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)

Recent evidence demonstrates that the protein kinase C zeta (zeta PKC) isoform is required for the activation of nuclear factor kappa B (NF-kappa B) and mitogenic signaling in Xenopus oocytes and mammalian cells. The mechanism whereby zeta PKC regulates NF-kappa B most probably involves the activation of a putative I kappa B kinase of molecular mass approximately 50 kDa, which phosphorylates and inactivates I kappa B. Tumor necrosis factor alpha (TNF alpha) and interleukin-1, besides activating the phospholipase C-mediated breakdown of phosphatidylcholine, also generate ceramide, which is produced by stimulation of sphingomyelin hydrolysis. We show here that exogenous addition of sphingomyelinase (SMase) to NIH-3T3 fibroblasts transactivates a kappa B-dependent chloramphenicol acetyltransferase reporter plasmid, to an extent similar to that produced by TNF alpha or phosphatidylcholine/phospholipase C. More importantly, the ability of SMase to stimulate this parameter is severely impaired by transfection of a zeta PKC kinase-defective dominant negative mutant, which suggests a critical role of zeta PKC in SMase signaling. In keeping with this notion, we also demonstrate here that zeta PKC is activated in vitro by ceramide and in vivo by treatment of NIH-3T3 fibroblasts with SMase.
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PMID:Protein kinase C zeta isoform is critical for kappa B-dependent promoter activation by sphingomyelinase. 803 80

Flavone-8-acetic (FAA) acid is a potential chemotherapeutic agent that has demonstrated strong immunomodulatory activity in murine model systems. The immunomodulatory activity of this drug in murine systems has been linked to its ability to rapidly induce cytokine gene expression in vivo and in mouse splenocytes ex vivo. We have now developed a tissue culture model for studying the molecular basis of induction of cytokine expression by FAA. Using the mouse macrophage cell line, ANA-1, we can demonstrate the direct induction of interferon beta (IFN beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), and interferon response factor-1 (IRF-1) mRNA expression following treatment with FAA. Furthermore, the induction of the IFN beta mRNA can occur in the absence of new protein synthesis. Nuclear run-on experiments indicate that at least part of the induction of IFN beta, IL-6, and TNF alpha mRNA occurs at the transcriptional level while the increase in IRF-1 mRNA appears largely post-transcriptional or due to the production of IFN beta protein. Additionally, experiments using agents that interfere with second messengers demonstrate that activation of the protein kinase C pathway is possibly involved in FAA gene induction. The use of this tissue culture model system should lead to a more complete understanding of the mechanisms involved in FAA-induced gene expression and help determine why this drug is inactive on human cells.
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PMID:Induction of multiple cytokine gene expression and IRF-1 mRNA by flavone acetic acid in a murine macrophage cell line. 803 45

Microglia, the resident macrophages of the brain, secrete a number of mediators involved in neural-immune function. The cytokines, IL-1 alpha and TNF alpha, are two such factors which are stored as inactive precursor molecules requiring post-translational proteolytic processing prior to release. From investigations of second messenger pathways involved in regulating the secretion of these cytokines, we have demonstrated that the PKC inhibitor, H-7, blocks the induction of TNF alpha secretion induced by LPS. In contrast, H-89 and HA-1077, inhibitors of cyclic nucleotide-dependent protein kinases (PKA and PKG), did not alter LPS-stimulation of TNF alpha release. Consistent with these observations, the weak PKC activator, mezerein, induced TNF alpha secretion in an H-7-reversible manner. In marked contrast, PKC activation did not induce IL-1 alpha secretion and H-7 potentiated IL-1 alpha release. In the case of the protein phosphatase inhibitor, okadaic acid, secretion of both cytokines was induced, indicating that protein phosphorylation is important for the induction of cytokine secretion but only in the case of TNF alpha is PKC involved. In the case of IL-1 alpha, a tonic inhibitory regulation involving PKC activation may be present. We therefore conclude that alterations in phosphorylation-dephosphorylation cycles may be important triggers in the switching of microglial cellular function from a resting to an activated state.
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PMID:Differential regulation of IL-1 alpha and TNF alpha release from immortalized murine microglia (BV-2). 806 28

Stimulated mast cells and cognate cultured cell lines produce and secrete a variety of cytokines including TNF. Because the mechanism by which cytokines are delivered to the external milieu is unknown, the release of TNF was studied in a rat mast cell line (RBL-2H3 cells). In these cells, TNF was not constitutively expressed nor incorporated into secretory granules but was generated de novo upon cell stimulation. It was then released by a process analogous to constitutive secretion in that brefeldin A, an agent known to disrupt Golgi membranes in these cells, inhibited this release without inhibiting release of secretory granules. Unlike constitutive secretion, however, the secretion of TNF was highly regulated by Ca2+ and protein kinase C. Studies with various stimulants and inhibitors indicated that simultaneous mobilization of Ca2+ and activation of protein kinase C were sufficient signals for secretion although optimal production of TNF may be dependent on additional synergistic signals. Because suppression of Ca2+ mobilization or inhibition of protein kinase C alone abrogated TNF secretion, the process may be amenable to therapeutic intervention.
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PMID:Secretion of TNF from a rat mast cell line is a brefeldin A-sensitive and a calcium/protein kinase C-regulated process. 807 71

