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)

The effect of cAMP on the in vitro expression of rabbit aortic fibronectin was examined using a previously characterized organ culture system. Elevation of intracellular cAMP in incubated aortic rings by use of forskolin or dibutyryl cAMP (dbcAMP) inhibited the normally observed increase in fibronectin mRNA to levels below that found in unincubated tissue. The effect of dbcAMP on fibronectin mRNA was dose dependent and reversible. dbcAMP did not affect overall protein biosynthesis or the changes in collagen or elastin mRNAs that normally occurred during in vitro incubation, suggesting a selective regulatory effect on fibronectin. The inhibitory effect of dbcAMP on steady-state fibronectin mRNA levels was independent of the dibutyrate moiety, was not a result of cytotoxicity, did not require de novo protein synthesis, and did not appear to occur through a protein kinase A pathway. The data suggested that suppression of fibronectin mRNA levels potentially occurred via an indirect mechanism that may have involved a dbcAMP-induced reduction in intracellular calcium ([Ca2+]i) levels. The resultant decrease in [Ca2+]i may have affected fibronectin expression via a reduction in protein kinase C activity but did not depend on a calmodulin or calmodulin kinase I or II mechanism.
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PMID:Cyclic AMP suppresses fibronectin expression in the rabbit aorta in vitro. 821 9

The fatty acid 12(S)-HETE may be a new second messenger capable of activating PKC. In tumor cells 12(S)-HETE stimulates cytoskeleton-dependent cellular responses such as adhesion and spreading. Analysis of 12(S)-HETE effects on B16a melanoma cell cytoskeleton revealed reversible rearrangement of microtubules, microfilaments, the actin-binding proteins, vinculin, myosin heavy (MHC) and light chains (MLC), as well as bundling of vimentin intermediate filaments. The alterations in microfilaments and intermediate filaments occurred very rapidly, i.e., 5 min after exposure of tumor cells to 12(S)-HETE. The 12(S)-HETE-induced cytoskeletal alterations were accompanied by centrifugal organelle-translocation. Interestingly, MLC exhibited clear association with the cytoplasmic organelles. Biochemical analysis of the 12(S)-HETE effect indicated a PKC-mediated reversible hyperphosphorylation of MLC, vimentin, and a 130 kD cytoskeletal-associated protein. Optimal effects were obtained after 5 min treatment with 12(S)-HETE at 0.1 microM concentration. 12(S)-HETE pretreatment induced tumor cell spreading on a fibronectin matrix which required the intactness of all three major cytoskeletal components. The spreading process was dependent upon the activity of PKC. Our data suggest that 12(S)-HETE is a physiological stimulant of PKC. Further, it induces rearrangement of the cytoskeleton of tumor cells in interphase resulting in the stimulation of cytoskeleton-dependent cell activity such as spreading.
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PMID:PKC mediates 12(S)-HETE-induced cytoskeletal rearrangement in B16a melanoma cells. 822 7

Fibroblasts have cell surface sites that mediate the assembly of fibronectin (Fn) into the extracellular matrix. Treatment of fibroblasts with kinase inhibitors (ML-7, H7, HA1004, calphostin C, and staurosporine) resulted in the rapid decrease in the binding of 125I-labeled plasma Fn and iodinated amino-terminal fragments of Fn. The dose responses of the four inhibitors suggest that the target kinase is protein kinase C (PKC) rather than the cyclic AMP- or cyclic GMP-dependent kinases. Three different fibroblastic cells were similarly affected. The inhibition was rapid and reversible and could not be overcome by increasing concentrations of Fn. Treatment of fibroblasts with phorbol esters and other agents that activate PKC resulted in increased amounts of 125I-labeled Fn binding to the cell surface. These results imply that Fn matrix assembly is modulated by PKC-mediated phosphorylation.
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PMID:Protein kinase C modulation of fibronectin matrix assembly. 822 36

Endothelial cells exposed to a fluid shear stress both in vivo and in vitro show an alignment with the direction of flow and an elongation of cells with a concomitant reorganization of their F-actin microfilament network. Specialized regions of the plasma membrane known as focal contacts are sites of transmembrane linkages between the actin microfilament bundles and the extracellular matrix (ECM) where cytoskeletal organization and, hence, cellular morphological changes may be modulated. Focal contact-associated proteins such as fibronectin receptors, vitronectin receptors and vinculin were shown in this study to play specific roles in the modulation of the cytoskeletal and cell shape changes. Data is also presented suggesting that protein kinase C is part of the cellular signaling system involved in shear stress-induced cytoskeletal reorganization.
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PMID:Endothelial cell signaling and cytoskeletal changes in response to shear stress. 832 80

