cornea. In vitro it was not effective against endothelial cells cultured from large vessels, but did act directly on those cultured from small vessels, inducing chemotaxis with an ED50 of 0.02-0.05 ng/ml, stimulating proliferation and activating mitogen activated protein kinase (MAPK). KGF also helped to maintain the barrier function of monolayers of capillary but not aortic endothelial cells, protecting against hydrogen peroxide and vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) induced increases in permeability with an ED50 of 0.2-0.5 ng/ml. These newfound abilities of KGF to induce angiogenesis and to stabilize endothelial barriers suggest that it functions in microvascular tissue as it does in epithelial tissues to protect them against mild insults and to speed their repair after major damage.
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PMID:Keratinocyte growth factor induces angiogenesis and protects endothelial barrier function. 1034 Dec 22

In animal models of herpes simplex virus type 1 (HSV-1) infection, ICP34.5-null viruses are avirulent and also fail to grow in a variety of cultured cells due to their inability to prevent RNA-dependent protein kinase (PKR)-mediated inhibition of protein synthesis. We show here that the inability of ICP34.5 mutants to grow in vitro is due specifically to the accumulation of phosphorylated eIF2 alpha. Mutations suppressing the in vitro phenotype of ICP34.5-null mutants have been described which map to the unique short region of the HSV-1 genome, resulting in dysregulated expression of the US11 gene. Despite the inability of the suppressor mutation to suppress the avirulent phenotype of the ICP34.5-null parental virus following intracranial inoculation, the suppressor mutation enhanced virus growth in the cornea, trigeminal ganglia, and periocular skin following corneal infection compared to that with the ICP34.5-null virus. The phosphorylation state of eIF2 alpha following in vitro infection with the suppressor virus was examined to determine if in vivo differences could be attributed to differential regulation of eIF2 alpha phosphorylation. The suppressor virus prevented accumulation of phosphorylated eIF2 alpha, while the wild-type virus substantially reduced eIF2 alpha phosphorylation levels. These data suggest that US11 functions as a PKR antagonist in vivo, although its activity may be modulated by tissue-specific differences in translation regulation.
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PMID:In vivo replication of an ICP34.5 second-site suppressor mutant following corneal infection correlates with in vitro regulation of eIF2 alpha phosphorylation. 1266 69

Activation of protein kinase C (PKC) by exposure of cultured human corneal epithelial cells to phorbol 12-myristate 13-acetate (PMA) resulted in an increase in paracellular permeability as evidenced by a decrease in transepithelial electrical resistance (TER). A change in the membrane distribution of the tight junction protein ZO-1 was also observed in the PMA-treated cells. In contrast, when the cells were treated with PMA in the presence of PD98059, a specific inhibitor of mitogen-activated protein kinase (MAPK) kinase, all barrier characteristics were preserved, suggesting that PKC induces tight junction disruption through the activation of MAPK. The role of this signaling pathway in the regulation of epithelial permeability was further elucidated by the use of corneal epithelial-derived cell lines expressing constitutively activated (ca) or dominant-negative (dn) mutants of MAPK kinase-1 (MEK1). Transfectants of caMEK1, when compared to parental cells, had higher levels of phosphorylated extracellular regulated protein kinase (ERK), altered distribution of ZO-1 and occludin, and much reduced TER. On the other hand, dnMEK1 transfectants had lower but detectable levels of ERK phosphorylation, more flattened morphology, and, most importantly, significantly higher TER when compared to parental cells. Our study demonstrates that activation of PKC causes the disruption of tight junctions through activation of MAP kinase and that the MAP kinase signaling pathway plays a key role in the regulation of epithelial cell morphology and barrier function in the cornea.
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PMID:Activation of ERK1/2 MAP kinase pathway induces tight junction disruption in human corneal epithelial cells. 1466 34

This review focuses on the experimental evidence supporting a role for endogenous electric fields in wound healing in vertebrates. Most wounds involve the disruption of epithelial layers composing the epidermis or surrounding organs in the body. These epithelia generate a steady voltage across themselves that will drive an injury current out of the wounded region, generating a lateral electric field that has been measured in four different cases to be 40-200 mV/mm. Many epithelial cells, including human keratinocytes, have the ability to detect electric fields of this magnitude and respond with directed migration. Their response typically requires Ca2+ influx, the presence of specific growth factors and intracellular kinase activity. Protein kinase C is required by neural crest cells and cAMP-dependent protein kinase is used in keratinocytes while mitogen-activated protein kinase is required by corneal epithelial cells. Several recent experiments support a role for electric fields in the stimulation of wound healing in the developing frog neurula, adult newt skin and adult mammalian cornea. Some experiments indicate that when the electric field is removed the wound healing rate is 25% slower. In addition, nearly every clinical trial using electric fields to stimulate healing in mammalian wounds reports a significant increase in the rate of healing from 13 to 50%. However, these trials have utilized many different field strengths and polarities, so much work is needed to optimize this approach for the treatment of mammalian wounds.
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PMID:A role for endogenous electric fields in wound healing. 1471 Oct 11

