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)

Microvascular endothelial cells express a variety of cell-surface integrins in vivo and in vitro with varying affinities for matrix proteins. The vitronectin receptor (VnR), a complex of the alpha v and beta 3 integrin chains, is capable of binding to a variety of matrix proteins that are deposited in injured tissues, including vitronectin, fibrinogen, and thrombin. Staining of frozen sections of human skin with antibodies recognizing the VnR and examination by immunofluorescence microscopy demonstrates staining in a vascular pattern suggesting in vivo expression of the vitronectin receptor on endothelial cells. Examination of pure cultures of human dermal microvascular endothelial cells (HDMEC) by flow-cytometric analysis and enzyme-linked immunosorbent assay confirmed that HDMEC also express cell surface VnR complex in vitro. Stimulation of human dermal microvascular endothelial cells in vitro with agents that stimulate protein kinase C resulted in dose- and time-dependent increases in expression of alpha v and beta 3 integrin chains. Additionally, stimulation with basic fibroblast growth factor induced similar increases, but stimulation with transforming growth factor-beta or interleukin-1 alpha failed to increase VnR expression. Increases in cell-surface VnR expression also correlated with an increased ability of microvascular endothelial cells to bind to vitronectin, but not fibronectin-coated surfaces. Although increases in cell-surface expression of beta 3 paralleled increases in expression of cell-surface alpha v, regulation of mRNA expression was distinct for each chain. These data suggests that microvascular endothelial cells express the VnR complex in vivo, that the cell-surface expression of this integrin on dermal microvascular endothelial cells can be regulated, and that this regulation may be important in cell adherence, cell migration, and wound healing.
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PMID:Expression and modulation of the vitronectin receptor on human dermal microvascular endothelial cells. 128 60

The adherence of cells to microvascular endothelium is important in a number of processes, including inflammatory responses and metastasis. It has been demonstrated that in human models, cytokines such as TNF, IL-1, IFN-gamma increase the adhesiveness of endothelium for cells of the immune and inflammatory system by stimulating the expression of cell adhesion molecules on endothelial cell surfaces. We and others have shown similar cytokine-induced endothelial adhesiveness for tumor cells in murine and human models. In contrast to the effect of those modulators, transforming growth factor-beta (TGF-beta) has been shown to inhibit the binding of human neutrophils and T lymphocytes to human endothelium, although the mechanism of TGF-beta action remains unknown. Little is known about the effect of TGF-beta on tumor cell-endothelial interaction. In the present study, we demonstrate that TGF-beta inhibits basal and TNF-enhanced binding of murine P815 mastocytoma cells to murine microvascular endothelium (MME). The alterations in MME mediated by TGF-beta, also lead to the inhibition of adherence of murine splenocytes, thymocytes, and human lymphoblastoid cells but do not inhibit adherence of murine B16 melanoma cells. The effect of TGF-beta is transient and inhibition of the endothelial adhesive phenotype is strongest 12 to 24 h after addition of the factor to MME. The TGF-beta-mediated inhibition of P815 basal binding to endothelium is dependent on protein synthesis because cycloheximide reverses the TGF-beta effect. TGF-beta does not appear to activate classical signal transduction pathways. Inhibitors of G proteins do not abolish TGF-beta action, protein kinase C and protein kinase A activators elicit an effect opposite to that of the factor, TGF-beta does not increase intracellular cAMP levels, and finally calcium-mobilizing agents do not mimic, but rather inhibit the effect of TGF-beta. However, TGF-beta-mediated inhibition of both basal binding and TNF-enhanced P815 binding to MME is completely abolished in the presence of the protein phosphatase inhibitor okadaic acid which suggests that TGF-beta may elicit its effect by stimulating protein phosphatase activity.
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PMID:Inhibition of basal and tumor necrosis factor-enhanced binding of murine tumor cells to murine endothelium by transforming growth factor-beta 1. 131 61