Rat IPC-81 promyelocytic leukemia cells responded to cAMP analog by undergoing apoptotic cell death both when anchored to fibronectin and when free in the medium. The protein kinase C stimulator 12-O-tetradecanoylphorbol 13-acetate enhanced the anchoring to substratum without impeding cAMP-induced cell death. The immobilized cells could be microinjected. This made it possible to study the effect on apoptosis of microinjected catalytic (C alpha) and regulatory (RI alpha D199) subunits of cAMP-dependent protein kinase as well as of phosphatase inhibitors. Microinjection of C alpha reproduced the morphological effects of cAMP, including nuclear fragmentation. RI alpha D199 blocked the effect of C alpha. Injection of microcystin-LR, which inhibits protein phosphatases 1 and 2A, led to pronounced apoptoid changes of the leukemia cells, but failed to produce nuclear fragmentation. Microinjection of peptide inhibitors ("inhibitor 1" and "inhibitor 2") specific for phosphatase 1 had no effect on cell morphology. The failure of the phosphatase inhibitors to reproduce completely the effect of the C subunit underscores the specificity of action of the latter.
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PMID:Microinjected catalytic subunit of cAMP-dependent protein kinase induces apoptosis in myeloid leukemia (IPC-81) cells. 838 20

Chemotaxis of the M27 variant of Lewis lung carcinoma to VGVAPG, an elastin-derived chemoattractant, is restricted by the basement membrane glycoprotein laminin. Laminin does not inhibit random migration of M27 tumor cells, nor does it inhibit M27 cell chemotaxis to a second chemotactic peptide, fMLF. The laminin sensitivity of VGVAPG chemotaxis appears to be independent of adhesion to laminin, and it is not due to competitive inhibition of VGVAPG receptor binding. Preincubation of M27 cells with laminin reduces the affinity of VGVAPG-specific binding without altering the number of available VGVAPG receptors. Reduced VGVAPG receptor affinity was previously observed: (a) a nonresponsive Lewis lung carcinoma variant, H59, expresses low-affinity VGVAPG binding and (b) maintenance of high-affinity VGVAPG receptors on M27 tumor cells is correlated with elevated protein kinase C activity in the particulate cell fraction (C. H. Blood and B. R. Zetter, J. Biol. Chem., 264: 10614-10620, 1989). The negative regulation of VGVAPG chemotaxis by laminin is consistent with these observations: laminin coordinately inhibits VGVAPG chemotaxis, reduces VGVAPG receptor affinity, and decreases protein kinase C activity in the particulate fraction of M27 cells. These parameters are not affected by a second glycoprotein, fibronectin. Anti-alpha 6 antibodies neutralize the laminin inhibition of both VGVAPG chemotaxis and protein kinase C activity. The results demonstrate that laminin can modulate cell behavior by regulating cell surface receptors for biologically active ligands.
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PMID:Laminin regulates a tumor cell chemotaxis receptor through the laminin-binding integrin subunit alpha 6. 838 19

A short and a long fibre sample of amosite asbestos were tested for their effects on cells of the human Type 2 alveolar epithelial cell-line A549 in vitro. The long amosite sample was found to cause a rapid detachment of the epithelial cells live from their substratum. At the highest dose, on average 28% of the cells present were detached in this way. Studies on the mechanism of the detachment injury showed that it did not involve oxidants since it was not ameliorated by scavengers of active oxygen species. Neither was the effect reduced by treatment of the fibres with the iron chelator Desferal. Treatments reported to increase the interaction between fibres and cells, serum and poly-L-lysine, did not influence the detachment injury, nor did lung lining fluid. Conversely, the fibronectin tripeptide RGD alone could cause detachment which suggested that a fibronectin-binding integrin was involved. This receptor could be reduced in activity by long fibre exposure, leading to detachment. The detaching effect of fibre could be mimicked by the protein kinase C activator PMA, and so the second messenger system of the cell could also be involved. This type of injury could be important in the pathology associated with exposure to long fibres.
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PMID:Asbestos fibre length-dependent detachment injury to alveolar epithelial cells in vitro: role of a fibronectin-binding receptor. 839 59

