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)

Intercellular adhesion molecule-1 (ICAM-1) is an inducible glycoprotein expressed on the surface of inflamed endothelium which mediates in part the extravasation of granulocytes into sites of infection or injury. ICAM-1 mRNA is not detected in unstimulated human umbilical vein endothelial cells (HUVECs), but accumulates transiently following tumor necrosis factor-alpha (TNF-alpha) or phorbol myristate acetate (PMA) treatment with maximal steady state levels occurring at 2 or 4 h, respectively. Pretreating HUVECs with PMA for 72 h down-regulates protein kinase C and inhibits the subsequent induction of ICAM-1 mRNA by PMA, but does not affect TNF-alpha-induced message accumulation. Nuclear run-on assays showed that the ICAM-1 gene is transcribed under basal conditions in HUVECs, and that TNF-alpha stimulates transcriptional activity 3- to 4-fold within 30 min of treatment. In contrast, PMA has little effect on ICAM-1 gene transcription up to 4 h following stimulation. Message stability studies established that ICAM-1 mRNA induced by PMA has a longer half-life than the TNF-alpha-induced message. These results suggest that PMA acts through protein kinase C to up-regulate ICAM-1 expression primarily at a post-transcriptional level by stabilizing ICAM-1 mRNA, whereas TNF-alpha transcriptionally regulates ICAM-1 gene expression through an undefined, protein kinase C-independent pathway.
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PMID:Intercellular adhesion molecule-1 gene expression in human endothelial cells. Differential regulation by tumor necrosis factor-alpha and phorbol myristate acetate. 135 Oct 55

Lysophosphatidylcholine (lyso-PC), a polar phospholipid product increased in atherogenic lipoproteins and atherosclerotic lesions, has been shown to differentially induce functional intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 and mRNA for platelet-derived growth factor (PDGF)-A and -B chains and heparin-binding epidermal growth factor-like growth factor in various cultured endothelial cells. In this study, we have demonstrated increased expression of cell- and matrix-associated forms of PDGF-B chain (PDGF-B) protein elicited by lyso-PC and further characterized potential signal transduction mechanisms responsible for lyso-PC-induced gene expression, focusing on PDGF-B and ICAM-1 genes in cultured human umbilical vein endothelial cell models. Cycloheximide almost completely inhibited PDGF-B but not ICAM-1 mRNA induction elicited by lyso-PC, suggesting that dependence on de novo protein synthesis for PDGF-B is different from that for ICAM-1. Prolonged exposure to phorbol myristate acetate (PMA), which depletes protein kinase C (PKC), or staurosporine, a PKC inhibitor, did not block lyso-PC-induced increases in PDGF-B or ICAM-1 mRNA. Forskolin and dibutyryl cAMP, which elevate intracellular cAMP levels, blocked both PDGF-B and ICAM-1 upregulation elicited by lyso-PC; however, these cAMP-elevating agents did not suppress ICAM-1 upregulation by PMA. Taken together, PDGF-B and ICAM-1 gene induction by lyso-PC may involve different signaling mechanisms; however, both appear to be independent of PMA-regulatable PKC activation but are suppressed by increased levels of intracellular cAMP.
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PMID:Elevated levels of cAMP inhibit protein kinase C--independent mechanisms of endothelial platelet-derived growth factor-B chain and intercellular adhesion molecule-1 gene induction by lysophosphatidylcholine. 764 23

We have identified 20-mer phosphorothioate oligodeoxynucleotides which potently (IC50 values of 100-200 nM) and specifically inhibit protein kinase C (PKC)-alpha mRNA and protein expression in human lung carcinoma (A549) cells. These oligonucleotides target multiple, diverse sites on PKC-alpha mRNA including the AUG translation codon and 3'-untranslated sequences. 2'-O-Methyl phosphorothioate analogs of these oligonucleotides were without effect on PKC-alpha mRNA levels, suggesting that the reduction in targeted PKC-alpha mRNA is through RNase H-mediated cleavage. One oligonucleotide, however, was effective at inhibiting PKC-alpha protein levels as a 2'-O-methyl phosphorothioate at concentrations 2-3-fold greater than its phosphorothioate/deoxy homolog. These results suggest that the ability to serve as an RNase H substrate, although not required for all oligonucleotides, certainly increases their potency. These oligonucleotides have been used to examine the role played by PKC-alpha in mediating the phorbol ester-induced changes in mRNA levels of the cell adhesion molecule ICAM-1. In A549 cells, ICAM-1 mRNA is increased 10-20-fold by treatment of cells with the phorbol ester phorbol 12-myristate 13-acetate. When PKC-alpha protein levels are depleted by oligonucleotide treatment of A549 cells, the increase in ICAM-1 expression in response to phorbol 12-myristate 13-acetate is greatly reduced, demonstrating that PKC-alpha plays a major role in this process.
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PMID:Inhibition of protein kinase C-alpha expression in human A549 cells by antisense oligonucleotides inhibits induction of intercellular adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. 791 67

