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 number of xenobiotic carboxylic acids, including 3-phenoxybenzoic acid (3PBA), have been shown to form 'hybrid' di- and tri-acylglycerols both in vivo and in vitro. Experiments were carried out to test the hypothesis that naturally occurring xenobiotic diacylglycerols may stimulate protein kinase C. The activity of protein kinase C was measured in the presence of different diacylglycerols. 1-Acyl-2-(3PBA)-sn-glycerol but not 1,2-di-3PBA-sn-glycerol stimulated protein kinase C, but less effectively than either dioleoylglycerol or phorbol 12-myristate 13-acetate. The xenobiotic diacylglycerols were also more resistant to lipolysis. The possibility exists therefore that some xenobiotic diacylglycerols may behave, like phorbol diesters, as tumour promoters.
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PMID:Activation of protein kinase C by an aromatic xenobiotic diacylglycerol analogue. 280 51

To help clarify whether elevation of gamma-glutamyltranspeptidase (GGT) in hepatocytes is associated with particular pattern(s) of liver differentiation, adult rat hepatocytes in primary culture were maintained for up to 5 days under conditions considered to alter differentiation in liver or other cells: basal GGT activity in untreated cultures and inducibility of the enzyme by known inducers such as dexamethasone, p,p'-dichlorodiphenyltrichloroethane or pregnenolone 16 alpha-carbonitrile were measured. Basal and induced GGT activities were maximal in confluent cultures and declined with decreasing cell density, an effect probably mediated by cell contact rather than factors in the culture medium. Opposite effects of cell density on GGT and DNA synthesis suggest that increased GGT activity is not linked with growth. Epidermal growth factor (EGF) increased basal GGT and augmented the action of xenobiotic inducers in lower density cultures, giving GGT activities approaching the levels in confluent cells. EGF had no effect on confluent cultures. Activators of protein kinase C such as tetradecanoyl phorbol acetate had significant but small inducing effects on GGT. Agents including all-trans retinoic acid, butyrate and dimethylsulfoxide which are considered to favour terminal differentiation in many cell types, all partly blocked induction of GGT by dexamethasone, EGF or xenobiotics. The results are consistent with (but do not prove) the view that elevated GGT activity may be associated with liver phenotype(s) distinct from terminal differentiation but not necessarily linked with growth.
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PMID:Modulation of gamma-glutamyltranspeptidase in normal rat hepatocytes in culture by cell density, epidermal growth factor and agents which alter cell differentiation. 289 Apr 44

Hepatic enzymes that metabolize endogenous and xenobiotic compounds have been shown to be altered in adult rats that had been exposed to xenobiotics as neonates. Protein kinase C (PKC) is important in intracellular signaling and has been implicated in the regulation of hepatic monooxygenases. Therefore, we examined the effects of neonatal exposure to diethylstilbestrol (DES) and phenobarbital (PB) on hepatic microsomal testosterone metabolism and on the alpha form of protein kinase C (PKC alpha) in adult rats. In adult males, neonatal exposure to DES altered adult testosterone metabolism such that 7 alpha-hydroxylation was increased by 58% but 2 alpha-, 16 alpha-, and 6 beta-hydroxylations and conversion to androstenedione were decreased 31-44%. In contrast, adult males neonatally exposed to PB showed increased (20-27%) testosterone 2 alpha- and 16 alpha-hydroxylations and androstenedione formation, but no effect was observed in the rate of 6 beta- or 7 alpha-hydroxylations. Western blot analyses indicated that cytosolic PKC alpha levels in male rats neonatally exposed to PB were decreased by approximately 63% relative to the vehicle control group but were not significantly altered in the DES males. The PKC alpha levels generally correlated (r = -.75) with 16 alpha-hydroxytestosterone formation in all samples. These results show that neonatal treatment with DES or PB differentially alters hepatic monooxygenase enzyme activities and PKC alpha levels in adult rats.
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PMID:Neonatal exposure to xenobiotics alters adult hepatic protein kinase C alpha levels and testosterone metabolism: differential effects by diethylstilbestrol and phenobarbital. 775 88