Glucocorticoids have a wide variety of effects which result in the dampening of inflammatory and immune responses and other challenges to homeostasis. An important site of steroid action may be on the control of transcription factor binding to DNA. The interaction of the transcription factors, activator protein 1 (AP-1) and nuclear factor kappa from B cells (NF kappa B) with DNA and glucocorticoid receptors was analysed by gel mobility shift assays following stimulation by tumour necrosis factor alpha (TNF alpha) and a phorbol ester (PMA) that activates protein kinase C. PMA and TNF alpha both caused significant (180-340%) increases in AP-1 and NF kappa B DNA binding which peaked at 15 minutes and decreased to a constant elevated level at between 1-3 hrs and was sustained for 24hrs. Dexamethasone (1 microM) caused a rapid and long lasting 40-50% decrease in both AP-1 and NF kappa B DNA binding lasting over 24hrs. Combined treatment with dexamethasone and PMA or TNF alpha prevented the increase in both AP-1 and NF kappa B binding due to PMA and TNF alpha returning levels to those seen in control untreated samples. This suggests that in human lung, the glucocorticoid receptor functionally interacts within the nucleus with other transcription factors that are induced by inflammatory mediators such as cytokines. This may be an important molecular site of steroid action in chronic inflammatory lung diseases such as asthma.
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PMID:The effects of glucocorticoids on phorbol ester and cytokine stimulated transcription factor activation in human lung. 809 56

Incubation of the human renal carcinoma cell line CaKi-1 with tumour necrosis factor alpha (TNF alpha) or the phorbol ester phorbol-12-myristate 13 acetate (PMA) strongly enhanced the immunocytochemical staining of the intercellular adhesion molecule ICAM-1, in a non-linear manner. Since PMA is capable of activating Ca2+/phospholipid-dependent protein kinase C (PKC), we investigated the role of this kinase during TNF alpha signal transduction. Calcium ionophore A23187 significantly enhanced PMA, but not TNF alpha-induced ICAM-1 staining. The PKC inhibitors H7, staurosporine and sphingosine abrogated the action of PMA, while TNF alpha was unaffected. Simultaneous incubation with TNF alpha and PMA resulted in maximal ICAM-1 staining significantly above values obtained when cultures were treated with either agent alone. Finally, chronic PMA treatment with subsequent TNF alpha stimulation enhanced ICAM-1 staining above values from cultures where TNF alpha was omitted. Our findings suggest that the immunocytochemical staining of ICAM-1 in CaKi-1 cells can be induced by TNF alpha through mainly PKC-independent mechanisms or by PMA through PKC-dependent mechanisms. The two agents may work synergistically in this respect.
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PMID:Comparison of the effects of tumour necrosis factor alpha stimulation and phorbol ester treatment on the immunocytochemical staining of intercellular adhesion molecule 1 in human renal carcinoma cell cultures. 809 20

Endotoxin, interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) dose-dependently increased the expression of tissue factor and at the same time induced thrombomodulin down-regulation on the surface of cultured bovine aortic endothelial cells. Chelerythrine, a selective protein kinase C inhibitor, strongly reduced endotoxin-, IL1 beta- and TNF alpha-induced tissue factor expression but remained without effect with regard to thrombomodulin down-regulation measured in parallel. On the contrary, staurosporine, a highly potent, non-selective PKC inhibitor, simultaneously abolished tissue factor expression and thrombomodulin down-regulation induced by endotoxin, IL1 beta and TNF alpha. These results show that protein kinase C is deeply involved in the process leading to pyrogen-induced tissue factor expression and suggest that thrombomodulin down-regulation is regulated by a different pathway.
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PMID:Chelerythrine, a selective protein kinase C inhibitor, counteracts pyrogen-induced expression of tissue factor without effect on thrombomodulin down-regulation in endothelial cells. 813 8

