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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipocortin I (LPC-I, also called annexin I) is a 35-kD protein that binds phospholipids and actin in a Ca(++)-dependent manner. It is also a major substrate for EGF receptor/kinase and protein kinase C, and a putative inhibitor of phospholipase A2, which produces chemical mediators to cause inflammation. Psoriasis (PS) is an inflammatory skin disease characterized by a rapid turnover of keratinocytes and a defect in keratinization with increased activities of phospholipase C and A2, and EGF receptor. To understand the mechanism of the PS lesion formation and the function of LPC-I, its distribution was studied in the epidermis of PS, subacute eczema and normal skin, and in tumor cells of seborrheic keratosis and Bowen's disease. This study involved immunofluorescence and immunoblotting using affinity-purified polyclonal and monoclonal antibodies specific to LPC-I and to its Ca(++)-bound form. In normal, nonlesional PS and subacute eczema epidermis, LPC-I was detected mainly in the cytoplasm of the suprabasal cells, although it was on the inner aspects of the plasma membrane in some parts of the granular layer. In lesional epidermis of PS, it was localized mainly on the inner aspects of the plasma membrane, but not in the cytoplasm of the whole suprabasal cells as the Ca(++)-bound form, indicating a preferential localization on the plasma membrane. This membrane-binding of LPC-I was also observed in seborrheic keratosis, but not in Bowen's disease. These results suggest that the binding of LPC-I to the plasma membrane occurs actually in living cells, plays a role, not necessarily disease specific, in the PS lesion formation, and has some relevance to normal or abnormal differentiation of keratinocytes.
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PMID:Lipocortin I (annexin I) is preferentially localized on the plasma membrane in keratinocytes of psoriatic lesional epidermis as shown by immunofluorescence microscopy. 183 17

Evidence suggests that the phospholipase C/protein kinase C signal transduction system participates in the regulation of epidermal cell growth and differentiation. Psoriatic epidermis is characterized by hyperproliferation, defective differentiation, and inflammation. In this report, we have determined the activity of phospholipase C-catalyzed hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) and 1,2-diacylglycerol content in normal and psoriatic involved and uninvolved epidermis. 1,2-diacylglycerol is formed from phospholipase C-catalyzed hydrolysis of PIP2 and is the physiologic activator of protein kinase C. PIP2 hydrolysis was assayed in soluble and particulate fractions prepared from keratome biopsies of normal and psoriatic skin. Total lipids were extracted from normal and psoriatic epidermis and 1,2-diradylglycerol (a mixture of 1,2-diacylglycerol and 1-ether, 2-acyl-glycerol) quantitated by enzyme assay. Because 1,2-diacylglycerol is a more potent activator of protein kinase C, the relative proportions of 1,2-diacyl and 1-ether, 2-acylglycerol in uninvolved and involved psoriatic epidermis were determined. This was accomplished by separation of acetate derivatives of 1,2-diacylglycerol and 1-ether, 2-acyl-glycerol by thin layer chromatography. Soluble and membrane-associated phospholipase C-catalyzed PIP2 hydrolysis were increased 3.7 times (p less than 0.001) and 3 times (p less than 0.004), respectively, in psoriatic involved compared to uninvolved and normal epidermis. 1,2-diradylglycerol content was also significantly elevated (3 times, p less than 0.01) in psoriatic involved versus uninvolved and normal epidermis. Analysis of the acetate derivatives of 1,2-diradylglycerol in psoriatic uninvolved and involved epidermis revealed that 1,2-diacylglycerol was the major species (86% and 95%, respectively). There were no significant differences in either phospholipase C-catalyzed PIP2 hydrolysis or 1,2-diacylglycerol content between uninvolved and normal epidermis. 1,2-diacylglycerol purified from normal and involved psoriatic epidermis was capable of activating protein kinase C from normal epidermis in vitro. In epidermal slices, activation of protein kinase C by addition of 12-0-tetradecanoylphorbol-13-acetate and 1,2-diacylglycerol (1,2-dioctanoylglycerol) resulted in subsequently decreased protein kinase C activity, a process termed down-regulation. These data are consistent with the possibility that the elevation in lesional 1,2-diacylglycerol content may account, in part, for the previously reported reduction of protein kinase C activity in psoriasis (Horn, Marks, Fisher, et al: J Invest Dermatol 88:220-222, 1987).
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PMID:Increased phospholipase C-catalyzed hydrolysis of phosphatidylinositol-4,5-bisphosphate and 1,2-sn-diacylglycerol content in psoriatic involved compared to uninvolved and normal epidermis. 217 May 39

