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)

Fibrates are widely used drugs in hyperlipidemic disorders. In addition to lowering serum triglyceride levels, fibrates have also been shown to reduce elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels in vivo. We demonstrate that fibrates suppress PAI-1 synthesis in cultured cynomolgus monkey hepatocytes in a concentration-dependent way (0.1 to 1.0 mmol/L) and independent of their lipid-lowering effect. Different fibrates showed different potency in suppressing PAI-1 production: gemfibrozil and clofibric acid, at a concentration of 1 mmol/L, reduced PAI-1 synthesis over 24 hours to 52 +/- 20% and 60 +/- 5%, while clofibrate and bezafibrate lowered PAI-1 synthesis to only 86 +/- 17% and 84 +/- 15% of control values, respectively. These changes in PAI-1 production by fibrates correlated with changes in PAI-1 mRNA levels and were also visible at the level of gene transcription. Fibrates did not lower basal PAI-1 synthesis but attenuated an acceleration of PAI-1 production during culture. The suppressing effect of fibrates on PAI-1 synthesis could not be mimicked with activators or inhibitors of protein kinase C (PKC). Furthermore, fibrates did not inhibit the increase in PAI-1 synthesis induced by epidermal growth factor or transforming growth factor-beta. These results make mechanisms involving PKC modulation or growth factor receptor inactivation as a mode of action of fibrates unlikely. The suppressing effect of fibrates on PAI-1 synthesis could involve the nuclear receptor peroxisome proliferator-activated receptor (PPAR) and its heterodimeric partner, the retinoid X receptor (RXR). The alpha forms of PPAR and RXR were both found to be expressed in cynomolgus monkey hepatocytes. the ligand for RXR alpha, 9-cis retinoic acid, suppressed PAI-1 synthesis to the same extent as gemfibrozil, while a combination of gemfibrozil and 9-cis retinoic acid had no more effect on PAI-1 synthesis than any of these compounds alone at optimal concentrations. In conclusion, fibrates downregulate an induced PAI-1 production in cynomolgus monkey hepatocytes independent of a decrease in triglyceride levels. A possible involvement of PPAR alpha/RXR alpha in this down-regulation is discussed.
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PMID:Studies on the mechanism of fibrate-inhibited expression of plasminogen activator inhibitor-1 in cultured hepatocytes from cynomolgus monkey. 901 33

Ciprofibrate, an hypolipidaemic peroxisome proliferator, induced differentiation of HL-60 cells. The effect was greatly potentiated by phorbol 12-myristate 13-acetate at a concentration where neither phorbol ester nor ciprofibrate alone had any effect on these cells. As occurs for HL-60 cell differentiation induced by high phorbol ester concentration, the ciprofibrate-induced phorbol ester-dependent differentiation of HL-60 cells proceeded through the monocytic/macrophage pathway and induced the phosphorylation of proteins with similar molecular weights suggesting that increased protein kinase C activity may be involved in the effect. The peroxisome proliferator-activated receptor (PPARalpha) transcription factor is expressed in HL-60 cells, but no changes were observed in its expression upon HL-60 cell differentiation.
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PMID:Enhanced differentiation of HL-60 leukemia cells to macrophages induced by ciprofibrate. 986 Jan 37

It has been known for many years that long-chain fatty acids derived from endogenous metabolism and/or nutrition can act as second messengers and regulators of cell signaling pathways. For example, fatty acids regulate the activity of protein kinase C (PKC) in a mechanism distinct from activation by diacylglycerol. Like PKC activators such as phorbol esters, essential fatty acids activate PKC and in doing so modulate the activity of growth factor receptors such as epidermal growth factor receptor (EGFR). Unsaturated fatty acids can inhibit GTPase activating protein, thereby quenching signals from p21-ras. These studies have shown that fatty acids can influence numerous signaling pathways and that these small lipophilic substances may be ancient second messengers. Fatty acids are also known modulators of the carcinogenic process, showing distinct tissue-specific pro- or anticancer effects. However, the reason for such a dichotomous effect on cellular processes has not been adequately described. In this article, the inclusion of a steroid hormone receptor-signaling pathway in mediating fatty acids' effects will be summarized. This signaling molecule has been deemed the peroxisome proliferator-activated receptor (PPAR) and has been extensively examined in regard to its response to xenobiotic, fatty acid-like chemicals (peroxisome proliferators, PP). PP, like fatty acids, activate PPAR and modulate tissue-specific responses. The goal of this review is to describe a potential role for PPAR in mediating the effects of fatty acids on gene expression, cell growth, differentiation and apoptosis.
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PMID:Peroxisome proliferator-activated receptors: a critical link among fatty acids, gene expression and carcinogenesis. 1006 36

Angiotensin II (Ang II) stimulates the activation of extracellular signal-regulated kinase (ERK), a subgroup of the mitogen-activated protein kinase (MAPK) family, in cultured vascular smooth muscle cells (VSMC). This ERK activation was recently shown to be a critical regulatory factor for Ang II-mediated migration and growth. It has been demonstrated that the thiazolidinedione troglitazone (TRO) blocked Ang II-induced DNA synthesis and migration in VSMC. Here we provide evidence for TRO to inhibit Ang II-induced ERK activation which was suggested to constitute the mechanism by which this agent blocks Ang II-induced VSMC growth and migration. We have found that pretreatment with PD98059, which selectively blocks the activity of ERK pathway at the level of MAPK kinase, decreased Ang II-induced AP-1 activation and that TRO is capable of inhibiting Ang II-induced AP-1 activation. On the other hand, the other thiazolidinediones pioglitazone (PIO) and rosiglitazone (ROSI) had little effect on Ang II-induced activation of ERK or AP-1, suggesting the inhibitory effects of TRO on VSMC activation by Ang II be independent of the peroxisome proliferator-activated receptor-gamma (PPARgamma) for which thiazolidinediones are ligands. Ang II-induced ERK activation was inhibited by protein kinase C (PKC)-specific inhibitor GF109203X, while TRO was also able to block PKC activator phorbol 12 myristate 13-acetate (PMA)-induced ERK activation. Accordingly, TRO may inhibit Ang II-induced MAPK activation at least partly by an inhibition of PKC. These results support the assumption that by targeting MAPK activation, TRO may inhibits the critical signaling steps leading to restenosis and atherosclerosis that may result in part from dysregulated VSMC growth and migration induced by Ang II.
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PMID:The effects of thiazolidinediones on vascular smooth muscle cell activation by angiotensin II. 1089 86