The fibronectin content of RMC cultures grown for 8-14 days in medium containing 30 mM (540 mg/dl) D-glucose was increased 30-60% relative to that of control cells cultured in 10 mM (180 mg/dl) glucose. Addition of equiosmolar concentrations (20 mM, 360 mg/dl) of L-glucose, 3-O-methylglucose, or mannitol to 10 mM glucose media did not alter fibronectin accumulation compared with values observed in 10 mM glucose alone. The basal phosphorylation of the 80,000-M(r) MARKS protein, which is a substrate for PKC, and the phosphorylation induced by acute (15-min) exposure of cells to 15% FCS or to 0.1 microM (50 ng/ml) PDBu were all increased in cells grown in 30 mM compared with 10 mM glucose. By contrast, phosphorylation of the 80,000-M(r) protein in response to a maximal concentration of PDBu (1 microM, 500 ng/ml) was not different in cells grown in 30 mM compared with 10 mM glucose. The acute increases in phosphorylation of the 80,000-M(r) protein were blocked by the PKC inhibitor calphostin C. Chronic (7-day) exposure of mesangial cells grown in 10 mM glucose to 0.1 microM of the PKC agonist PDBu also resulted in a sustained 40% increase in 80,000-M(r) phosphorylation and a 20-30% increase in fibronectin accumulation. As assessed by [35S]methionine incorporation, mesangial cell fibronectin synthesis was increased by exposure to PDBu, a finding consistent with earlier observations with 30 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role for protein kinase C in the mediation of increased fibronectin accumulation by mesangial cells grown in high-glucose medium. 842 Aug 8

Fibronectin (Fn) fragments have recently been shown to stimulate tumor necrosis factor (TNF) secretion by human monocytes. In this study, we investigated the signal transduction mechanisms involved in Fn-induced TNF secretion. Treatment of human monocytes with Fn120, a chymotryptic cell-binding fragment of plasma Fn, failed to cause a detectable rise in Ca2+ mobilization. Fn120-induced TNF secretion could be inhibited with Ca2+ channel blockers. The protein kinase C (PKC) inhibitors H-7 and sphingosine inhibited the TNF-inducing activity of Fn120. HA1004 was used as a control for the isoquinoline sulfonamide derivatives and did not change Fn120-induced TNF secretion by monocytes. H-8 inhibited TNF secretion at higher concentrations. A calmodulin-dependent kinase inhibitor, W-7, was found to be effective, with 50% inhibition of Fn120-induced TNF secretion at 5 microM. The activation and translocation of PKC were measured directly. In unstimulated monocytes, approximately 70% of PKC activity was found in the cytosol and 30% in the membrane. Following the stimulation of monocytes with phorbol myristate acetate (100 nM), rapid and sustained translocation of PKC from the cytosol to the membrane was observed. The stimulation of monocytes with Fn120 triggered a rapid translocation of PKC within 2 to 5 min, followed by a return to normal levels within 8 min. These findings support the conclusion that Fn120-induced TNF secretion requires the activation of PKC.
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PMID:Fibronectin cell-binding domain triggered transmembrane signal transduction in human monocytes. 842 95

Like the renal glomerular mesangium in patients with diabetic nephropathy, glomerular mesangial cell cultures grown in 30 mM glucose accumulate increased amounts of the extracellular matrix (ECM) proteins fibronectin, laminin, and type IV collagen. This is due to increased ECM protein synthesis and mRNA levels. Similar to other cells types that are affected by the diabetic state (such as, vascular cells and peripheral nerve), mesangial cells transport glucose by an insulin-independent, facilitated diffusion transport system. Kinetic studies reveal that intracellular glucose levels may reach the ambient glucose concentrations achieved in diabetes. Growth studies reveal that glucose does not exert its effect on mesangial cell ECM accumulation by affecting cell growth, but rather it causes an increase in diacylglycerol (DAG) mass and activates protein kinase C. Agents such as phorbol myristate acetate (PMA) and the cell permeable DAG analogue, oleoyl acetyl glycerol (OAG) which activate protein kinase C also increase ECM mRNAs. These results implicate protein kinase C activation in the increased ECM accumulation observed in mesangial cell cultures grown in high glucose.
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PMID:The glomerular mesangium in diabetes mellitus. 843 49


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