Phosphatidylinositol (PI) kinase is activated by growth factors, such as epidermal growth factor (EGF), and is thought to be involved in cellular proliferation. Psoriasis is a hyperproliferative epidermal disease in which EGF receptor expression is altered and phospholipase C activity is increased. Considering the potential importance of growth factor stimulated phosphoinositide metabolism in the genesis of abnormal growth, we measured PI kinase activity in epidermal keratome biopsies from normal skin and the lesional and nonlesional skin of psoriatic patients. The PI kinase activity in 10 psoriatic involved plaques was increased 6.7-fold (Vmax = 67.1 +/- 23.9 pmol formed/min/mg protein +/- SE) when compared with 11 normal epidermal biopsies (Vmax = 10.0 +/- 1.3 pmol/min/mg protein, p less than 0.025). Similar results were noted when enzyme activity was standardized using DNA content. The apparent Km of PI kinase for ATP in involved psoriatic biopsies (0.45 +/- 0.14 mM) was also significantly (p less than 0.025) increased compared with normals (0.11 +/- 0.02 mM). The PI kinase activity in 11 biopsies of nonlesional psoriatic epidermis was not statistically different from normal epidermis. Both psoriatic and normal PI kinases required Mg++ and were inhibited by Ca++. The polyamine, spermine, a known activator of PI kinase in other tissues, stimulated normal but not psoriatic epidermal PI kinase. Both normal and psoriatic PI kinase activities had an apparent mol wt of 85,000. Increased synthesis of phosphoinositides by PI kinase in psoriatic tissue may provide more substrate for phospholipase C; a key enzyme in growth factor-mediated signal transduction.
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PMID:Increased phosphatidylinositol kinase activity in psoriatic epidermis. 254 14

Hyperproliferation of keratinocytes (KCs) in psoriasis has been found to be associated with excessive activation of a phospholipase C (PLC)/protein kinase C (PKC) signal transduction system. The molecular species of PLCs which are activated in psoriasis have not been thoroughly investigated. It was envisaged that if glycosylphosphatidylinositol (GPI)-specific PLC was activated in the membrane of psoriatic epidermal cells, it would render these cells devoid of those proteins which are anchored to the cell membrane through their GPI moiety. In order to test this possibility, four GPI proteins (CD16, CD55, CD58, and CD59) were determined immunohistochemically in normal and psoriatic skin. In normal skin, CD55 and CD59 were strongly expressed on epithelium and vascular structures, whereas CD16 and CD58 were strongly expressed only on epithelium. The expression of all four GPI proteins was decreased in non-lesional psoriatic skin and virtually abolished in lesional psoriatic skin. A control transmembrane protein, CD46, was strongly expressed in normal and non-lesional psoriatic skin, and its expression was not significantly decreased in psoriatic lesions. The absence or reduction of GPI proteins was not seen in the lesions of several other inflammatory and proliferative diseases studied.
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PMID:Glycosylphosphatidylinositol (GPI)-anchored membrane proteins are constitutively down-regulated in psoriatic skin. 751 54

1.25-dihydroxyvitamin D3 is of clinical importance (e.g. in the treatment of psoriasis) given its ability to regulate the proliferation and differentiation of human keratinocytes. 1.25-Dihydroxyvitamin D3 mediates its action via genomic and nongenomic pathways. The nongenomic actions begin with the activation of phospholipase C and the subsequent rapid rise in calcium within the cells. We incorporated 1.25-dihydroxyvitamin D3 in liposomes of varying compositions in an attempt to improve their effect/negative side effect ratio. The influence of empty liposomes (1 mM) and free and liposomally incorporated 1.25-dihydroxyvitamin D3 (10 nM) on the rapid release of sulfidoleucotrien and inositole 1,4,5 triphosphate was examined in keratinocytes in vitro. Free 10 nM 1.25-dihydroxyvitamin D3 provoked a rapid rise in sulfidoleucotriens within 30 seconds, followed by a swift decrease in sulfidoleucotrien and inositole 1,4,5-triphosphate concentration after 10 minutes. Empty liposomes and liposomal-incorporated 1.25-dihydroxyvitamin D3 did not show such a strong effect. These results suggest the occurrence of specific binding sites for 1.25-dihydroxyvitamin D3 on the membrane level that are incapable of recognizing 1.25-dihydroxyvitamin D3 trapped within liposomal membrane.
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PMID:Liposomal incorporation changes the effect of 1.25-dihydroxyvitamin D3 on the phospholipase C signal transduction pathway and the eicosanoid cascade on keratinocytes in vitro. 857 90

