scholarly journals Protein Kinase C-δ Regulates Thrombin-Induced ICAM-1 Gene Expression in Endothelial Cells via Activation of p38 Mitogen-Activated Protein Kinase

2001 ◽  
Vol 21 (16) ◽  
pp. 5554-5565 ◽  
Author(s):  
Arshad Rahman ◽  
Khandaker N. Anwar ◽  
Shahab Uddin ◽  
Ning Xu ◽  
Richard D. Ye ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Map Kinase ◽  
Critical Role ◽  
P38 Map Kinase ◽  
Intercellular Adhesion Molecule ◽  
Kinase C ◽  
Mitogen Activated Protein

ABSTRACT The procoagulant thrombin promotes the adhesion of polymorphonuclear leukocytes to endothelial cells by a mechanism involving expression of intercellular adhesion molecule 1 (ICAM-1) via an NF-κB-dependent pathway. We now provide evidence that protein kinase C-δ (PKC-δ) and the p38 mitogen-activated protein (MAP) kinase pathway play a critical role in the mechanism of thrombin-induced ICAM-1 gene expression in endothelial cells. We observed the phosphorylation of PKC-δ and p38 MAP kinase within 1 min after thrombin challenge of human umbilical vein endothelial cells. Pretreatment of these cells with the PKC-δ inhibitor rottlerin prevented the thrombin-induced phosphorylation of p38 MAP kinase, suggesting that p38 MAP kinase signals downstream of PKC-δ. Inhibition of PKC-δ or p38 MAP kinase by pharmacological and genetic approaches markedly decreased the thrombin-induced NF-κB activity and resultant ICAM-1 expression. The effects of PKC-δ inhibition were secondary to inhibition of IKKβ activation and of subsequent NF-κB binding to the ICAM-1 promoter. The effects of p38 MAP kinase inhibition occurred downstream of IκBα degradation without affecting the DNA binding function of nuclear NF-κB. Thus, PKC-δ signals thrombin-induced ICAM-1 gene transcription by a dual mechanism involving activation of IKKβ, which mediates NF-κB binding to the ICAM-1 promoter, and p38 MAP kinase, which enhances transactivation potential of the bound NF-κB p65 (RelA).

scholarly journals The Streptococcal Exotoxin Streptolysin O Activates Mast Cells To Produce Tumor Necrosis Factor Alpha by p38 Mitogen-Activated Protein Kinase- and Protein Kinase C-Dependent Pathways

2003 ◽  
Vol 71 (11) ◽  
pp. 6171-6177 ◽  
Author(s):  
Michael Stassen ◽  
Christian Müller ◽  
Christoph Richter ◽  
Christine Neudörfl ◽  
Lothar Hültner ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Mast Cells ◽  
Protein Kinase ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Necrosis Factor Alpha ◽  
Kinase C ◽  
Streptolysin O ◽  
Tnf Α ◽  
Mitogen Activated Protein

ABSTRACT Streptolysin O (SLO), a major virulence factor of pyogenic streptococci, binds to cholesterol in the membranes of eukaryotic cells and oligomerizes to form large transmembrane pores. While high toxin doses are rapidly cytocidal, low doses are tolerated because a limited number of lesions can be resealed. Here, we report that at sublethal doses, SLO activates primary murine bone marrow-derived mast cells to degranulate and to rapidly induce or enhance the production of several cytokine mRNAs, including tumor necrosis factor alpha (TNF-α). Mast cell-derived TNF-α plays an important protective role in murine models of acute inflammation, and the production of this cytokine was analyzed in more detail. Release of biologically active TNF-α peaked ∼4 h after stimulation with SLO. Production of TNF-α was blunted upon depletion of protein kinase C by pretreatment of the cells with phorbol-12 myristate-13 acetate. Transient permeabilization of mast cells with SLO also led to the activation of the stress-activated protein kinases p38 mitogen-activated protein (MAP) kinase and c-jun N-terminal kinase (JNK), and inhibition of p38 MAP kinase markedly reduced production of TNF-α. In contrast, secretion of preformed granule constituents triggered by membrane permeabilization was not dependent on p38 MAP kinase or on protein kinase C. Thus, transcriptional activation of mast cells following transient permeabilization might contribute to host defense against infections via the beneficial effects of TNF-α. However, hyperstimulation of mast cells might also lead to overproduction of TNF-α, which would then promote the development of toxic streptococcal syndromes.

