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)

Working with cultured dermal fibroblasts derived from control individuals and patients with systemic sclerosis (SSc), we have examined the effects of protein kinase C-delta (PKC-delta) on type I collagen biosynthesis and steady-state levels of COL1A1 and COL3A1 mRNAs. Rottlerin, a specific inhibitor of PKC-delta, exerted a powerful, dose-dependent inhibition of type I and type III collagen gene expression in normal and SSc cells. Optimal rottlerin concentrations caused a 70-90% inhibition of type I collagen production, a >80% reduction in COL1A1 mRNA, and a >70% reduction in COL3A1 mRNA in both cell types. In vitro nuclear transcription assays and transient transfections with COL1A1 promoter deletion constructs demonstrated that rottlerin profoundly reduced COL1A1 transcription and that this effect required a 129-bp promoter region encompassing nucleotides -804 to -675. This COL1A1 segment imparted rottlerin sensitivity to a heterologous promoter. Cotransfections of COL1A1 promoter constructs with a dominant-negative PKC-delta expression plasmid showed that suppression of this kinase silenced COL1A1 promoter activity. The results indicate that PKC-delta participates in the upregulation of collagen gene transcription in SSc and suggest that treatment with PKC-delta inhibitors could suppress fibrosis in this disease.
 ...
PMID:Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts. 1169 85

Lung injury, characterized by the flooding of interstitial and alveolar spaces with serum proteins, induces the expression of fibronectin (FN). This cell-adhesive extracellular matrix (ECM) glycoprotein is believed to modulate inflammation and wound repair. Murine NIH/3T3 fibroblasts transfected with a 1.2-kb human FN promoter-reporter gene were studied to gain insight into the mechanisms involved in the induction of FN by serum. Transcription of the FN gene, followed by FN protein production, was enhanced by 10% fetal bovine serum. This effect was blocked by inhibitors of protein kinase C and mitogen-activated protein kinases. ECMs typically found in injured tissues (i.e., type I collagen, fibrin, and FN) had no effect. Conversely, disruption of actin microfilaments inhibited, whereas disruption of microtubular assembly enhanced, the serum-induced FN response. The stimulatory effects of serum and microtubular disruption on FN gene transcription were related to increased DNA binding of the transcription factor cAMP response element binding protein. The data suggest that regulation of serum-induced FN expression in fibroblasts is dependent on protein kinases and on cytoskeletal integrity.
 ...
PMID:Regulation of serum-induced fibronectin expression by protein kinases, cytoskeletal integrity, and CREB. 1179 34

Ets-1 is a transcription factor regulating the expression of matrix-degrading proteinases and is believed to play a critical role in cell migration and tumor invasion. The aim of this study is to investigate the direct induction of ets-1 with consequential upregulation of collagenase-1 (MMP-1) by cell adhesion to extracellular matrix and to identify intracellular signal transduction pathways involved in ets-1 induction in cultured endothelial cells. The expressions of ets-1 mRNA and protein as well as MMP-1 protein were induced by cell adhesion to type I collagen and antisense ets-1 oligonucleotides impaired that MMP-1 expression. In addition, protein tyrosine kinase (PTK) and protein kinase C (PKC) inhibitors abrogated their induction, showing the suppression of focal adhesion kinase phosphorylation. These results suggest that ets-1 induced by cell adhesion to extracellular matrix directly upregulates MMP-1 expression via PTK and PKC activation in cultured endothelial cells.
 ...
PMID:Ets-1 upregulates matrix metalloproteinase-1 expression through extracellular matrix adhesion in vascular endothelial cells. 1182 72

Although protein kinase C (PKC) activation is required for endothelial cell (EC) growth, migration, adhesion, and vessel formation, the role of individual PKC isoenzymes in these events is not defined. Because PKCalpha has been previously linked with enhanced EC migration and response to angiogenic growth factors, we characterized a specific phosphorothioate-modified 21-mer antisense PKCalpha (AS-PKCalpha). AS-PKCalpha (500 nmol/L) prevented the expression of PKCalpha protein by 90% in human ECs and did not reduce the expression of any other PKC isoenzyme. AS-PKCalpha reduced human EC migration by 64% compared with its control oligonucleotide in a "scratch" wounding assay, and AS-PKCalpha reduced human EC adhesion to the extracellular matrix protein vitronectin by 18%. Phosphorylation of mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) induced by vascular endothelial growth factor was inhibited by 30% in human ECs transfected with AS-PKCalpha. Compared with control, AS-PKCalpha also reduced the number of EC tubes formed in a 3D type I collagen gel assay by 37.5%. Finally, using an osmotic minipump, we infused AS-PKCalpha into mice in which myocardial infarction was induced by coronary ligation and found that the oligonucleotide was primarily taken up by intramyocardial blood vessels. Compared with the results with control oligonucleotide, AS-PKCalpha oligonucleotide inhibited the number of anti-PKCalpha-stained blood vessels by 48% and reduced the total vessel number by 72% as well. In conclusion, the expression of PKCalpha is required for full EC migration, adhesion to vitronectin, vascular endothelial growth factor-induced extracellular signal-regulated kinase activation, and tube formation and is likely to be of importance in myocardial angiogenesis in vivo after ischemia.
 ...
PMID:Inhibition of protein kinase Calpha prevents endothelial cell migration and vascular tube formation in vitro and myocardial neovascularization in vivo. 1190 26

