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)

A series of alpha-terthiophene derivatives were prepared and their protein kinase C inhibitory activity were evaluated. The aldehyde derivatives were most potent inhibitors (IC50 < 1 microM). alpha-Terthiophene monoaldehyde was inactive in the inhibitions of protein kinase A, mitogen activated protein kinase and protein tyrosine kinase.
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PMID:Novel protein kinase C inhibitors: alpha-terthiophene derivatives. 987 5

Apoptosis was induced in human glioma cell lines by exposure to 100 nM calphostin C, a specific inhibitor of protein kinase C. Calphostin C-induced apoptosis was associated with synchronous down-regulation of Bcl-2 and Bcl-xL as well as activation of caspase-3 but not caspase-1. The exposure to calphostin C led to activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) and p38 kinase and concurrent inhibition of extracellular signal-regulated kinase (ERK). Upstream of ERK, Shc was shown to be activated, but its downstream Raf1 and ERK were inhibited. The pretreatment with acetyl-Tyr-Val-Ala-Asp-aldehyde, a relatively selective inhibitor of caspase-3, or benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.fmk), a broad spectrum caspase inhibitor, similarly inhibited calphostin C-induced activation of SAPK/JNK and p38 kinase as well as apoptotic nuclear damages (chromatin condensation and DNA fragmentation) and cell shrinkage, suggesting that caspase-3 functions upstream of SAPK/JNK and p38 kinase, but did not block calphostin C-induced surface blebbing and cell death. On the other hand, the inhibition of SAPK/JNK by transfection of dominant negative SAPK/JNK and that of p38 kinase by SB203580 induced similar effects on the calphostin C-induced apoptotic phenotypes and cell death as did z-VAD.fmk and acetyl-Tyr-Val-Ala-Asp-aldehyde, but the calphostin C-induced PARP cleavage was not changed, suggesting that SAPK/JNK and p38 kinase are involved in the DNA fragmentation pathway downstream of caspase-3. The present findings suggest, therefore, that the activation of SAPK/JNK and p38 kinase is dispensable for calphostin C-mediated and z-VAD.fmk-resistant cell death.
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PMID:Activation of stress-activated protein kinase/c-Jun NH2-terminal kinase and p38 kinase in calphostin C-induced apoptosis requires caspase-3-like proteases but is dispensable for cell death. 1002 38

Bronchitis, asthma, and cystic fibrosis, marked by inflammation and mucus hypersecretion, can be caused or exacerbated by airway pathogens or irritants including acrolein, an aldehyde present in tobacco smoke. To determine whether acrolein and inflammatory mediators alter mucin gene expression, steady-state mRNA levels of two airway mucins, MUC5AC and MUC5B, were measured (by RT-PCR) in human lung carcinoma cells (NCI-H292). MUC5AC mRNA levels increased after >/=0.01 nM acrolein, 10 microM prostaglandin E2 or 15-hydroxyeicosatetraenoic acid, 1.0 nM tumor necrosis factor-alpha (TNF-alpha), or 10 nM phorbol 12-myristate 13-acetate (a protein kinase C activator). In contrast, MUC5B mRNA levels, although easily detected, were unaffected by these agonists, suggesting that irritants and associated inflammatory mediators increase mucin biosynthesis by inducing MUC5AC message levels, whereas MUC5B is constitutively expressed. When transcription was inhibited, TNF-alpha exposure increased MUC5AC message half-life compared with control level, suggesting that transcript stabilization is a major mechanism controlling increased MUC5AC message levels. Together, these findings imply that irritants like acrolein can directly and indirectly (via inflammatory mediators) increase airway mucin transcripts in epithelial cells.
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PMID:Regulation of human airway mucins by acrolein and inflammatory mediators. 1019 52

A major aldehydic end product of the peroxidation of arachidonic acid, 4-hydroxy-2,3-nonenal (HNE), has recently been considered for its potential involvement in a variety of cell functions. Here we report on the differential regulation of rat hepatocyte protein kinase C (PKC) isoforms by concentrations of HNE actually detectable in specific biological fluids or tissues. PKC betaI and, to a much greater extent, PKC betaII activities were markedly increased by 0.1 micromol/L HNE (final concentration in cell medium) whereas they were unaffected or even inhibited by 1 to 10 micromol/L HNE. On the contrary, the calcium independent PKC delta activity was inhibited by 0.1 micromol/L and increased by 1 and 10 micromol/L. Further, we show here that HNE-induced stimulation of PKC betaI and betaII activities, both in cytosolic and in membrane fractions, is paralleled by a marked stimulation of the anterograde transport of a lysosomal enzyme within the central vacuolar system. In fact, the treatment with 0.1 micromol/L HNE accelerated the PKC-dependent transport of lysosomal procathepsin D from the trans-Golgi network to the endosomal-lysosomal compartment and, in addition, increased the exocytosis of mature cathepsin D (CD) from these compartments. On the other hand, hepatocyte cotreatment with a selective inhibitor of classic PKCs prevented the aldehyde-induced activation of CD transport. These results support the possible involvement of HNE in the PKC-dependent regulation of the traffic of secretory glycoproteins, and point to remarkable implications of this aldehyde in the pathophysiology of various exocytic processes including hepatocyte lipoprotein secretion.
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PMID:Regulation of rat hepatocyte protein kinase C beta isoenzymes by the lipid peroxidation product 4-hydroxy-2,3-nonenal: A signaling pathway to modulate vesicular transport of glycoproteins. 1021 44

