Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the response of a human squamous cell carcinoma cell line, SCC-12F, to human complement attack and found that the cells were completely resistant to complement lysis. In the absence of lysis, there was significant C3 deposition and C5b-9 deposition on the cells. Removal of the lipid-linked complement regulatory proteins CD59 and decay-accelerating factor (DAF) by treatment of the cells with phosphatidylinositol-specific phospholipase C (PIPLC) resulted in increased C3b and C5b-9 deposition on the cells and a slight increase in cell death. Treatment of the cells with complement caused them to release membrane vesicles containing the terminal complement proteins. In addition, complement induced SCC-12F to produce significant amounts of prostaglandin F2alpha (PGF2alpha). We conclude that CD59 and DAF are important in the resistance of SCC-12F to complement and that these cells produce membrane vesicles and PGF2alpha in response to complement attack. These responses, in the absence of cell death, may be important in the pathogenesis of inflammatory skin disease in which complement is deposited.
J Invest Dermatol 1997 Jul
PMID:Response of SCC-12F, a human squamous cell carcinoma cell line, to complement attack. 920 53

Release of inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) generated by phospholipase C (PLC) upon receptor stimulation plays an important role in the regulation of cell growth and differentiation. A second, completely different, signal transduction system involves retinoic acid (RA) and related derivatives. Binding to intracellular receptor sites can modulate keratinocyte growth and inhibits differentiation. The present study was aimed at characterizing possible interactions between the two signalling pathways in HaCaT keratinocytes. As determined by anion exchange chromatography and HPLC analysis, HaCaT keratinocytes treated with 1 microM RA for up to 72 h showed a marked decrease in Ins(1,4,5)P3 release upon stimulation with 10 microM bradykinin or 10 microM ionomycin. Thin-layer chromatography of phosphatidylinositol phosphates, the substrates of PLC, revealed no differences between RA-treated and untreated cells. Western blot analysis of the PLC isozymes present in HaCaT cells, PLC beta 3 and PLC gamma 1, showed no alterations in the expression of these proteins in RA-treated cells as compared to vehicle-treated controls. In addition, expression of the PLC-activating G protein G alpha q was not affected by RA treatment. Our results show that RA downregulates the PLC-mediated signaling system. The point of interference of this signal transduction crosstalk has yet to be elucidated. Our results suggest, furthermore, that RA-induced attenuation of keratinocyte differentiation might be mediated at least in part by the downregulation of Ins(1,4,5)P3 release.
Arch Dermatol Res 1997 Aug
PMID:Retinoic acid attenuates phospholipase C-mediated signaling in HaCaT keratinocytes. 934 74

We previously found that the binding of pemphigus IgG to desmogleins caused marked activation of phospholipase C, a transient increase in inositol 1,4,5-trisphosphate production, and a concomitant increase in the intracellular calcium concentration in DJM-1 cells, a squamous cell carcinoma line. The binding of pemphigus IgG to cell membranes increased the activity of urokinase plasminogen activator in culture medium and induced subsequent cell-cell detachment in DJM-1 cells. Because urokinase plasminogen activator activates the conversion of plasminogen to plasmin by binding to urokinase plasminogen activator receptor evading inhibitors in serum, it is likely that plasmin is generated only in microenvironments adjacent to urokinase plasminogen activator receptor on the cell surface. It is not known whether pemphigus IgG causes acantholysis by inducing urokinase plasminogen activator receptor expression on the cell surface and secreting urokinase plasminogen activator in inhibitor-rich environments. We examined the effects of pemphigus IgG on urokinase plasminogen activator receptor expression in DJM-1 cells and normal keratinocytes by immunoblot analysis and immunofluorescence microscopy using antibodies to urokinase plasminogen activator receptor. IgG were obtained from serum samples from eight patients with bullous pemphigoid, five patients with pemphigus vulgaris, seven patients with pemphigus foliaceus, and eight normal subjects. Pemphigus vulgaris and pemphigus foliaceus IgG significantly increased the urokinase plasminogen activator receptor expression on the surface of DJM-1 cells and normal keratinocytes after 3- and 7-d incubation compared with normal IgG. These results suggest that enhanced urokinase plasminogen activator activity and urokinase plasminogen activator receptor expression activates plasmin in the limited cell surface of pemphigus IgG-bound keratinocytes and may contribute to the pathogenesis of differential acantholysis in pemphigus vulgaris and pemphigus foliaceus.
J Invest Dermatol 1997 Nov
PMID:Pemphigus IgG induces expression of urokinase plasminogen activator receptor on the cell surface of cultured keratinocytes. 934 94