Over the past several decades emphasis has been given to the elucidation of mechanisms involved in the onset and progression of cardiovascular disorders. Stroke, hypertension, and atherosclerosis continue to rank as primary causes of death in the western world. In the case of atherosclerosis, the preferential localization of atheroma to large- and medium-sized blood vessels and the sequence of events leading to plaque development have been well defined. Damage to luminal endothelial and/or medial smooth muscle cells, migration of inflammatory cells, diffusion or local delivery of mediators within the vessel wall, proliferation of vascular smooth muscle cells, and cellular accumulation of lipids are now recognized as hallmarks of the pathologic process. Although these events have been established with a fair degree of certainty, the mechanisms responsible for initiation of the atherosclerotic process are not yet completely understood. Environmental chemicals have come under increasing scrutiny as evidence continues to accumulate suggesting that toxic insult plays an important role in the initiation and/or progression of atherosclerotic disorders. This review focuses on various aspects of xenobiotic-induced vascular injury with emphasis on the toxic effects of allylamine and benzo[a]pyrene in smooth muscle cells, the primary cellular component of atherosclerotic lesions. Both of these chemicals modulate growth and differentiation programs in aortic smooth muscle cells and have been implicated in the development of atherosclerotic-like lesions in laboratory animals. The major findings from recent studies examining the cellular and molecular basis of toxicant-induced phenotypic modulation of vascular smooth muscle cells to a proliferative state and the role of oxidative metabolism, phospholipid turnover, protein kinase C, ras-related signal transduction, and matrix interactions in the vasculotoxic response to allylamine and benzo[a]pyrene are discussed.
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PMID:Responses of vascular smooth muscle cells to toxic insult: cellular and molecular perspectives for environmental toxicants. 799 Jan 68

9-Hydroxy ellipticine (9-OHE), a metabolite of the anti-neoplastic agent ellipticine, is known to bind the aryl hydrocarbon (Ah) receptor in rat lung cytosol and to inhibit aryl hydrocarbon hydroxylase activity (AHH) in rat hepatic microsomes. In this study, the effects of 9-OHE on the transformation of the rat hepatic cytosolic Ah receptor to a form that binds the xenobiotic responsive enhancer element-3 (XRE-3) of the cytochrome P4501A1 gene was investigated. Sucrose density gradient analysis of [3H]-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) binding in rat hepatic cytosol indicated that 9-OHE inhibited binding of the radiolabeled ligand to the Ah receptor with an IC50 of 90 microM. Gel retardation assays revealed that at low concentrations of 9-OHE the Ah receptor bound to XRE-3, as was the case with the TCDD-liganded receptor. However, in the presence of high concentrations of 9-OHE, the Ah receptor failed to transform to a form that could bind to XRE-3. In vitro studies indicated that incubation of rat hepatic cytosol with TCDD resulted in concentration-dependent increases in levels of protein kinase C (PKC) mediated phosphorylation as compared to vehicle-treated extracts. Furthermore, 9-OHE concentrations that exhibited agonist activity with respect to Ah receptor transformation did not alter PKC phosphorylation in hepatic cytosol, whereas higher concentrations exhibited significant concentration-dependent decrease in PKC-mediated phosphorylation. These results demonstrate that the antagonistic effect of 9-OHE observed at high concentrations is due to inhibition of Ah receptor-XRE complex formation, a phenomenon that correlates with alterations in PKC activity.
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PMID:Inhibition of Ah (dioxin) receptor transformation by 9-hydroxy ellipticine. Involvement of protein kinase C? 824 Mar 92

Signal transduction by dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) is mediated by the intracellular dioxin receptor which, in its dioxin-activated state, regulates transcription of target genes encoding drug-metabolizing enzymes, such as cytochrome P-450IA1 and glutathione S-transferase Ya. Exposure of the dioxin receptor to dioxin leads to an apparent translocation of the receptor to the nucleus in vivo and to a rapid conversion of the receptor from a latent, non-DNA-binding form to a species that binds to dioxin-responsive positive control elements in vitro. This DNA-binding form of receptor appears to be a heterodimeric complex with the helix-loop-helix factor Arnt. In this study, we show that activation of the cytochrome P-450IA1 gene and minimal dioxin-responsive reporter constructs by the dioxin receptor was inhibited following prolonged treatment of human keratinocytes with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Inhibition of the receptor-mediated activation response was also achieved by treatment of the cells with a number of protein kinase inhibitors, one of which, calphostin C, shows selectivity for protein kinase C. Taken together, these data suggest that protein kinase C-dependent phosphorylation may play an essential role in the dioxin signaling pathway. This hypothesis is supported by the observation that pretreatment of the cells with 12-O-tetradecanoylphorbol-13-acetate inhibited the DNA-binding activity of the dioxin receptor in vivo. In vivo, the dioxin receptor was found to be a phosphoprotein. In vitro, dephosphorylation of the ligand-activated, heteromeric dioxin receptor form or dephosphorylation of the individual ligand-binding and Arnt receptor subunits inhibited the xenobiotic response element-binding activity. Moreover, dephosphorylation experiments with the individual receptor subunits prior to assembly of the xenobiotic response element-binding receptor form indicated that phosphorylation seemed to be important for the DNA-binding activity per se of the receptor, whereas Arnt appeared to require phosphorylation to interact with the receptor. Finally, a protein kinase C inhibitor-sensitive cytosolic catalytic activity that could restore the DNA-binding activity of the dephosphorylated dioxin receptor form was identified.
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PMID:Cross-coupling of signal transduction pathways: the dioxin receptor mediates induction of cytochrome P-450IA1 expression via a protein kinase C-dependent mechanism. 838 Feb 31