The nuclear factor kappa B (NF-kappa B) is a eukaryotic transcription factor. In B cells and macrophages it is constitutively present in cell nuclei, whereas in many other cell types, NF-kappa B translocates from cytosol to nucleus as a result of transduction by tumor necrosis factor alpha (TNF alpha), phorbol ester, and other polyclonal signals. Using neuroblastoma cell lines as models, we have shown that in neural cells NF-kappa B was present in the cytosol and translocated into nuclei as a result of TNF alpha treatment. The TNF alpha-activated NF-kappa B was transcriptionally functional. NF-kappa B activation by TNF alpha was not correlated with cell differentiation or proliferation. However, reagents such as nerve growth factor (NGF) and the phorbol ester phorbol 12-myristate 13-acetate (PMA), which induce phenotypical differentiation of the SH-SY5Y neuroblastoma cell line, activated NF-kappa B, but only in that particular cell line. In a NGF-responsive rat pheochromocytoma cell line, PC12, PMA activated NF-kappa B, whereas NGF did not. In other neuroblastoma cell lines, such as SK-N-Be(2), the lack of PMA induction of differentiation was correlated with the lack of NF-kappa B activation. We found, moreover, that in SK-N-Be(2) cells protein kinase C (PKC) enzymatic activity was much lower compared with that in a control cell line and that the low PKC enzymatic activity was due to low PKC protein expression. NF-kappa B was not activated by retinoic acid, which induced morphological differentiation of all the neuroblastoma cell lines used in the present study. Thus, NF-kappa B activation was not required for neuroblastoma cell differentiation. Furthermore, the results obtained with TNF alpha proved that NF-kappa B activation was not sufficient for induction of neuroblastoma differentiation.
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PMID:Activation of nuclear factor kappa B in human neuroblastoma cell lines. 815 22

Studies were undertaken to characterize the cytokines and cytokine-cytokine interactions that stimulate human lung fibroblast leukemia inhibitory factor (LIF) production and the mechanisms of these regulatory effects were investigated. Unstimulated fibroblasts did not produce significant amounts of LIF, whereas recombinant interleukin-1 alpha (rIL-1 alpha), transforming growth factor-beta (TGF-beta), and recombinant tumor necrosis factor (rTNF) were dose-dependent stimulators of LIF production. TGF-beta and rIL-1 alpha also interacted in a synergistic fashion to further increase LIF elaboration. Under all conditions alterations in LIF production were associated with comparable alterations in LIF mRNA accumulation. The kinetics of mRNA induction, however, differed with rIL-1-induced LIF mRNA being readily detected after 2 h, TGF-beta 1 induction peaking after 16-24 h, and the induction caused by rIL-1 alpha plus TGF-beta 1 being most prominent after 2-4 h and decreasing with additional incubation. Protein synthesis was not required for LIF induction. In addition, even though A23187 was an effective stimulator of LIF production, the calmodulin antagonists W-7 and trifluoperazone dichoride (TFP) did not significantly alter the LIF-stimulatory effects of IL-1 and TGF-beta. PKC did appear to play an important role in this induction, however, since LIF was induced by PMA and cytokine induction of LIF production was markedly diminished by chronic phorbol ester preincubation, staurosporine, and H-7, but not by HA1004. These studies demonstrate that 1) rIL-1, TGF-beta, TNF, agents that increase intracellular calcium and agents that activate PKC, stimulate lung fibroblast LIF production; 2) rIL-1 and TGF-beta interact in a synergistic fashion to further increase fibroblast LIF production; and 3) rIL-1 and TGF-beta stimulate lung fibroblast LIF production via a pretranslational activation pathway that is largely PKC-dependent and protein synthesis-, cyclic nucleotide-, and calmodulin-independent. Cytokine-stimulated LIF production may play an important role in homeostasis and repair in the human lung.
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PMID:Cytokine-cytokine synergy and protein kinase C in the regulation of lung fibroblast leukemia inhibitory factor. 817 19

Bacterial LPS induce production of cytokines such as IL-1, IL-6, and TNF in mononuclear phagocytes, and this represents a central component in the pathogenesis of septic shock syndrome. However, the mechanisms by which LPS activates these cells to express cytokines are not completely characterized. The present study addressed the role of different protein kinases in the LPS induction of cytokines. It is shown that LPS induced a 12- to 16-fold increase in IL-1 beta, IL-6, and TNF-alpha mRNA levels, and this was completely or more than 80% blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1.7 and 37 microM, respectively. Protein kinase C inhibition by staurosporine reduced LPS induction of TNF-alpha, whereas it had no effects on IL-6 and IL-1 beta. Inhibition of protein kinase A by H89 reduced IL-6 mRNA levels but did not detectably change IL-1 beta or TNF-alpha mRNA levels. In contrast, LPS did not increase leukemia inhibitory factor mRNA, which was constitutively expressed and not significantly reduced by these inhibitors. In addition to cytokine mRNA levels, LPS-induced IL-6 protein synthesis and IL-6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein. Both PTK inhibitors also reduced the LPS activation of nuclear factor-kappa B (NF-kappa B), which is a transcription factor involved in the expression of cytokine genes such as IL-6 and TNF-alpha. The activation of NF-kappa B was also reduced by H89, whereas staurosporine had no effect on this response. In summary, these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines, whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF-kappa B activation in monocytes.
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PMID:Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. 825 85


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