Squamous cell carcinomas (SCC) derived from human epidermis fail to differentiate normally under the influence of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] despite the presence of the vitamin D receptor. Previous studies from our laboratory showed that phospholipase C-gamma1 (PLC-gamma1) was upregulated transcriptionally by 1,25(OH)2D3 in normal human keratinocytes, and a vitamin D responsive element (VDRE) in its promoter region has been identified. To examine the inducibility of human PLC-gamma1 transcription by 1,25(OH)2D3 and/or retinoic acid in SCC cell lines, we transiently transfected SCC4 and SCC12B2 cells with human PLC-gamma1 promoter-luciferase constructs containing the VDRE and tested the response of these constructs to 1,25(OH)2D3 and/or all-trans retinoic acid. The induction of the human PLC-gamma1 VDRE by 1,25(OH)2D3 was synergistic with all-trans retinoic acid in normal human keratinocytes, but none of the constructs was induced by 1,25(OH)2D3 and/or all-trans retinoic acid in SCC4 and SCC12B2 cells. In contrast, the construct containing the VDRE of the human 24-hydroxylase gene was induced several fold by 1,25(OH)2D3 in normal human keratinocytes and by both 1,25(OH)2D3 and all-trans retinoic acid in SCC4 and SCC12B2 cells. DNA mobility shift assays showed that both the vitamin D receptor and the retinoic acid receptor in SCC4 and SCC12B2 cells bound the human PLC-gamma1 VDRE similarly to that seen in normal keratinocytes. The data indicate that the VDRE in the human PLC-gamma1 gene is not functional in SCC4 and SCC12B2 cells, unlike normal human keratinocytes, even though vitamin D receptors bind normally to it. Failure of transcriptional control of the PLC-gamma1 gene by 1,25(OH)2D3 suggests the lack of a cofactor(s) linking the VDRE to the transcriptional machinery.
J Invest Dermatol 1998 May
PMID:Differential regulation of vitamin D responsive elements in normal and transformed keratinocytes. 957 36

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.
J Investig Dermatol Symp Proc 1996 Apr
PMID:1,25(OH)2D3-modulated calcium induced keratinocyte differentiation. 962 87

Histamine is present in the epidermis in intracellular and extracellular area and is released from mast cells and keratinocytes in the early stage of inflammation of the skin. Such release may contribute to common itching or intensify the inflammatory responses. Histamine binds to its receptors and participate in regulation of the inflammatory responses by acting on endothelial cells, nerve endings, lymphocytes, monocytes, and leukocytes. Histamine has direct effects on keratinocytes as well. Histamine modulates the proliferation of keratinocytes. The binding of histamine to the receptor on keratinocyte membrane induces activation of adenylate cyclase and phospholipase C through GTP binding protein. We previously reported that histamine induces transient increase in intracellular Ca2+ in cultured normal human epidermal keratinocytes (NHEK) and normal epidermis. H1 and H2 histamine receptors are widely distributed in many tissues and cells. In this study, we investigated which types of histamine receptors are related to the increase in intracellular Ca2+ by histamine stimulation in cultured human epidermal keratinocytes. NHEK were cultured in serum-free KGM medium. With H1 antihistamines, mepyramine and diphenhydramine, histamine responses were moderately but not statistically significantly inhibited. With H2 antihistamine, cimetidine, histamine response was significantly inhibited. Epinephrine response was not affected by these antihistamines. Thus, it is considered that H2 antihistamines specifically block histamine-mediated increase in intracellular Ca2+ of cultured normal human keratinocytes.
J Dermatol Sci 1999 Sep
PMID:H2 histamine receptor-mediated increase in intracellular Ca2+ in cultured human keratinocytes. 1051 81