Because transcription factors NF-kappaB and activator protein-1 (AP-1) are known to regulate gene expression, we have analyzed the role of acetaldehyde in the activation of NF-kappaB and AP-1 in HepG2 cells. Binding activity and transactivation of NF-kappaB and AP-1 were determined by gel retardation assays and transfection of a luciferase reporter construct controlled by kappaB and AP-1 binding sites, respectively. Acetaldehyde enhanced the DNA binding of NF-kappaB and AP-1 by 1 and 4 h, respectively, increasing the kappaB- and AP-1-dependent luciferase expression. Supershift assays revealed the presence of NF-kappaB heterodimers p65/p50 and p50/p52, whereas nuclear c-Jun levels correlated with the DNA binding of AP-1. The enhanced binding of NF-kappaB to DNA by acetaldehyde in intact cells was accompanied by the proteolytic degradation of IkappaB-alpha. However, the addition of acetaldehyde to cytostolic extracts from untreated Hep G2 cells did not affect the DNA binding of AP-1 but activated the NF-kappaB heterodimer p65/p50 in the absence of IkappaB-alpha degradation. Preincubation of HepG2 cells with protein kinase C inhibitors abolished the enhanced DNA binding of NF-kappaB and AP-1 caused by acetaldehyde. Hence, these findings uncover a previously unrecognized role for acetaldehyde in the activation of NF-kappaB and AP-1, which may be of relevance in the alcohol-induced liver disease.
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PMID:Enhanced DNA binding and activation of transcription factors NF-kappa B and AP-1 by acetaldehyde in HEPG2 cells. 1079 56

4-Hydroxynonenal (HNE) is a highly reactive aldehyde, produced by cellular lipid peroxidation, able to inhibit proliferation and to induce differentiation in MEL cells at concentrations similar to those detected in several normal tissues. Inducer-mediated differentiation of murine erythroleukemia (MEL) cells is a multiple step process characterized by modulation of several genes as well as by a transient increase in the amount of membrane-associated protein kinase C (PKC) activity. Here we demonstrate that a rapid translocation of PKC activity from cytosol to the membranes occurs during the differentiation induced by HNE. When PKC is completely translocated by phorbol-12-myristate-13-acetate (TPA), the degree of HNE-induced MEL cells differentiation is highly decreased. However, if TPA is washed out from the culture medium before the exposition to the aldehyde, HNE gradually resumes its differentiative ability. The incubation of cells with a selective inhibitor of PKC activity, bisindolylmaleimide GF 109203X, partially prevents the HNE-induced differentiation in MEL cells. In conclusion, our results demonstrate that HNE-induced MEL cell differentiation is preceded by a rapid translocation of PKC activity, and that the inhibition of this phenomenon prevents the onset of terminal differentiation.
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PMID:4-Hydroxynonenal-induced MEL cell differentiation involves PKC activity translocation. 1087 5

Previously, we have found that acetaldehyde, a volatile component of cigarette smoke, stimulates the protein kinase C (PKC) pathway and inhibits ciliary motility. A "smokeless" cigarette (Eclipse) now exists in which most of the tobacco is not burned, reducing the pyrolyzed components in the extract. We hypothesized that acetaldehyde is a component of cigarette smoke that activates PKC in the airway epithelial cell, and therefore the Eclipse cigarette would not activate epithelial cell PKC. In this study, bovine bronchial epithelial cells (BBEC) were incubated with cigarette smoke extract (CSE) or Eclipse smoke extract (ESE). We found that PKC activity was significantly higher in cells exposed to 5% CSE than cells exposed to 5% ESE or media. When acetaldehyde levels of both extracts were measured by gas chromatography, CSE was found to have 15-20 times greater concentration (microM) of acetaldehyde than ESE. When BBEC were treated with 5% CSE, ciliary beating was further decreased from baseline levels. This decrease in ciliary beating was not observed in cells treated with ESE, suggesting that acetaldehyde contained in CSE slows cilia. These results suggest that volatile components such as acetaldehyde in cigarette smoke may inhibit ciliary motility via a PKC-dependent mechanism.
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PMID:Acetaldehyde-stimulated PKC activity in airway epithelial cells treated with smoke extract from normal and smokeless cigarettes. 1099 3