Several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) are expressed by astrocytes, the predominant glial cell of the central nervous system (CNS). Such molecules are important in the trafficking of leukocytes to sites of inflammation, and in lymphocyte activation. ICAM-1 is constitutively expressed by neonatal rat astrocytes, and expression is enhanced by the proinflammatory cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma), with IL-1 beta and TNF-alpha being the strongest inducers. In this study, we have examined the nature of the second messengers involved in ICAM-1 gene expression induced by the cytokines IL-1 beta and TNF-alpha. Our results indicate that stimuli related to protein kinase C (PKC) such as the phorbol ester phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 increase ICAM-1 mRNA expression, whereas cyclic nucleotide analogs and PKA agonists have no effect. Pharmacologic inhibitors of PKC such as H7, H8, and calphostin C inhibit ICAM-1 gene expression inducible by IL-1 beta and TNF-alpha. Prolonged treatment of astrocytes with PMA results in a time-dependent downregulation of the PKC isoforms alpha, delta, and epsilon, and a concomitant diminution of ICAM-1 mRNA expression induced by IL-1 beta, TNF-alpha, and PMA itself at specific time points post-PMA treatment. These data, collectively, demonstrate a role for various PKC isoforms in IL-1 beta and TNF-alpha enhancement of ICAM-1 gene expression in rat astrocytes.
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PMID:Interleukin 1-beta- and tumor necrosis factor-alpha-mediated regulation of ICAM-1 gene expression in astrocytes requires protein kinase C activity. 853 Jan 84

TNF-alpha has been implicated in glomerular cell activation to produce adhesion molecules and monocyte chemoattractants associated with glomerular monocyte infiltration. This study examined the regulatory role of protein kinases and cAMP on TNF-alpha-induced intercellular adhesion molecules-1 (ICAM-1) expression and monocyte adhesion to mesangial cells. Activation of mesangial cells with TNF-alpha induced ICAM-1 mRNA and protein expression. Mesangial cells preincubated with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, stimulated both the gene and protein expression of ICAM-1. Mesangial cell PKC depletion abolished ICAM-1 mRNA message, while activation with TNF-alpha did not inhibit ICAM-1 transcripts. Preincubation of mesangial cells with calphostin C did not affect TNF-alpha-induced mesangial cell ICAM-1 message, while it blocked PMA-induced ICAM-1 mRNA expression. Protein tyrosine kinase (PTK) inhibitors blocked TNF-alpha-mediated mesangial cell ICAM-1 transcripts. cAMP-generating substances (e.g., pertussis toxin, isoproterenol, or dibutyryl cAMP) did not induce mesangial cell ICAM-1 gene expression. However, incubation of mesangial cells with TNF-alpha and dibutyrl cAMP blocked TNF-alpha-induced ICAM-1 message. Finally, preincubation of mesangial cells with TNF-alpha increased monocyte adhesion that could be blocked by anti-ICAM-1. Parallel to ICAM-1 gene expression data, TNF-alpha-induced monocyte-mesangial cell adhesion was inhibited by PTK inhibitors, but was not regulated through either PKC or intracellular cAMP-associated pathways. These results suggest that increased ICAM-1 expression by TNF-alpha activation of mesangial cells is one of the major pathways involved in monocyte adhesion to the mesangium, a phenomenon presumably regulated by signal-transduction pathways dependent on PTK, but not PKC or cAMP.
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PMID:TNF-alpha stimulates monocyte adhesion to glomerular mesangial cells. The role of intercellular adhesion molecule-1 gene expression and protein kinases. 878 21