The precise mechanism of the acantholysis after pemphigus IgGs bind to desmoglein (Dsg) 3 and/or Dsg 1 on the cell surface is as yet unknown. We have previously reported that pemphigus IgG (P-IgG) causes a transient increase in intracellular calcium and inositol 1,4,5-trisphosphate concentration, and subsequent activation of protein kinase C (PKC) in DJM-1 cells, a squamous cell carcinoma line. In order to see whether phosphatidylcholine (PC)-specific phospholipase C (PLC) or phospholipase D (PLD) is involved in the P-IgG-induced signaling process, the production of 1,2-diacylglycerol (DAG) and phosphatidylbutanol (PBut), a potential marker for the determination of PLD activity in the presence of butanol, was determined in DJM-1 cells. A biphasic accumulation of DAG, which consisted of a first transient phase and a second sustained phase, was observed. The second phase of DAG accumulation was profoundly inhibited by pretreatment with D609, a selective inhibitor of PC-PLC, but not by propranolol, an inhibitor of phosphatidate phosphohydrolase. Pemphigus serum after preadsortion of antibodies to Dsg 3 and Dsg 1 with recombinant Dsg 3 and Dsg 1 did not show formation of DAG. PBut was not generated following the addition of P-IgG. In addition, the levels of [3H]phosphocholine, a direct metabolite of PC-PLC, were elevated after the addition of P-IgG. These results suggest that the PC-PLC pathway plays a major role in P-IgG-induced transmembrane signaling by causing prolonged generation of DAG, which may lead to long-term activation of PKC.
Arch Dermatol Res 1999 Nov
PMID:Phosphatidylcholine-specific phospholipase C, but not phospholipase D, is involved in pemphigus IgG-induced signal transduction. 1063 34

To investigate the effect of nucleotides on cytosolic free calcium mobilization and proliferation activity in HaCaT keratinocytes, nucleotides-induced intracellular free calcium concentration ([Ca(2+)](i)) and cell proliferation observed. [Ca(2+)](i) to the extracellular nucleotides was determined using Ca(2+) sensitive indicator, Fura-2/AM with digital video fluorescence imaging microscopy, and cell proliferation was evaluated by counting of cell number. An adenosine 5'-triphosphate (ATP)-induced [Ca(2+)](i) increase was observed from the concentration of 10(-8) M and was more conspicuous at higher concentrations in a concentration-dependent manner. Additionally, other nucleotides such as ADP, UTP, and 2-me-S-ATP also induced a [Ca(2+)](i) increase in a concentration-dependent manner. However, adenosine induced a slight increase of [Ca(2+)](i) only at 10(-3) M. alpha,-methylene-ATP did not evoke any rise in [Ca(2+)](i). The maximal response observed occurred with ATP and UTP at a concentration of 10(-4) M. The ATP-induced transient [Ca(2+)](i) increase was attenuated by the pretreatment with phospholipase C (PLC) inhibitor, U-73122 (10 microM) for 30 min. ATP-induced [Ca(2+)](i) increase and cell proliferation were inhibited by putative P2Y receptor antagonist, suramin (10(-4) M). When the HaCaT cells were stimulated with nucleotides on a concentration of 10(-4) M and cultured for 5 days, the order of effect on cell proliferation was observed to be ATP>UTP>ADP>2-me-S-ATP. Based on these results, we suggest that extracellular ATP stimulate HaCaT keratinocytes proliferation via purinoceptor-mediated [Ca(2+)](i) mobilization
J Dermatol Sci 2001 Feb
PMID:Purinoceptor-mediated calcium mobilization and proliferation in HaCaT keratinocytes. 1116 6