MKK1 and MKK2, which encode Saccharomyces cerevisiae mitogen-activated protein kinase-kinase homologs, function in the pathway mediated by protein kinase C

1993 ◽  
Vol 13 (5) ◽  
pp. 3076-3083
Author(s):  
K Irie ◽  
M Takase ◽  
K S Lee ◽  
D E Levin ◽  
H Araki ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Map Kinase ◽  
Protein Kinases ◽  
Cell Lysis ◽  
Yeast Cells ◽  
Temperature Sensitive ◽  
Kinase C ◽  
Mitogen Activated Protein

The PKC1 gene of Saccharomyces cerevisiae encodes a homolog of mammalian protein kinase C that is required for normal growth and division of yeast cells. We report here the isolation of the yeast MKK1 and MKK2 (for mitogen-activated protein [MAP] kinase-kinase) genes which, when overexpressed, suppress the cell lysis defect of a temperature-sensitive pkc1 mutant. The MKK genes encode protein kinases most similar to the STE7 product of S. cerevisiae, the byr1 product of Schizosaccharomyces pombe, and vertebrate MAP kinase-kinases. Deletion of either MKK gene alone did not cause any apparent phenotypic defects, but deletion of both MKK1 and MKK2 resulted in a temperature-sensitive cell lysis defect that was suppressed by osmotic stabilizers. This phenotypic defect is similar to that associated with deletion of the BCK1 gene, which is thought to function in the pathway mediated by PCK1. The BCK1 gene also encodes a predicted protein kinase. Overexpression of MKK1 suppressed the growth defect caused by deletion of BCK1, whereas an activated allele of BCK1 (BCK1-20) did not suppress the defect of the mkk1 mkk2 double disruption. Furthermore, overexpression of MPK1, which encodes a protein kinase closely related to vertebrate MAP kinases, suppressed the defect of the mkk1 mkk2 double mutant. These results suggest that MKK1 and MKK2 function in a signal transduction pathway involving the protein kinases encoded by PKC1, BCK1, and MPK1. Genetic epistasis experiments indicated that the site of action for MKK1 and MKK2 is between BCK1 and MPK1.

TNF-α and interleukin 1 activate gastrin gene expression via MAPK- and PKC-dependent mechanisms

2001 ◽  
Vol 281 (6) ◽  
pp. G1405-G1412 ◽  
Author(s):  
T. Suzuki ◽  
E. Grand ◽  
C. Bowman ◽  
J. L. Merchant ◽  
A. Todisco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
G Cells ◽  
Kinase C ◽  
Tnf Α ◽  
Mitogen Activated Protein

Helicobacter pyloriand proinflammatory cytokines have a direct stimulatory effect on gastrin release from isolated G cells, but little is known about the mechanism by which these factors regulate gastrin gene expression. We explored whether tumor necrosis factor (TNF)-α and interleukin (IL)-1 directly regulate gastrin gene expression and, if so, by what mechanism. TNF-α and IL-1 significantly increased gastrin mRNA in canine G cells to 181 ± 18% and 187 ± 28% of control, respectively, after 24 h of treatment. TNF-α and IL-1 stimulated gastrin promoter activity to a maximal level of 285 ± 12% and 415 ± 26% of control. PD-98059 (a mitogen-activated protein kinase kinase inhibitor), SB-202190 (a p38 kinase inhibitor), and GF-109203 (a protein kinase C inhibitor) inhibited the stimulatory action of both cytokines on the gastrin promoter. In conclusion, both cytokines can directly regulate gastrin gene expression via a mitogen-activated protein kinase- and protein kinase C-dependent mechanism. These data suggest that TNF-α and IL-1 may play a direct role in Helicobacter pylori-induced hypergastrinemia.

scholarly journals Heparin down-regulates the phorbol ester-induced protein kinase C gene expression in human endothelial cells: enzyme-mediated autoregulation of protein kinase C-α and -δ genes1

FEBS Letters ◽  
1999 ◽  
Vol 449 (2-3) ◽  
pp. 135-140 ◽  
Author(s):  
Gianfranco Pintus ◽  
Bruna Tadolini ◽  
Margherita Maioli ◽  
Anna M. Posadino ◽  
Leonardo Gaspa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Phorbol Ester ◽  
Human Endothelial Cells ◽  
Kinase C

scholarly journals Bombesin and epidermal growth factor stimulate the mitogen-activated protein kinase through different pathways in Swiss 3T3 cells

1993 ◽  
Vol 289 (1) ◽  
pp. 283-287 ◽  
Author(s):  
L Pang ◽  
S J Decker ◽  
A R Saltiel
Keyword(s):  
Enzyme Activity ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Map Kinase ◽  
3T3 Cells ◽  
Kinase C ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Swiss 3T3 ◽  
Stimulation Of

