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 M27 and H59 variants of Lewis lung carcinoma differ in their responsiveness to the chemotactic elastin peptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG). M27 cells, selected for metastasis to lung, are highly responsive to a positive gradient of VGVAPG. H59 cells, selected for metastasis to liver, do not migrate in response to VGVAPG. Although both cell types bind radiolabeled VGVAPG, Scatchard analysis of 125I-Tyr-VGVAPG binding reveals that M27 cells bind the chemoattractant with a Kd of 2.7 nM, whereas nonresponsive H59 cells bind the peptide with a Kd of 67 nM. These findings indicate that the failure of H59 cells to migrate in response to VGVAPG may be due to the reduced affinity of their VGVAPG receptors. Both receptor affinity and chemotactic responsiveness to VGVAPG can be modulated in each of these two tumor cell lines by the levels of active membrane-associated protein kinase C. Treatment of nonresponsive H59 cells with 12-O-tetradecanoylphorbol 13-acetate increases the level of membrane-bound protein kinase C activity with a concomitant increase in VGVAPG binding affinity and induction of chemotactic responsiveness to VGVAPG. Treatment of M27 cells with the protein kinase C inhibitor, staurosporine, reduces VGVAPG binding affinity and abrogates the chemotactic response. We conclude that chemotactic responsiveness of M27 and H59 tumor cells is dependent upon high VGVAPG receptor affinity, which is strongly correlated to high levels of membrane-bound protein kinase C activity.
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PMID:Membrane-bound protein kinase C modulates receptor affinity and chemotactic responsiveness of Lewis lung carcinoma sublines to an elastin-derived peptide. 254 74

In previous studies, we related increased elastolytic activity in pulmonary arteries (PA) with endothelial injury to the later development of PA hypertension in rats. As the mechanism causing the increased PA elastase was unknown, we hypothesized that serum factors which are accessible to vascular smooth muscle cells (SMC) following endothelial injury stimulate their elastolytic activity. To test this, we developed an in vitro assay in which we added [3H]-elastin to cultured vascular SMC after 24 h serum starvation and monitored elastolysis following a further 24 h incubation with fetal bovine serum (FBS). We observed that serum induced increased elastolytic activity in both PA and aorta-derived SMC but not in endothelial cells or SMC with low basal levels of elastolytic activity. Maximum stimulation of SMC elastolytic activity occurred with a concentration as low as 1% FBS and despite elastase inhibitors in serum, suggesting that the activity is confined to the immediate pericellular region where enzyme concentration is high. Serum-stimulated elastolytic activity was not reproduced by growth factors or cytokines known to be associated with vascular disease or to induce release of elastases in other cells. The serum inducing elastolytic activity was heat and acid labile. It was associated with increased elastin adhesion to the 67 kD elastin binding protein on SMC surfaces and was prevented by tyrosine kinase inhibitors but not protein kinase C or A inhibitors. Our studies therefore suggest a mechanism whereby serum induction of SMC elastase requires signalling through the elastin binding protein and activation of tyrosine kinase.
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PMID:Serum-induced vascular smooth muscle cell elastolytic activity through tyrosine kinase intracellular signalling. 802 Dec 92

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

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

Increased elastin production and accumulation is a rapid and sensitive response to elevated vascular wall stress in both systemic and pulmonary hypertension. While initially protecting the vessel wall, these structural changes may in the longer term result in reinforcement of the hypertensive state and contribute to the persistence of the pathology of hypertension. Rapid responses apparently uncorrelated with increased elastin mRNA, at least in the case of systemic vessels, suggest novel mechanisms perhaps including increased efficiency of message translation or matrix accumulation of the protein. Investigations using in vitro organ and cell culture models have indicated a role for phospholipases and protein kinases, including protein kinase C, in stretch-induced elastin synthesis. In addition, tyrosine phosphorylation of membrane/sub-membrane/cytoskeletal sensors, including focal adhesion kinase and members of the lipocortin family, have been shown to be important in this transduction mechanism. Because its turnover is normally very slow, additional vascular elastin accumulated during hypertensive episodes, together with its consequences for the physical properties of the vessel wall, may persist long after blood pressure is restored to normal levels. Thus, recent interest has been drawn to the possibility of achieving regression of accumulated matrix elastin by promoting turnover of this protein through activation of endogenous vascular elastase and collagenase activities.
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PMID:Elastin in systemic and pulmonary hypertension. 857 61

It is now well established that the interaction of tumour cells with elastin is important during invasion and metastasis. This is due to the fact that the elastin receptor complex is widely expressed by tumour cells and is overexpressed in highly metastatic variants. There is evidence that the elastin receptor complex is associated with a signal system involving G proteins, phospholipase C, the phosphoinositol cycle and protein kinase C. Therefore, activation of the elastin receptor system results in activation of protein kinase C-dependent cellular processes such as enzyme secretion and migration. Accordingly, soluble elastin can be used in vivo to interfere with tumour cell dissemination into elastin-rich tissues such as lung, skin or blood vessels. The importance of elastin-tumour cell interactions is emphasized by the observation that the 67 kDa receptor for laminin may well be identical to the 67 kDa elastin receptor of the elastin receptor complex. Interference with the function of this receptor system by the use of both laminin peptides and elastin ligands may provide the basis for a novel and more powerful antimetastatic intervention.
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PMID:Interaction of tumour cells with elastin and the metastatic phenotype. 857 65