Inflammatory adherence to, and locomotion through the interstitium is an important component of the immune response. Conditions such as microgravity and modeled microgravity (MMG) severely inhibit lymphocyte locomotion in vitro through gelled type I collagen. We used the NASA rotating wall vessel bioreactor or slow-turning lateral vessel as a prototype for MMG in ground-based experiments. Previous experiments from our laboratory revealed that when lymphocytes (human peripheral blood mononuclear cells [PBMCs]) were first activated with phytohemaglutinin followed by exposure to MMG, locomotory capacity was not affected. In the present study, MMG inhibits lymphocyte locomotion in a manner similar to that observed in microgravity. Phorbol myristate acetate (PMA) treatment of PBMCs restored lost locomotory capacity by a maximum of 87%. Augmentation of cellular calcium flux with ionomycin had no restorative effect. Treatment of lymphocytes with mitomycin C prior to exposure to MMG, followed by PMA, restored locomotion to the same extent as when nonmitomycin C-treated lymphocytes were exposed to MMG (80-87%), suggesting that deoxyribonucleic acid replication is not essential for the restoration of locomotion. Thus, direct activation of protein kinase C (PKC) with PMA was effective in restoring locomotion in MMG comparable to the normal levels seen in Ig cultures. Therefore, in MMG, lymphocyte calcium signaling pathways were functional, with defects occurring at either the level of PKC or upstream of PKC.
 ...
PMID:Loss of signal transduction and inhibition of lymphocyte locomotion in a ground-based model of microgravity. 1192 94

We examined the effects of ruscogenin glycoside (Lm-3), isolated from Liriope muscari, on lymphocyte adhesion to extracellular matrix. Adhesion of Jurkat cells activated by anti-CD3 to type I collagen was inhibited by Lm-3 in a concentration- and time-dependent manner. Lm-3 also inhibited the cell attachment to fibronectin and laminin. However, the saponin did not influence anti-CD3-induced cell proliferation and Mn2+-induced adhesion. Protein kinase C activator, phorbol 12,13-dibutyrate, significantly enhanced, while its inhibitor, chlorpromazine, almost completely blocked, the adhesion of anti-CD3-activated Jurkat cells to collagen. Against phorbol 12,13-dibutyrate-activated Jurkat cells, Lm-3 treatment, either before or after activation, significantly inhibited the cell adhesion to collagen. Lm-3 also inhibited the adhesion activated by both anti-CD3 and phorbol 12,13-dibutyrate. Similar inhibition by Lm-3 of the phorbol 12,13-dibutyrate-induced adhesion to collagen was also observed in lymphocytes freshly isolated from mice with contact dermatitis. Furthermore, Lm-3 significantly decreased the leucocyte accumulation in an animal model of experimental pleurisy. These results suggest that the blockade of lymphocyte adhesion to extracellular matrix through interference with the protein kinase C pathway may be one of the mechanisms by which Lm-3 exerts anti-inflammatory activity.
 ...
PMID:Ruscogenin glycoside (Lm-3) isolated from Liriope muscari inhibits lymphocyte adhesion to extracellular matrix. 1216 15

Interaction of immunocompetent cells with extracellular matrix is one of the main stages in their homing and circulation. In this connection we investigated quantitative and dynamic parameters of interaction between splenocytes and 3D collagen matrix in vitro. It was found out that, about 20% of mouse spleen lymphocytes exhibited ability to bind to type I collagen that reflected as their adhesion to and/or migration in collagen matrix. The number of lymphocytes capable of the interaction with collagen gained successively as far as the time of their incubation on collagen matrix was increased and reached maximum by 24 h. The lymphocyte-collagen interaction was energy-dependent and engaged collagen receptors, which probably have been already expressed on cells before spleen lymphocytes were isolated. The series of intracellular interchanges as activation of protein kinase C, assembly of actin filaments and depolymerization of tubulin microtubules were critical for lymphocytes to adhere to and further to migrate in collagen matrix. Long lasting incubation (24 h and more) of lymphocytes in adhesion excluding conditions did not reduce the number of cells able to interact with collagen, but to a great extent changed mechanisms providing their adhesion and/or migration.
 ...
PMID:Dynamics and Mechanisms of Interaction of Mouse Spleen Lymphocytes with 3D Collagen Matrix in vitro. 1268 54