We studied the relationship between cAMP and house dust mite-induced cytokine production in T cells from mite-sensitive patients with atopic dermatitis. T cells from atopic dermatitis patients secreted high level of interleukin-13 (mean 851.1 pg per ml) when cultured with autologous monocytes pulsed with Dermatophagoides pteronyssinus extract. Dermato- phagoides pteronyssinus-induced interleukin-13 secretion was not detected in normal subjects. Adenylate cyclase inhibitor MDL 12,330A and cyclic nucleotide phosphodiesterase type 4 inhibitor rolipram blocked Dermatophagoides pteronyssinus-induced interleukin-13 secretion in atopic dermatitis T cells. In atopic dermatitis T cells, cAMP level rose at 5 min after Dermatophagoides pteronyssinus stimulus then decreased to the basal level at 1 h. MDL 12,330A blocked the Dermatophagoides pteronyssinus-induced cAMP elevation while rolipram blocked its reversal. In atopic dermatitis T cells, adenylate cyclase activity increased at 5 min after Dermatophagoides pteronyssinus stimulus, followed by the increase of cyclic nucleotide phosphodiesterase activity at 15 min. In atopic dermatitis T cells, phospholipase C inhibitor ET-18-OCH3 blocked Dermatophagoides pteronyssinus-induced activation of adenylate cyclase, while rolipram, protein kinase A inhibitor H-89, and MDL 12,330A blocked the activation of cyclic nucleotide phosphodiesterase. These results suggest that Dermatophagoides pteronyssinus may first increase cAMP in atopic dermatitis T cells by activating adenylate cyclase via phospholipase C, and next decrease cAMP by activating cyclic nucleotide phosphodiesterase 4 via protein kinase A, which may be activated by adenylate cyclase-generated cAMP signal. These events are required for interleukin-13 response Dermatophagoides pteronyssinus.
J Invest Dermatol 2001 Jan
PMID:Intracellular 3',5'-adenosine cyclic monophosphate level regulates house dust mite-induced interleukin-13 production by T cells from mite-sensitive patients with atopic dermatitis. 1116 92

We showed previously that pemphigus IgG enhanced both the activity of urokinase plasminogen activator (uPA) in cultured cells and the expression of its receptor (uPAR) on uPA-binding keratinocytes. In the present study, to clarify whether uPAR and uPA-activated plasmin are actually involved in the blistering process after pemphigus IgG binding to the cell surface, we examined the effects of the following on uPAR expression and on cell-cell detachment in DJM-1 cells, a squamous cell carcinoma line: (i) phosphatidylinositol-specific phospholipase C (PI-PLC) - which releases uPAR from the membrane surface into the culture medium by cleaving the glycosylphosphatidylinositol anchor thus inhibiting uPAR activity, and (ii) uPA inhibitors (tranexamic acid, aprotinin, p-aminobenzonic acid and dexamethasone). Preincubation with PI-PLC decreased dramatically the pemphigus IgG-induced uPAR expression in a dose-dependent manner, and inhibited pemphigus IgG-induced cell-cell detachment at 10 microg/mL. On the other hand, tranexamic acid (15 mM) inhibited pemphigus IgG-induced cell-cell detachment without reduction of uPAR expression, although aprotinin, p-aminobenzonic acid and dexamethasone failed to alter either of these parameters. Although uPAR expression on the pemphigus IgG-bound cell surface and uPA activation may contribute significantly to the pathogenesis of acantholysis in pemphigus, the mechanisms are complicated and should be defined further.
Clin Exp Dermatol 2001 May
PMID:Phosphatidylinositol-specific-phospholipase C cleaves urokinase plasminogen activator receptor from the cell surface and leads to inhibition of pemphigus-IgG-induced acantholysis in DJM-1 cells, a squamous cell carcinoma line. 1142 78


<< Previous 1 2 3 4 5 6 7 Next >>