The effect of heparin on elastin expression in the proliferating and quiescent phases of growth of smooth muscle cells was studied. Heparin stimulated elastin synthesis and its mRNA level 2-3 fold in the proliferating cells while it inhibited the cell proliferation. The inhibition of cell proliferation and the stimulation of elastin expression by heparin in the proliferating cells were mimicked by a potent protein kinase C antagonist, H-7, but not by H-89, W-7, and HA1004, suggesting that the effect of heparin is mediated by the inhibition of protein kinase C. In contrast, heparin inhibited elastin synthesis and its mRNA level slightly but exhibited no effect on cell proliferation in the growth-arrested cells. This result indicates that heparin reciprocally affects elastin expression depending on the growth state of smooth muscle cells. Heparin thus exerts a complex influence on elastin expression in smooth muscle cells.
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PMID:Modulation of elastin expression by heparin is dependent on the growth condition of vascular smooth muscle cells: up-regulation of elastin expression by heparin in the proliferating cells is mediated by the inhibition of protein kinase C activity. 869 Jul 21

Aging of the vascular wall, arteriosclerosis and focal lipidic plaques, atheromatosis, often occur together but may occur separately as lipidic lesions in young children or vascular aging in some animal species resistant to lipid-rich diet as the rat. Most theories of athero-arteriosclerosis claim an endothelial lesion for its initiation, without proposing a detailed mechanism. The elastin-laminin receptor present also on endothelial cells, mediates NO.-dependent vasorelaxation. It could be shown that chronic exposure to higher concentrations of the agonist, elastin peptides, present in human blood at microgram/ml concentrations, and also during aging, the receptor gets "uncoupled" from its transmission pathway (G-protein, PLC, PKC) but continues releasing free radicals as superoxyde. NO. and O2-. give peroxynitrite, a toxic anion, needing GSH for its neutralisation. GSH production decreases with age. This process decreases available NO. for vasorelaxation and could then contribute to age-dependent blood pressure increase and produce the endothelial lesions leading to the development of athero-arteriosclerosis.
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PMID:Aging of the vascular wall and atherogenesis: role of the elastin-laminin receptor. 878 48

Okadaic acid (OA), a specific serine/threonine protein phosphatase inhibitor, downregulated tropoelastin formation and elastin mRNA levels in a dose-related and cycloheximide-sensitive fashion in cultured lung fibroblasts. Treatment with a tyrosine phosphatase inhibitor at high concentrations did not alter elastin mRNA levels, however. Nuclear run-on analysis indicated that OA primarily suppressed elastin gene expression through a transcriptional mechanism. In contrast to its effects on elastin expression, OA downregulated alpha 1(I) mRNA to significantly lesser degrees. The mechanism by which OA decreased elastin mRNA levels did not appear to involve protein kinase C or share the signaling pathway of IL-1 beta. Prolonged treatment with phorbol ester promoted the inhibitory effects of OA on elastin, as did shorter treatment with IL-1 beta. Moreover, transient transfection studies indicated that OA and IL-1 beta do not act through the same cis-acting element in the elastin promoter. Finally, unlike the transient effects of IL-1 beta, OA induced persistent inhibition of elastin expression by a transcriptional mechanism. Taken together, these data indicate that serine/threonine protein phosphorylation can regulate the amount and composition of extracellular matrix secreted by fibroblasts into the interstitium of the lung.
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PMID:Effect of okadaic acid on elastin gene expression in interstitial lung fibroblasts. 899 64

alpha-Elastin with an average molecular mass of 70 kDa, an oxalic acid fragmentation product of highly purified insoluble elastin, induced the migration of macrophages, with maximum activity at 10(-1) microg/ml. Relative to the positive control of 10(-8) M N-formylmethionyl-leucyl-phenylalanine (fMLP), the responsiveness of macrophages to alpha-elastin was nearly the same. Checkerboard analysis demonstrated that the cell movement is chemotaxis and not chemokinesis. A homologous deactivation test showed the possibility of the existence of alpha-elastin-recognizing sites on macrophages. In connection with macrophage chemotaxis in response to alpha-elastin, the intracellular signaling pathway was examined. The guanosine 3', 5'-cyclic monophosphate (cGMP) level was enhanced in macrophages stimulated by alpha-elastin, whereas the adenosine 3',5'-cyclic monophosphate (cAMP) level was not. Chemotaxis assaying of macrophages treated with 8-Br cGMP- and dibutyryl cAMP-loaded macrophages indicated that cGMP promotes cell movement and cAMP suppresses cell locomotion. The possible involvement of protein kinases in the alpha-elastin signaling pathway was explored by use of inhibitors specific for cGMP-dependent protein kinase (PKG), cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and tyrosine kinase. The macrophage chemotactic response to alpha-elastin was inhibited by the PKG inhibitor, but not by the PKA, PKC, or tyrosine kinase inhibitor. These results suggested that the increase in the cGMP level and the activation of PKG in macrophages are involved in alpha-elastin induced macrophage chemotaxis.
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PMID:Involvement of intracellular cyclic GMP and cyclic GMP-dependent protein kinase in alpha-elastin-induced macrophage chemotaxis. 919 26


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