In this paper, the effect of Si-Ni-San, a famous traditional Chinese prescription, on ear contact sensitivity was examined. Si-Ni-San significantly inhibited the ear swelling when administered during the induction phase of picryl-chloride-induced ear contact sensitivity in mice. The adhesion to type I collagen of isolated spleen cells was significantly decreased in the Si-Ni-San group, especially in the presence of protein kinase C activator, phorbol 12,13-dibutyrate. The inhibition of adhesion was seen in purified T cells from the spleen, as well as in Jurkat cells. Furthermore, the adhesion to collagen involves the production of matrix metalloproteinase-2 and -9 in spleen cells, and the oral administration of Si-Ni-San remarkably reduced the matrix metalloproteinase production. Three drug-pairs composed in Si-Ni-San were used for comparison. The combination of Chaihu and Shaoyao showed a similar effect to Si-Ni-San, while Chaihu and Zhishi, and Shaoyao and Gancao only showed a tendency in most situations. These results suggest that Si-Ni-San may contribute to the treatment of immunologically related diseases by down-regulating the activation and function of T lymphocytes, especially the cell adhesion and matrix metalloproteinase production. Its effect is mainly displayed by the combination of Chaihu and Shaoyao.
 ...
PMID:Si-Ni-San, a traditional Chinese prescription, and its drug-pairs suppress contact sensitivity in mice via inhibition of the activity of metalloproteinases and adhesion of T lymphocytes. 1284 46

The Cbfa1/Runx2 transcription factor is essential for osteoblast differentiation. However, levels of Runx2 are often not well correlated with its transcriptional activity suggesting that this factor must be activated either by covalent modification or through interactions with other nuclear components. Runx2 is phosphorylated and activated by the mitogen-activated protein kinase (MAPK) pathway. This pathway is stimulated in at least two ways: by binding of type I collagen to alpha2beta1 integrins on the osteoblast surface and by treatment of cells with the osteogenic growth factor, FGF2. Protein kinase A (PKA) also may phosphorylate/activate Runx2 under certain conditions. Runx2 activity also is enhanced by factors known to stimulate specific signal transduction pathways such as PTH/PTHrP (signals through PKA and PKC pathways) and BMPs (Signal through Smad proteins). Interactions with Runx2 are complex involving both binding of distinct components such as AP-1 factors and Smads to separate sites on DNA, direct interactions between Runx2 and AP-1/Smad factors and MAPK or PKA-dependent Runx2 phosphorylation. These findings suggest that Runx2 plays a central role in coordinating multiple signals involved in osteoblast differentiation.
 ...
PMID:Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. 1295 83

We examined the effect of PTH-related peptide (PTHrP) on modulating adipogenesis and osteoblastogenesis in the pluripotent mesenchymal cell line C3H10T(1/2). These cells express the type 1 PTH/PTHrP receptor, thereby allowing PTHrP to inhibit bone morphogenetic protein 2 (BMP2) from enhancing gene expression of peroxisome proliferator-activated receptor gamma and the adipocyte-specific protein aP2 and from augmenting the accumulation of lipid. In the presence of BMP2, PTHrP or a protein kinase C (PKC) stimulator (phorbol ester) increased the expression of indexes of the osteoblast phenotype, including alkaline phosphatase, type I collagen, and osteocalcin, whereas a PKC inhibitor (chelerythrin chloride) inhibited PTHrP action. PTHrP and a phorbol ester increased gene expression of the BMP IA receptor, and both enhanced BMP2-dependent increases in promoter activity of the signaling molecule SMAD6. Overexpression of the BMP IA receptor facilitated the capacity of BMP2 to increase osteoblastogenesis in the absence of PTHrP and a dominant negative BMP IA receptor variant inhibited this effect of BMP2. These results demonstrate that PTHrP can direct osteoblastic, rather then adipogenic, commitment of mesenchymal cells, implicate PKC signaling in this activity, and show that PTHrP action involves enhanced gene expression of the BMP IA receptor, which facilitates BMP2 action in enhancing osteoblastogenesis in pluripotent mesenchymal cells.
 ...
PMID:Parathyroid hormone-related peptide interacts with bone morphogenetic protein 2 to increase osteoblastogenesis and decrease adipogenesis in pluripotent C3H10T 1/2 mesenchymal cells. 1296 89


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