We have previously shown that basic fibroblast growth factor (bFGF) inhibits the FSH-induced differentiation of cultured rat granulosa cells, as manifested by prominent reduction of the LH receptor expression. We now investigate the possible sites and mechanism of action of bFGF. Whereas bFGF decreased the cAMP formation induced by FSH, it enhanced the cAMP production caused by cholera toxin and forskolin, suggesting that bFGF exerted its inhibitory action on cell differentiation at a step to cAMP production. Photoaffinity labeling with 8-azido-[32P]cAMP revealed that bFGF markedly reduced the FSH-induced increase in the level of regulatory subunit RII beta of the cAMP-dependent protein kinase (PKA) type II. In contrast to its striking effect on RII beta expression (70-80% inhibition), bFGF decreased PKA enzymatic activity by only 30%. On the other hand, transforming growth factor-beta (TGF beta) slightly amplified the stimulatory action of FSH and antagonized the bFGF inhibitory effect on both LH receptor expression and RII beta synthesis. We report that the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate (TPA), which impaired granulosa cell differentiation, also abolished the RII beta synthesis induced by FSH. The activation of PKC by bFGF in granulosa cells was supported by the following findings: (i) bFGF markedly enhanced the production of diacylglycerol (2.3-fold stimulation at 5 min), the intracellular activator of PKC; (ii) bFGF promoted tight association of PKC to cellular membranes, a process that is believed to correlate with the enzyme activation; (iii) bFGF induced the phosphorylation of an endogenous M(r) 78,000/pI 4.7 protein that appears as a specific PKC substrate; (iv) bFGF mimicked the TPA-induced transmodulation of the epidermal growth factor (EGF) receptor, reducing by 36% the 125I-EGF binding on granulosa cells. We conclude that bFGF may exert its repressive action on RII beta synthesis, PKA activity, and granulosa cell differentiation by primarily targeting PKC activation.
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PMID:Regulation of cyclic adenosine 3',5'-monophosphate-dependent protein kinase activity and regulatory subunit RII beta content by basic fibroblast growth factor (bFGF) during granulosa cell differentiation: possible implication of protein kinase C in bFGF action. 132 4

The CD20 molecule is a unique phosphoprotein exclusively expressed on B cells during most stages of B cell ontogeny. We here report that rIL-4 down-regulates the expression of CD20 with anti-Leu-16 mAb (clone L27) on both unstimulated and anti-mu preactivated normal and leukemic B cells. None of the other recombinant lymphokines tested (IL-1, IL-2, IL-3, IL-6, IFN-alpha, and IFN-gamma, granulocyte/macrophage-CSF, transforming growth factor-beta, TNF-alpha, and lymphotoxin) decreased CD20 expression. Incubation of unstimulated or anti-mu preactivated B cells with IL-4 did not affect the steady state CD20 mRNA, suggesting that IL-4 exerted its effect mainly at a nontranscriptional level. Hence, IL-4 selectively down-regulates the CD20 epitope recognized by clone L27 without affecting seven other different epitopes, indicating that IL-4 acts by modifying the conformation of the CD20 molecule rather than by inhibiting its production or inducing its internalization. IL-4 most likely utilizes a protein kinase C-independent signal transduction pathway to modify CD20 molecule inasmuch as staurosporine, an inhibitor of protein kinase C, antagonizes phorbol esters (PMA) but not IL-4-induced CD20 down-regulation. In contrast, anti-CD40 mAb reverses the IL-4 but not the PMA inhibitory effect on CD20 expression. Given that CD20 may be part of a Ca2+ ion channel and plays a role in B cell activation and proliferation, it is proposed that the ability of anti-CD40 mAb to maintain the CD20 molecule in a given epitopic configuration on IL-4-stimulated B cells may be related to the long term proliferation of normal B cells that are strictly dependent on the presence of IL-4 and cross-linked anti-CD40 mAb for their continuous growth.
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PMID:IL-4 induces conformational change of CD20 antigen via a protein kinase C-independent pathway. Antagonistic effect of anti-CD40 monoclonal antibody. 137 68