It has been proposed that toxins and other bacterial protein products of Staphylococcus aureus can act as triggers or persistence factors in several inflammatory skin diseases. In this study, we examined the S. aureus isolates from the skin of patients with atopic dermatitis and psoriasis. We found that the bacterial isolates from these patients exhibited either characteristic superantigenic toxins or thermolabile toxins believed to be staphylococcal alpha-toxin. All of these staphylococcal strains also secreted extracellular staphylococcal protein A. We found significant differences in the action of these toxins on human keratinocytes and keratinocyte cell lines. The superantigenic toxins toxic shock syndrome toxin-1, staphylococcal enterotoxins A and B, and exfoliative toxin-A, as well as staphylococcal protein A, did not induce significant cytotoxic damage in the keratinocyte cell line HaCaT, whereas the staphylococcal alpha-toxin produced profound cytotoxicity. Keratinocyte cytotoxicity induced by staphylococcal alpha-toxin was time and concentration dependent and demonstrated the morphologic and functional characteristics of necrosis, not apoptosis. Addition of alpha-toxin to keratinocytes simultaneously induced cell lysis and tumor necrosis factor-alpha release into the medium within 30 min; apparently, it was constitutive tumor necrosis factor-alpha. On the other hand, superantigenic toxins and, in particular, protein A showed stimulation of tumor necrosis factor-alpha secretion in keratinocytes and release of this cytokine after 6-12 h of incubation. Thus, staphylococcal protein A, alpha-toxin, and superantigenic toxins found in S. aureus isolates from patients with psoriasis and atopic dermatitis can produce direct pro-inflammatory effects on keratinocytes through the release of tumor necrosis factor-alpha. We propose that these effects may be relevant to the induction and persistence of lesions in these two diseases.
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PMID:Staphylococcal toxins and protein A differentially induce cytotoxicity and release of tumor necrosis factor-alpha from human keratinocytes. 882 68

Keratinocytes produce vitamin D3, metabolize it to its most biologically active form, 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), and respond to the 1,25(OH)2D3 they produce with a decrease in proliferation and an increase in differentiation. 1,25(OH)2D3 production by keratinocytes is tightly controlled and changes as the cells differentiate, increasing during the early stages of differentiation, then decreasing again as terminal differentiation ensues. The 1,25(OH)2D3 produced endogenously or supplied exogenously acts in concert with calcium to stimulate the transition from a proliferating basal cell to a terminally differentiated corneocyte. The mRNA levels for proteins involved in the differentiation process are controlled not only by calcium- and 1,25(OH)2D3-induced increase in gene transcription, but by subsequent calcium- and 1,25(OH)2D3-induced destabilization of the mRNA after adequate levels of the proteins have been produced. 1,25(OH)2D3 increases intracellular calcium in part by inducing phospholipase C, which when activated by hormones, cleaves phosphoinositol bisphosphate into two important signaling molecules inositol tris phosphate and diacylglycerol. Inositol tris phosphate releases intracellular calcium from intracellular stores, and the increase in intracellular calcium opens up the nonspecific cation channel through which calcium enters the cell. Diacylglycerol and intracellular calcium promote protein kinase C activity that can further enhance the differentiation process. These actions of 1,25(OH)2D3 provide the rationale for the effectiveness of 1,25(OH)2D3 and its analogs in psoriasis.
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PMID:1,25(OH)2D3-modulated calcium induced keratinocyte differentiation. 962 87