Understanding the molecular regulation of the sulfotransferases is important because these enzymes are essential to a number of critical biological processes. Sulfotransferase expression clearly plays a role in xenobiotic detoxication, carcinogen activation, prodrug processing, cellular signaling pathways, and the regulation of intratissue active androgen and estrogen levels. Although cytosolic sulfotransferases are present in the gut, adrenal, kidney, lung, skin, brain, and other extrahepatic tissues, the basis for the molecular regulation of this complicated gene family has been best characterized in the rat liver, where sulfotransferase levels are relatively abundant. Advances in genomic cloning and in the molecular characterization of individual sulfotransferase cDNAs have inspired new insights into the mechanisms involved in sulfotransferase gene regulation. In particular, the hypothalamic-pituitary-gonadal-adrenocortical axis appears to play a significant role in the regulation of individual sulfotransferase genes. The molecular signals that fluctuate with developmental age, gender, and the occurrence of systemic endocrinopathies also influence sulfotransferase gene expression. For example, diabetes, which disrupts glucose and ketone homeostasis, insulin sensitivity, gonadal and neuroendocrine hormone balance, protein kinase C isoform expression, and P450 metabolism, also disturbs hepatic sulfotransferase gene expression. What role does sulfotransferase expression play in target organ toxicity? Do xenobiotic-mediated changes in sulfotransferase expression compromise detoxication? Does deregulated sulfotransferase expression during development lead to birth defects by perturbing the delicate balance of active hormone levels in fetal tissues? Do conditions of glucocorticoid excess, such as stress or high-dose glucocorticoid therapy induce sulfotransferase expression and place toxicant and carcinogen bioactivation systems in overdrive? This review will summarize our current understanding of the molecular and cellular regulation of the major rodent cytosolic sulfotransferases. Only by thoroughly dissecting the regulation of this important multigene family in rodent liver, where sulfotransferase expression is most abundant, can we begin to focus on more pressing questions concerning the role of the sulfotransferases in the genesis of endocrinopathies and cancer in humans.
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PMID:Regulation of expression of the rodent cytosolic sulfotransferases. 903 52

The Ah receptor binds aryl hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with high affinity. After binding aryl hydrocarbons, the receptor releases the 90-kDa heat shock protein and forms a dimer with the Arnt protein capable of binding at xenobiotic-responsive elements (XREs) and stimulating the transcription of genes involved in the metabolism of aryl hydrocarbons. The activity of the Ah receptor/ Arnt dimer can be decreased by treatments causing the down-regulation of protein kinase C and decreasing the nuclear accumulation of the receptor. Incubation with acid phosphatase or with alkaline phosphatase has been reported to block XRE binding. Thus the literature suggests that phosphorylation regulates Ah receptor activity by affecting DNA binding and/or nuclear transport. A reporter plasmid containing two XREs was used to investigate the effects of phosphatase inhibitors on TCDD-dependent transcription by the Hepa-1 mouse liver cell line. The inhibitors calyculin A and okadaic acid caused two- to threefold increases in TCDD-dependent transcription at concentrations capable of selectively inhibiting protein phosphatase 1 and protein phosphatase 2A. The inhibitor cyclosporin A doubled TCDD-dependent transcription at a concentration capable of selectively inhibiting protein phosphatase 2B. All three of the phosphatase inhibitors increased TCDD-dependent transcription without affecting transcription in the absence of TCDD. Nuclear extracts were prepared from cells treated with concentrations of okadaic acid or cyclosporin A which substantially stimulated TCDD-dependent transcription. Neither of the inhibitors significantly increased the level of TCDD-dependent XRE binding in the extracts. GAL4-Arnt fusion proteins were used to further investigate whether the phosphatase inhibitors affected a step other than DNA binding. Okadaic acid treatment specifically increased the ability of a GAL4 fusion protein containing the Arnt PAS and transactivation domains to stimulate transcription. These results suggest that serine/threonine-specific protein phosphatases can act at a level subsequent to XRE binding to inhibit the ability of the Ah receptor/Arnt dimer to stimulate transcription.
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PMID:Inhibitors of serine/threonine-specific protein phosphatases stimulate transcription by the Ah receptor/Arnt dimer by affecting a step subsequent to XRE binding. 912 79