To evaluate the anti-HSV-1 mechanisms of murine IFN-beta in ocular infection, mice were transduced with an adenoviral vector expressing murine IFN-beta (Ad:IFN-beta). Ocular transduction with Ad:IFN-beta resulted in enhanced survival following infection with HSV-1. The protective effect was associated with a reduction in 1) viral titer, 2) viral gene expression, 3) IFN-gamma levels, and 4) the percentage of CD8(+) T lymphocyte and NK cell infiltration in infected tissue. Expression of IFN-beta resulted in an elevation of the IFN-induced antiviral gene 2',5'-oligoadenylate synthetase (OAS1a) but not dsRNA-dependent protein kinase R (PKR) in the cornea and trigeminal ganglion (TG). Mice deficient in the downstream effector molecule of the OAS pathway, RNase L, were no more sensitive to ocular HSV-1 compared with wild-type controls in the TG based on measurements of viral titer. However, the efficacy of Ad:IFN-beta was transiently lost in the eyes of RNase L mice. By comparison, PKR-deficient mice were more susceptible to ocular HSV-1 infection, and the antiviral efficacy following transduction with Ad:IFN-beta was significantly diminished in the eye and TG. These results suggest that PKR is central in controlling ocular HSV-1 infection in the absence of exogenous IFN, whereas the OAS pathway appears to respond to exogenous IFN, contributing to the establishment of an antiviral environment in a tissue-restricted manner.
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PMID:Distinctive roles for 2',5'-oligoadenylate synthetases and double-stranded RNA-dependent protein kinase R in the in vivo antiviral effect of an adenoviral vector expressing murine IFN-beta. 1510 Mar 8

Activated protein C (APC), a natural anticoagulant, has recently been demonstrated to activate the mitogen-activated protein kinase (MAPK) pathway in endothelial cells in vitro. Because the MAPK pathway is implicated in endothelial cell proliferation, it is possible that APC induces endothelial cell proliferation, thereby causing angiogenesis. We examined this possibility in the present study. APC activated the MAPK pathway, increased DNA synthesis, and induced proliferation in cultured human umbilical vein endothelial cells dependent on its serine protease activity. Antibody against the endothelial protein C receptor (EPCR) inhibited these events. Early activation of the MAPK pathway was inhibited by an antibody against protease-activated receptor-1, whereas neither late and complete activation of the MAPK pathway nor endothelial cell proliferation were inhibited by this antibody. APC activated endothelial nitric oxide synthase (eNOS) via phosphatidylinositol 3-kinase-dependent phosphorylation, followed by activation of protein kinase G, suggesting that APC bound to EPCR might activate the endothelial MAPK pathway by a mechanism similar to that of VEGF. APC induced morphogenetic changes resembling tube-like structures of endothelial cells, whereas DIP-APC did not. When applied topically to the mouse cornea, APC clearly induced angiogenesis in wild-type mice, but not in eNOS knockout mice. These in vitro events induced by APC might at least partly explain the angiogenic activity in vivo. This angiogenic activity of APC might contribute to maintain proper microcirculation in addition to its antithrombotic activity.
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PMID:Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. 1516 95

The present study investigated the role of interferon-inducible pathways in herpes simplex virus type 1-infected mice transduced with an adenoviral vector expressing murine interferon-beta (Ad:IFN-beta). Wild type mice or RNase L(-/-) mice deficient in responses to 2'-5' oligoadenylate synthetase activation, or lacking RNA-dependent protein kinase and transduced with Ad:IFN-beta showed enhanced survival following HSV-1 infection. The protective effect was associated with a reduction in viral gene expression in the cornea and trigeminal ganglion in wild type mice as well as the trigeminal ganglion of RNase L(-/-) mice. However, the efficacy of Ad:IFN-beta was lost in the corneas of RNase L(-/-) mice and significantly diminished in both the cornea and trigeminal ganglion as measured by viral gene expression in RNA-dependent protein kinase deficient mice. Collectively, the data suggest survival rates of viral-infected mice do not reflect the replication capacity as measured by herpes simplex virus type one lytic gene expression.
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PMID:Dichotomy between survival and lytic gene expression in RNase L- and PKR-deficient mice transduced with an adenoviral vector expressing murine IFN-beta following ocular HSV-1 infection. 1567 Jul 95

An adenoviral (Ad) vector containing the murine IFN-gamma transgene (Ad:IFN-gamma) was evaluated for its capacity to inhibit HSV-1. To measure effectiveness, viral titers were analyzed in cornea and trigeminal ganglia (TG) during acute ocular HSV-1 infection. Ad:IFN-gamma potently suppressed HSV-1 replication in a dose-dependent fashion, requiring IFN-gamma receptor. Moreover, Ad:IFN-gamma was effective when delivered -72 and -24 h before infection as well as 24 h postinfection. Associated with antiviral opposition, TG from Ad:IFN-gamma-transduced mice harbored fewer T cells. Also related to T cell involvement, Ad:IFN-gamma was effective but attenuated in TG from alphabeta TCR-deficient mice. In corneas, alphabeta TCR(+) T cells were obligatory for protection against viral multiplication. Type I IFN involvement amid antiviral efficacy of Ad:IFN-gamma was further investigated because types I and II IFN pathways have synergistic anti-HSV-1 activity. Ad:IFN-gamma inhibited viral reproduction in corneas and TG from alphabeta IFNR-deficient (CD118(-/-)) mice, although viral titers were 2- to 3-fold higher in cornea and TG compared with wild-type mice. The absence of IFN-stimulated antiviral proteins, 2'-5' oligoadenylate synthetase/RNase L, and dsRNA-dependent protein kinase R completely eliminated the antiviral effectiveness of Ad:IFN-gamma. Collectively, the results demonstrate the following: 1) nonexistence of type I IFN receptor does not abolish defense of Ad:IFN-gamma against HSV-1; 2) antiviral pathways oligoadenylate synthetase-RNase L and protein kinase R are mandatory; and 3) alphabeta TCR(+) T cells are compulsory for Ad:IFN-gamma effectiveness against HSV-1 in cornea but not in TG.
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PMID:Oligoadenylate synthetase/protein kinase R pathways and alphabeta TCR+ T cells are required for adenovirus vector: IFN-gamma inhibition of herpes simplex virus-1 in cornea. 1740 99


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