Ethanol induces liver fibrosis by several means that include, among others, the direct fibrogenic action of acetaldehyde on hepatic stellate cells (HSC). However the mechanisms responsible for this effect are not well understood. In this communication we investigated signal transduction pathways triggered by acetaldehyde leading to upregulation of alpha2(I) collagen and fibronectin gene expression in human HSC. Run-on assays showed that acetaldehyde-enhanced transcription of these 2 genes as early as 2 hours, via de novo protein synthesis-independent and -dependent mechanisms. It also stimulated a time-dependent induction in phosphorylation of pp70(S6K) and extracellular-regulated kinase (1/2) (ERK1/2). These effects were completely prevented by calphostin C, a protein kinase C inhibitor. As expected, acetaldehyde-elicited ERK1/2 phosphorylation was inhibited by PD98059, a MEK inhibitor, but not by wortmannin, a PI3K inhibitor. On the other hand, both of these inhibitors partially inhibited phosphorylation of pp70(S6K) induced by acetaldehyde suggesting that its activation is ERK1/2- and PI3K-dependent. Acetaldehyde-elicited fibronectin and alpha2(I) collagen upregulation was inhibited by calphostin C. However, while PD98059, wortmannin and rapamycin (a pp70(S6K) inhibitor) completely abrogated alpha2(I) collagen upregulation, they had no effect on fibronectin expression. Overall, these data suggest that protein kinase C is an upstream component from which acetaldehyde signals are transduced to other pathways such as PI3K and ERK1/2. In addition, differential activation of these pathways is needed for the increase in fibronectin and alpha2(I) collagen gene expression induced by acetaldehyde in human HSC.
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PMID:Intracellular signaling pathways involved in acetaldehyde-induced collagen and fibronectin gene expression in human hepatic stellate cells. 1134 41

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Geoffrey M. Thiele and Simon Worrall. The presentations were (1) The chemistry of malondialdehyde-acetaldehyde (MAA) adducts, by Dean J. Tuma; (2) The formation and clearance of MAA adducts in ethanol-fed rats, by Simon Worrall; (3) Immune responses to MAA adducts may play a role in the development of alcoholic liver disease, by Lynell W. Klassen; (4) Unique biological responses to MAA-modified proteins that may play a role in the development and/or progression of alcoholic liver disease, by Geoffrey M. Thiele; (5) MAA-adducted bovine serum albumin activates protein kinase C and stimulates interleukin-8 release in bovine bronchial epithelial cells, by Todd A. Wyatt; and (6) An enzyme immune assay for serum antiacetaldehyde adduct antibody using low-density lipoprotein-adduct and its significance in alcoholic liver injury and ALDH2 heterozygotes, by Naruhiko Nagata.
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PMID:The chemistry and biological effects of malondialdehyde-acetaldehyde adducts. 1139 Oct 74

Previous study results have demonstrated that cigarette smoke or acetaldehyde rapidly stimulates protein kinase C (PKC)-mediated release of interleukin-8 (IL-8) in bovine bronchial epithelial cells (BECs). Low concentrations of acetaldehyde combine synergistically with malondialdehyde to increase significantly maximal BEC PKC activity at 48 to 96 h stimulation. Because more than 95% of alcoholics are cigarette smokers, we hypothesized that malondialdehyde, an inflammation product of lipid peroxidation, and acetaldehyde, both a product of ethanol metabolism and a component of cigarette smoke, might stimulate PKC-mediated IL-8 release in BECs by malondialdehyde-acetaldehyde (MAA) adduct formation, rather than as free aldehydes. Protein kinase C activity is maximally elevated in BECs treated with 50 microg/ml of BSA-MAA from approximately 1 to 3 h. This activity subsequently begins to decrease by 4 to 6 h, with a return to baseline unstimulated kinase activity levels by 24 h. No activation of cyclic AMP-dependent protein kinase (PKA) or cyclic GMP-dependent protein kinase (PKG) was observed in BSA-MAA-treated BECs. The MAA adduct activation of PKC was followed by a fourfold to tenfold greater release of IL-8 over that observed for both BECs exposed to media only and BSA control-treated BECs. Protein kinase C activation and IL-8 release were blocked by pretreating BECs with 1 microM calphostin C or 100 nM of the PKC alpha-specific inhibitor, Go 6976. Isoform-specific inhibitors to PKC beta, PKC delta, and PKC zeta failed to inhibit completely MAA adduct-stimulated PKC or IL-8 release. Results of these studies indicate that metabolites derived from ethanol and cigarette smoke, such as acetaldehyde and malondialdehyde, form adducts that stimulate airway epithelial cell PKC alpha-mediated release of promigratory cytokines.
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PMID:Malondialdehyde-acetaldehyde-adducted bovine serum albumin activates protein kinase C and stimulates interleukin-8 release in bovine bronchial epithelial cells. 1183 59


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