Skin infections with Staphylococcus aureus are not only an important cause of morbidity and even mortality, but are thought to serve as initiation and/or persistance factors for numerous inflammatory skin diseases, including psoriasis and atopic dermatitis. One mechanism by which S. aureus can modulate the immune system is through the production of proteins such as superantigenic toxins, Protein A, as well through the cytolytic alpha-toxin. This review serves to discuss the biology of these three types of proteins, with emphasis on their ability to stimulate the production of powerful pro-inflammatory lipid- and protein-derived cytokines in keratinocytes. Characterization of interactions between these proteins and the keratinocyte can provide a better understanding of how bacterial infection modulates inflammatory skin diseases, as well as provide the basis for improved therapies involving antibacterial agents.
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PMID:The keratinocyte as a target for staphylococcal bacterial toxins. 1192 32

A neuropeptide substance P is related to skin inflammation. Interferon-induced protein of 10 kDa (IP-10) chemoattracts T helper 1 cells, and interferon-induced protein of 10 kDa production by keratinocytes is enhanced in inflammatory skin diseases such as psoriasis. We examined the in vitro effects of substance P on interferon-induced protein of 10 kDa production by human keratinocytes. Though substance P alone did not induce interferon-induced protein of 10 kDa production, it enhanced interferon-induced protein of 10 kDa secretion, mRNA expression, and promoter activity induced by suboptimal concentrations of interferon-gamma. Interferon-stimulated response element and two nuclear factor-kappaB sites on interferon-induced protein of 10 kDa promoter were responsible for the enhancement by substance P. Substance P alone enhanced transcriptional activity and transcription factor binding through the two nuclear factor-kappaB sites, whereas it did not alter interferon-gamma-induced transcriptional activity and transcription factor binding through interferon-stimulated response element. The effects of substance P on interferon-induced protein of 10 kDa production and nuclear factor-kappaB activation were inhibited by neurokinin-1 receptor antagonist, phospholipase C inhibitor, intracellular Ca2+ chelator, and anti-oxidant. These results suggest that substance P may induce nuclear factor-kappaB activation and interferon-induced protein of 10 kDa production in synergy with interferon-gamma via neurokinin-1 receptor on keratinocytes. These effects of substance P may be mediated via phospholipase C activation, intra-cellular Ca2+ signal, and reactive oxygen intermediates.
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PMID:Substance P enhances the production of interferon-induced protein of 10 kDa by human keratinocytes in synergy with interferon-gamma. 1248 30

Nerve growth factor induces innervation and epidermal hyperplasia in inflammatory skin diseases like psoriasis. Nerve growth factor production by keratinocytes is increased in the inflammatory lesions. Nerve growth factor induces histamine release from mast cells. We examined the in vitro effects of histamine on nerve growth factor production in human keratinocytes. Histamine enhanced nerve growth factor secretion, mRNA expression, and promoter activity in keratinocytes. Two TPA-response elements on the nerve growth factor promoter were responsible for the activation by histamine. Histamine enhanced transcriptional activity and DNA binding of activator protein 1 at the two TPA-response elements. It shifted the TPA-response-element-binding activator protein 1 composition from c-Jun homodimers to c-Fos/c-Jun heterodimers. Histamine transiently induced c-Fos mRNA expression, which was not detectable in unstimulated keratinocytes, whereas c-Jun mRNA expression was constitutive and was not altered by histamine. Histamine-induced enhancement of nerve growth factor secretion, promoter activity, activator protein 1 transcriptional activity, and c-Fos expression was suppressed by H1 antagonist pyrilamine, protein kinase C inhibitor calphostin C, and PD98059, an inhibitor of mitogen-activated protein kinase kinase 1. Histamine induced the translocation of protein kinase C activity from cytosol to membrane, which was suppressed by phospholipase C inhibitor U73122. It stimulated the phosphorylation of extracellular signal-regulated kinase, which was blocked by pyrilamine, calphostin C, and PD98059. These results suggest that histamine may enhance nerve growth factor production by inducing c-Fos expression in keratinocytes. These effects may be mediated by the H1-receptor-induced signaling cascade of phospholipase C-protein kinase C-mitogen-activated protein kinase kinase 1-extracellular signal-regulated kinase.
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PMID:Histamine enhances the production of nerve growth factor in human keratinocytes. 1292 17


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