Lysophosphatidylcholine (lyso-PC) selectively upregulates the mRNA level of intercellular adhesion molecule-1 (ICAM-1) but not that of vascular cell adhesion molecule-1 (VCAM-1) in cultured human umbilical vein endothelial cells. Transfection studies show that lyso-PC activates the ICAM-1 promoter but not the VCAM-1 promoter. Gel mobility shift assays document an increase in NF-kappa B binding in cells treated with lyso-PC. The increases of ICAM-1 mRNA and NF-kappa B binding were inhibited by the protein tyrosine kinase inhibitors, genistein and lavendustin A, but not by inhibitors for cyclic AMP-dependent protein kinases or protein kinase C. Our results suggest that lyso-PC induces ICAM-1 expression most likely by activating NF-kappa B, and that the effect appears to be protein tyrosine kinase-dependent.
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PMID:Activation of ICAM-1 promoter by lysophosphatidylcholine: possible involvement of protein tyrosine kinases. 908 6

Lysophosphatidylcholine (lyso-PC) is a major phospholipid component of atherogenic lipoproteins. Lyso-PC has been shown to differentially upregulate the adhesion molecules, such as VCAM-1 and ICAM-1, as well as smooth muscle growth factors, such as PDGF-A, B chains and HB-EGF gene expression in various cultured endothelial cells. In this paper, we demonstrate increased expression of cell- and matrix-associated forms of PDGF-B protein elicited by lyso-PC and further characterized potential signal transduction mechanisms responsible for lyso-PC-induced human umbilical vein endothelial cell. Cycloheximide inhibited PDGF-B but not ICAM-1 mRNA induction by lyso-PC, suggesting the dependence on de novo protein synthesis for PDGF-B, but not ICAM-1. A protein kinase C (PKC) inhibitor did not block lyso-PC-induced increases in PDGF-B or ICAM-1 mRNA. The elevated level of cAMP blocked both PDGF-B and ICAM-1 upregulation by lyso-PC. However cAMP-elevating agents did not suppress ICAM-1 upregulation by PMA. Taken together, PDGF-B and ICAM-1 gene induction by lyso-PC may involve different signaling mechanisms; however, both appear to be independent of PMA-regulatable PKC activation but are suppressed by increased levels of intracellular cAMP.
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PMID:Induction of endothelial platelet-derived growth factor-B-chain and intercellular adhesion molecule-1 by lysophosphatidylcholine. 918 86

In this study, the regulatory elements involved in ICAM-1 transcriptional response to phorbol ester (12-0-tetradecanoylphorbol-13-acetate; TPA) have been investigated in the human neuroblastoma cell line, SK-N-SH. TPA induced intercellular adhesion molecule 1 (ICAM-1) protein expression in SK-N-SH cells within 24 h of treatment as judged by indirect immunofluorescence. Basal ICAM-1 mRNA levels were barely detectable in untreated SK-N-SH cells but were induced by TPA to a maximal level with 4 h and were reduced thereafter. Analysis of the 5' promoter sequence of ICAM-1 revealed two regions that functioned equally in the TPA induction of ICAM-1 transcription. The first region (-145 to -227) contained a nuclear factor-kappa B (NF kappa B) element. The second region (-316 to -390) contained a putative TPA-responsive element (TRE; TGATTCA) and a TATA box. Deletion and point mutation of the latter region indicated that the TRE was indeed the functional element within this region and acted fully and independently of all other elements including the TATA box at position -352. This TRE bound TPA induced specific nuclear complexes in vitro containing junD, c-jun, c-fos, and fra2 but not cAMP-responsive element binding/activating transcription factor family proteins. ICAM-TRE binding activity was induced within 30 min following TPA treatment. This preceded the appearance of ICAM-NF kappa B site binding activity. Cotransfection of c-jun and c-fos expression vectors into SK-N-SH cells induced transactivation from ICAM-1 promoter constructs containing the intact but not mutated TRE site. Primer extension analyses revealed that TPA had induced transcription exclusively at two sites -40 and -41 bp upstream of the translation start site. These data show that the ICAM-TRE and its cognate jun- and fos-containing transcription factors play a predominant role in the transcriptional response of ICAM-1 to the protein kinase C activator TPA in SK-N-SH cells.
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PMID:Transcriptional regulation of intercellular adhesion molecule 1 by phorbol ester in human neuroblastoma cell line SK-N-SH involves jun- and fos-containing activator protein 1 site binding complex(es). 921 73