The role of protein kinase C and protein phosphatases was examined in the control of mutagenic metabolites of aromatic amines. Various metabolic activating systems derived from rat liver were treated with: 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C modulator; okadaic acid (OA), a potent inhibitor of serine/threonine protein phosphatases (PP1 and PP2A); and ortho-vanadate (OV), an inhibitor of tyrosine phosphatases. TPA used over a wide concentration range (10(-9)-10(-6) M) did not affect the bacterial mutagenicity of the aromatic amines and of the aromatic amide investigated, 2-aminoanthracene, 2-aminofluorene and 2-acetylaminofluorene (2AAF). At the molecular level, TPA did not affect the function of cytochrome P450s 1A1 or 1A2, which are known key factors for the activation and inactivation of aromatic amines/amides. By contrast the OA and OV treatment of rat hepatocytes, rat liver homogenate, fraction S9 and the nuclear fraction drastically reduced (by > 80%) the mutagenicity of the aromatic amines/amide investigated. This is by far the most pronounced change in genotoxicity observed to date via modulation of phosphorylation. Whilst the mutagenicity of the primary toxication product 2-N-OH-acetylaminofluorene (2-N-OH-AAF) in the presence of exogenous activating systems (hepatocytes, S9-fraction, nuclear fraction) was also reduced by OV, OA had no influence. Thus the tyrosine protein phosphatase inhibitor and the serine/threonine protein phosphatase inhibitor influence the genotoxicity of aromatic amines/amides on different levels. Moreover, this shows that the drastic reduction in mutagenicity by OA was due to its influence on a step prior to the presence of the primary toxication product 2-N-OH-AAF. This reduction could be due to changes in the activity of cytochrome P4501A1 and/or 1A2. However, no incorporation of 32P-labelled phosphate from intracellularly prelabelled [32P]-ATP into cytochromes P450 1A1 or 1A2 nor any change in their catalytic activities was observed in the presence of OA. Furthermore, a phosphorylation dependent change in the function of P-glycoprotein (known for its role in the transport of diverse xenobiotic substances and their metabolites) was shown not to contribute to the observed decrease in mutagenicity. Our results reveal an important role for protein phosphatase 1 and/or 2A and tyrosine phosphatase(s) in the control of the genotoxicity of aromatic amines and amides. However, the present study does not distinguish between effects mediated by individual proteins affected by these protein phosphatases.
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PMID:Control of the mutagenicity of aromatic amines by protein kinases and phosphatases. I. The protein phosphatase inhibitors okadaic acid and ortho-vanadate drastically reduce the mutagenicity of aromatic amines. 933 96

We have investigated mechanisms of omeprazole (OME)-mediated induction of CYP1A1 and CYP3A, using the rat hepatoma H4IIE cell line, in comparison with mechanisms exerted by traditional aryl hydrocarbon receptor (AhR) ligands such as benso(a)pyrene (B(a)P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). OME did not bind specifically to AhR, and it could not activate the AhR complex in rat cytosol to a xenobiotic-responsive element (XRE)-binding form in vitro. Genistein, a tyrosine kinase inhibitor, and daidzein, an inhibitor of casein kinase II, efficiently inhibited OME-mediated but not B(a)P- or TCDD-mediated induction of CYP1A1, as monitored at the transcriptional, mRNA, and protein levels as well as by analysis of activation of XRE-luciferase reporter constructs transfected into H4IIE cells. The protease inhibitor Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) and lavendustin A also had similar OME-specific effects. In addition, insulin pretreatment caused an almost complete inhibition of OME-dependent CYP1A1 induction but only partially affected TCDD and B(a)P-mediated induction of CYP1A1. Staurosporine, an inhibitor of protein kinase C, impaired the induction by both B(a)P and OME. OME caused an approximately 2-fold increase in the level of CYP3A expression, but all inhibitors used were ineffective in preventing this induction. Gel shift analysis with radiolabeled XRE and specific peptide antibodies toward AhR and aryl hydrocarbon receptor nuclear translocator protein (Arnt) revealed an OME-mediated translocation of the AhR.Arnt complex into the nuclei. Genistein inhibited the specific nuclear XRE binding caused by OME, but it potentiated the formation of the TCDD-induced XRE.AhR complex. Although daidzein was able to effectively inhibit the OME-stimulated CYP1A1 gene transcription, it did not influence the OME-dependent AhR.XRE complex formation. The data are consistent with a mechanism for OME-mediated induction of CYP1A1 that involves activation of the AhR complex via intracellular signal transduction systems and that is distinct from induction mediated by AhR ligands.
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PMID:Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells. 939 20


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