Expression of the rat stromelysin (transin) gene is stimulated by growth factors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), and inhibited by transforming growth factor-beta (TGF beta). Stimulation by both EGF and PDGF requires the presence of factors that recognize the AP-1 binding site in the stromelysin promoter, but PDGF stimulation requires induction of the protooncogene c-fos, while EGF acts through a FOS-independent pathway. The FOS-independent pathway appears to involve protein kinase C (PKC), since EGF, but not PDGF, requires activated protein kinase C to stimulate stromelysin expression. TGF beta inhibition of stromelysin gene expression requires an upstream sequence, referred to as the TGF beta inhibitory element (TIE). FOS is also a part of a protein complex that binds to the TIE. The protooncogene FOS is therefore involved in both stimulation and inhibition of stromelysin gene expression.
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PMID:The role of C-Fos in growth factor regulation of stromelysin/transin gene expression. 148 19

The inhibitory effect of a serine protease-inhibiting tetra-benzamidine derivative, TAPP-Br, on the cell growth of 8 human colon carcinoma cell lines was examined and the mechanism of the inhibition was analyzed. TAPP-Br inhibited the cell growth of all the colon carcinoma cell lines, and this effect was irreversible. The expression of mRNAs for nuclear oncogenes such as MYC, FOS and JUN was decreased by TAPP-Br after treatment for 3 h and the effect continued for 48 h. mRNA expression of epidermal growth factor receptor, transforming growth factor-beta and type IV collagenase was suppressed at 48 h after the initiation of TAPP-Br treatment, suggesting an indirect action of TAPP-Br. TAPP-Br decreased protein kinase C activity in the particulate fraction, whereas it increased the enzyme activity in the soluble fraction. These findings overall suggest that the serine protease inhibitor, TAPP-Br, might inhibit the cell growth of colon carcinoma cell lines through suppressing the expression of genes whose promoter contains a 12-O-tetradecanoylphorbol-13-acetate-responsive element or serum-responsive element.
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PMID:A serine protease-inhibitory benzamidine derivative inhibits the growth of human colon carcinoma cells. 151 49

cMG1 is a primary response gene first identified in a rat intestinal epithelial (RIE-1) cell-line [(1990) Oncogene 5, 1081-1083]. A number of mitogens, including epidermal growth factor (EGF), angiotensin II (AII), serum and insulin rapidly induced 2- to 6-fold increases of cMG1 mRNA in RIE-1 cells, while transforming growth factor-beta caused a small reduction. Cyclic AMP-elevating agents blocked the increase of cMG1 mRNA induced by EGF. The AII-stimulated increase of cMG1 mRNA was blocked by the depletion of protein kinase C, whereas the EGF-stimulated increase was not affected, indicating that protein kinase C-dependent and -independent signalling pathways stimulate cMG1 expression.
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PMID:Mitogen-induced expression of the primary response gene cMG1 in a rat intestinal epithelial cell-line (RIE-1). 162 38

To understand further the roles that negative regulatory signals may play in B cell immune responses, we compared three inhibitors of B cell proliferation: cross-linking CD19 with monoclonal antibody (mAb), signaling through Fc receptors by intact anti-mu mAb, and transforming growth factor-beta (TGF-beta). Each agent was tested for its ability to block proliferation and specific activation events induced in human tonsilar B cells activated by either cross-linking surface immunoglobulin, signaling through CD20, or direct activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate. We found that each inhibitor was functionally distinct. Both anti-CD19 mAb and anti-mu mAb inhibited anti-immunoglobulin activated cells and anti-CD20-activated cells, but neither inhibited cells activated by phorbol 12-myristate 13-acetate. TGF-beta, on the other hand, inhibited equally profoundly cells activated by each of the three regimens. These results suggest that TGF-beta blocks B cell activation at a step following the activation of PKC, whereas both signaling through CD19 and Fc receptor block early steps in the PKC activation pathway. Signaling through anti-CD19 mAb was unique in that proliferation of anti-immunoglobulin-activated cells was reduced on day 3 and then augmented subsequently. With all other inhibitory combinations the block was permanent. We conclude that each of these three inhibitors has unique important functions and therefore suggest that the effectiveness of negative signaling in B cell immune regulation will depend on the combinations of specific inhibitors modulating a specific activation program.
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PMID:Signaling through CD19, Fc receptors or transforming growth factor-beta: each inhibits the activation of resting human B cells differently. 169 30