Intercellular adhesion molecule-1 (ICAM-1) mediates two important functional aspects of tumor biology, namely enhancement of tumor metastasis and mediation of host defense mechanisms such as lymphocyte-mediated tumor cytotoxicity. Since ICAM-1 is expressed by most renal cell carcinomas (RCC), the regulation of ICAM-1 expression is important in understanding the biological behavior of RCC. We report an investigation on ICAM-1 expression and molecular regulation by cytokines and protein kinase C activator on RCC cell lines. Of the various cytokines, tumor necrosis factor alpha (TNF alpha), interferon-gamma (IFN gamma), and phorbol myristate acetate (PMA) strongly upregulated ICAM-1 protein expression on RCC. The kinetics of ICAM-1 message induction was studied by Northern analysis of total RNA extracted from RCC and normal kidney proximal tubular (NKPT) cells. Time course studies showed that ICAM-1 mRNA was upregulated by INF gamma, TNF alpha, and PMA, plateaued after 2 h, and remained increased for up to 24 h. Although ICAM-1 mRNA in NKPT cells was upregulated by these cytokines, their messages returned to basal levels after 24 h. ICAM-1 mRNA stability assays showed that both unstimulated and stimulated RCC cells had very stable ICAM-1 mRNA up to 24 h. In order to investigate whether increased gene transcription contributes to ICAM-1 upregulation, RCC cells were treated with TNF alpha, IFN gamma, or PMA with or without simultaneous addition of actinomycin D. ICAM-1 message induction-blocking studies suggested that primary upregulation of ICAM-1 mRNA may be caused by transcriptional upregulation. These results suggest that long-lasting ICAM-1 message upregulation in response to cytokines or PMA may be due to transcriptional upregulation in the early phase and stabilization of ICAM-1 message in the later phase (after 4 h). These observations suggest that RCC may lack the normal downregulatory mechanisms which control ICAM-1 expression and may explain the high frequency of ICAM-1 expression observed on primary human RCC.
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PMID:Molecular regulation of intercellular adhesion molecule 1 (ICAM-1) expression in renal cell carcinoma. 928 30

The mechanism of the expression of intercellular adhesion molecule-1 (ICAM-1) on epithelial cells was analyzed using NCI-H292 cells, a human bronchial epithelial cell line. Treatment with interferon-gamma (100 U/ml) or the protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA) (16.2 nM) induced ICAM-1 expression. The interferon-gamma-induced ICAM-1 expression was reduced by the tyrosine kinase inhibitor genistein (4',5,7-trihydroxyisoflavone) (37 to 185 microM), but not by the protein kinase C inhibitor Ro 31-8425 ((3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido [1.2-a]indol-10-yl]-4-(1-methyl-1 H-pyrrole-2,3-dione) (10 microM). The TPA-induced ICAM-1 expression was reduced by the protein kinase C inhibitor Ro 31-8425 (1 to 10 microM), but not by the tyrosine kinase inhibitor genistein (185 microM). The protein kinase A inhibitor H-89 (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide) did not affect the ICAM-1 expression induced by interferon-gamma or TPA. Pyrrolidine dithiocarbamate (1-pyrrolidinecarbodithioic acid) (100 microM), an inhibitor of nuclear factor kappaB (NF-kappaB) activation. enhanced the ICAM-1 expression induced by interferon-y, but reduced that induced by TPA. The changes in ICAM-1 expression on the cell surface were correlated with the changes in ICAM-1 mRNA levels. Combined treatment with interferon-gamma and TPA induced more than additive ICAM-1 expression. These findings suggest that interferon-gamma induces ICAM-1 expression by a tyrosine kinase-dependent mechanism, but that TPA induces it by a protein kinase C- and NF-kappaB-dependent mechanism.
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PMID:Analysis of the expression of intercellular adhesion molecule-1 in cells of the human bronchial epithelial cell line NCI-H292. 960 Jun 38


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