Both bombesin and epidermal growth factor (EGF) are potent mitogens in Swiss 3T3 cells that nonetheless have dissimilar receptor structures. To explore possible common intracellular events involved in the stimulation of cellular growth by these two peptides, we have evaluated the regulation of the mitogen-activated protein (MAP) kinase. Exposure of Swiss 3T3 cells to bombesin, EGF or the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) causes the rapid and transient stimulation of the enzyme activity. Pretreatment of cells with the protein kinase inhibitor H-7, or down-regulation of cellular protein kinase C by prolonged exposure to PMA, causes a decrease of over 90% in the activation of MAP kinase by bombesin. In contrast, these treatments have no effect on the stimulation of MAP kinase by EGF. The stimulation of MAP kinase activity by bombesin is dose-dependent, occurring over a narrow concentration range of the peptide. Both EGF and bombesin stimulate the phosphorylation of an immunoprecipitable MAP kinase protein migrating at 42 kDa on SDS/PAGE. Phosphoamino acid analysis of this phosphorylated protein reveals that EGF and bombesin stimulate phosphorylation on tyrosine, threonine and serine residues. Tyrosine phosphorylation of the enzyme, as evaluated by antiphosphotyrosine blotting of the immunoprecipitated protein, reveals that the time course of phosphorylation by both mitogens correlates with stimulation of enzyme activity. These results provide further evidence for the convergence of discrete pathways emanating from tyrosine kinase and G-protein-linked receptors in the regulation of MAP kinase.

Cholecystokinin rapidly activates mitogen-activated protein kinase in rat pancreatic acini

1994 ◽  
Vol 267 (3) ◽  
pp. G401-G408 ◽  
Author(s):  
R. D. Duan ◽  
J. A. Williams
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Map Kinase ◽  
Threshold Concentration ◽  
Mitogen Activated Protein Kinase ◽  
Maximal Effect ◽  
Pancreatic Acini ◽  
Kinase C ◽  
Mitogen Activated Protein

The existence and activation of mitogen-activated protein (MAP) kinase in isolated pancreatic acini have been demonstrated. Immunoblotting and immunoprecipitation revealed two forms of MAP kinase in pancreatic acini, with relative molecular masses of approximately 42 and 44 kDa. Both forms of MAP kinase were activated by cholecystokinin (CCK). The threshold concentration of CCK was approximately 3 pM, and the maximal effect occurred at 1 nM, which enhanced MAP kinase activity by 2.5-fold, as determined in polyacrylamide gel copolymerized with substrate myelin basic protein. Activation of MAP kinase by CCK was rapid, reaching a maximum within 5-10 min that subsequently declined. Bombesin and carbachol but not secretin or vasoactive intestinal peptide also activated MAP kinase. CCK-induced activation of MAP kinase may be mediated by protein kinase C, since 12-O-tetradecanoylphorbol 13-acetate (TPA) mimicked the effect of CCK and staurosporine concentration dependently inhibited the action of CCK. Treatment of acini with thapsigargin, ionomycin, or ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid did not influence MAP kinase, indicating that mobilization of intracellular calcium by CCK is not important in activation of acinar MAP kinase. CCK and TPA increased tyrosine phosphorylation of both 42- and 44-kDa forms. Genistein and tyrphostin 23, the inhibitors of tyrosine kinase, suppressed the activation of MAP kinase by CCK. In conclusion, MAP kinase in pancreatic acini is activated by agonists related to hydrolysis of phosphoinositide, via a mechanism involving protein kinase C and tyrosine kinase.

Cigarette smoke extract induces endothelin-1 via protein kinase C in pulmonary artery endothelial cells

2001 ◽  
Vol 281 (2) ◽  
pp. L403-L411 ◽  
Author(s):  
Sang-Do Lee ◽  
Dong-Soon Lee ◽  
Yong-Gam Chun ◽  
Tae-Sun Shim ◽  
Chae-Man Lim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Pulmonary Artery ◽  
Cigarette Smoke ◽  
De Novo ◽  
Ex Vivo ◽  
Cigarette Smoke Extract ◽  
Kinase C

We examined the mechanism of endothelin (ET)-1 regulation by cigarette smoke extract (CSE) and the effect of platelets on CSE-induced stimulation of ET-1 gene expression in human and bovine pulmonary artery endothelial cells (PAECs). Our data show that CSE (1%) induces ET-1 gene expression (after 1 h) and ET-1 peptide synthesis (after 4 h) in bovine PAECs. The induction of preproET-1 mRNA level was due to de novo transcription, and new protein synthesis was not required for this induction. The protein kinase C inhibitors staurosporine (10−8mol/l) and calphostin C (10−7mol/l) abolished the induction of ET-1 gene expression by CSE in bovine and human PAECs. Although a lower concentration of platelets (106cells/ml in bovine PAECs; 107cells/ml in human PAECs) did not significantly alter ET-1 gene expression in PAECs, incubation of platelets with CSE (1%) and PAECs produced a significant increase in preproET-1 mRNA and ET-1 peptide compared with the values in the presence of CSE (1%) alone. CSE (1%) induced platelet aggregation and increased the expression of platelet membrane glycoproteins ex vivo. Thus our data suggest that CSE stimulates ET-1 gene expression via PKC in PAECs. CSE and platelets showed a synergistic effect on ET-1 gene expression, possibly through the activation of platelets by CSE.

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