The inability of CD4+ T cells of HIV-1-infected patients to mount an effective immune response is widely believed to explain the increased susceptibility of these patients to opportunistic infections. Although the full explanation for T-cell dysfunction in HIV-1 infection is not yet understood, at least two fundamentally distinct mechanisms are thought to contribute: depletion of CD4+ T cells and qualitative CD4+ T-cell dysfunction independent of T-cell depletion. Many HIV-1-infected patients manifest reduced T-cell responses to recall antigens prior to measurable CD4+ T-cell depletion, and among the proposed explanations for this phenomenon are gp120-mediated interference with T-cell activation by way of inhibition of CD4-class II major histocompatibility complex (MHC) determinant interactions, gp41-mediated inhibition of protein kinase C-dependent T-cell activation, formation of gp41 cross-reactive antibodies that react with MHC class II determinants, transforming growth factor-beta (TGF-beta)-mediated immunosuppression, and decreased functions of antigen-presenting and antigen-processing cells (macrophages and bone marrow-derived dendritic cells). Despite their detection in most HIV-1-infected patients, these qualitative T-cell defects do not herald the onset of life-threatening disease. The appearance of severe clinical manifestations of AIDS, particularly opportunistic infections, occurs primarily in patients whose CD4+ T-cell count is significantly reduced. Depletion of CD4+ T cells may be a direct consequence of HIV-1 infection that occurs as a result of syncytia formation, autoantibody-mediated cytolysis, gp120-specific antibody-dependent cytolysis, and/or gp120-specific T-cell mediated cytolysis. The thymus is severely affected in patients with late-stage disease, and although there is no proof that the failure of the thymus to regenerate new T cells contributes to T-cell depletion in patients with AIDS, the likelihood seems high that this is the case. Indeed, if prolonged suppression of HIV-1 replication can be achieved with newer anti-HIV drugs or combinations of drugs, reconstitution of a normal immune system seems likely, provided that the capacity to regenerate T cells has not been irrevocably lost as a consequence of viral infection. In summary, available evidence indicates that HIV-1 uses a complex array of mechanisms to disrupt T-cell mediated immunity, but because most of these involve a direct role for HIV-1 proteins, such mechanisms are likely to be reversible if suppression of HIV-1 replication can be achieved.
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PMID:Impaired immunity in AIDS. The mechanisms responsible and their potential reversal by antiviral therapy. 198 24

Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. Recent evidence suggests that vasoconstrictive substances, such as angiotensin II (AII), may function as a vascular smooth muscle growth promoting substance. To explore the role of the counterregulatory hormone, atrial natriuretic polypeptide (ANP) in this process, we examined the effect of ANP (alpha-rat ANP [1-28]) on the growth characteristics of cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) significantly suppressed the proliferative effect of 1% and 5% serum as measured by 3H-thymidine incorporation and cell number, confirming ANP as an antimitogenic factor. In quiescent RASM cells, ANP (10(-7), 10(-6) M) significantly suppressed the basal incorporations of 3H-uridine and leucine by 50 and 30%, respectively. ANP (10(-7), 10(-6) M) also suppressed AII-induced RNA and protein syntheses (by 30-40%) with the concomitant reduction of the cell size. Furthermore, ANP also significantly attenuated the increase of 3H-uridine and leucine incorporations caused by transforming growth factor-beta (4 x 10(-11), 4 x 10(-10) M), a potent hypertrophic factor. These results indicate that ANP possesses an antihypertrophic action on vascular smooth muscle cells. Down-regulation of protein kinase C by 24-h treatment with phorbol 12,13-dibutyrate did not inhibit ANP-induced suppression on 3H-uridine incorporation. Based on the observation that ANP was more potent than a ring-deleted analogue of ANP on inhibiting 3H-uridine incorporation, we conclude that the ANP's inhibitory effect is primarily mediated via the activation of a guanylate cyclase-linked ANP receptor(s). Indeed 8-bromo cGMP mimicked the antihypertrophic action of ANP. Accordingly, we speculate that in addition to its vasorelaxant and natriuretic effects, the antihypertrophic action of ANP observed in the present study may serve as an additional compensatory mechanism of ANP in hypertension.
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PMID:Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells. 217 26


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