Oxidized low-density lipoprotein (oxLDL) has been shown to modulate transactivation by the peroxisome proliferator-activated receptor (PPAR)-gamma and by nuclear factor-kappaB (NF-kappaB). In the present study, the oxLDL signalling pathways involved in NF-kappaB transactivation were investigated by utilizing a reporter construct driven by three upstream NF-kappaB binding sites, and various pharmacological inhibitors. OxLDL and its constituent lysophophatidylcholine (lysoPC) induced a rapid and transient increase in intracellular calcium and stimulated NF-kappaB transactivation in resting RAW264.7 macrophage cells in an oxidation-dependent manner. NF-kappaB activation by oxLDL or lysoPC was inhibited by inhibitors of protein kinase C or by a chelator of intracellular calcium. Tyrosine kinase or phosphatidylinositol 3-kinase inhibitors did not block NF-kappaB transactivation. Furthermore, oxLDL-induced NF-kappaB activity was abolished by PPAR-gamma ligands. When the endocytosis of oxLDL was blocked by cytochalasin B, NF-kappaB transactivation by oxLDL was synergistically increased, while PPAR transactivation was blocked. These results suggest that oxLDL activates NF-kappaB in resting macrophages via protein kinase C- and/or calcium-dependent pathways, and that this does not involve the endocytic processing of oxLDL. The endocytosis-dependent activation of PPAR-gamma by oxLDL may function as a route of inactivation of the oxLDL-induced NF-kappaB signal.
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PMID:Role of endocytosis in the transactivation of nuclear factor-kappaB by oxidized low-density lipoprotein. 1097 Jul 99

The first PPAR (peroxisome proliferator-activated receptor) was cloned in 1990 by Issemann and Green (Nature 347:645-650). This nuclear receptor was so named since it is activated by peroxisome proliferators including several drugs of the fibrate family, plasticizers, and herbicides. This receptor belongs to the steroid receptor superfamily. After activation by a specific ligand, it binds to a DNA response element, PPRE (peroxisome proliferator response element), which is a DR-1 direct repeat of the consensus sequence TGACCT x TGACCT. This mechanism leads to the transcriptional activation of target genes (Motojima et al., J Biol Chem 273:16710-16714, 1998). After the first discovery, several isoforms were characterized in most of the vertebrates investigated. PPAR alpha, activated by hypolipidemic agents of the fibrate family or by leukotrienes; regulates lipid metabolism as well as the detoxifying enzyme-encoding genes. PPAR beta/delta, which is not very well known yet, appears to be more specifically activated by fatty acids. PPAR gamma (subisoforms 1, 2, 3) is activated by the prostaglandin PGJ2 or by antidiabetic thiazolidinediones (Vamecq and Latruffe, Lancet 354:411-418, 1999). This latter isoform is involved in adipogenesis. The level of PPAR expression is largely dependent on the tissue type. PPAR alpha is mainly expressed in liver and kidney, while PPAR beta/delta is almost constitutively expressed. In contrast, PPAR gamma is largely expressed in white adipose tissue. PPAR is a transcriptional factor that requires other nuclear proteins in order to function, i.e. RXRalpha (9-cis-retinoic acid receptor alpha) in all cases in addition to other regulatory proteins. Peroxisomes are specific organelles for very long-chain and polyunsaturated fatty acid catabolism. From our results and those of others, the inventory of the role of PPAR alpha in the regulation of peroxisomal fatty acid beta-oxidation is presented. In relation to this, we showed that PPAR alpha activates peroxisomal beta-oxidation-encoding genes such as acyl-CoA oxidase, multifunctional protein, and thiolase (Bardot et al., FEBS Lett 360:183-186, 1995). Moreover, rat liver PPAR alpha regulatory activity is dependent on its phosphorylated state (Passilly et al., Biochem Pharmacol 58:1001-1008, 1999). On the other hand, some signal transduction pathways such as protein kinase C are modified by peroxisome proliferators that increase the phosphorylation level of some specific proteins (Passilly et al. Eur J Biochem 230:316-321, 1995). From all these findings, PPAR alpha and kinases appear to play an important role in lipid homeostasis.
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PMID:Regulation of the peroxisomal beta-oxidation-dependent pathway by peroxisome proliferator-activated receptor alpha and kinases. 1100 38

The mitogen-activated protein (MAP) kinases mediate the response of renal glomerular mesangial cells to a variety of physiologic and pathologic stimuli. This investigation examines the effect of the cyclopentenone prostaglandin 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) on MAP kinases in human mesangial cells. We show that 15d-PGJ2 dose-dependently increases the extracellular signal-regulated kinase (ERK) activity of human mesangial cells, but has no effect on Jun-NH2-terminal kinase or p38 MAP kinase. Despite the fact that 15d-PGJ2 is a peroxisome proliferator-activated receptor (PPAR) ligand, and PPARgamma is shown to be expressed by mesangial cells, the thiazolidinedione PPARgamma agonist ciglitazone does not activate ERK. Additionally, a synthetic PPARgamma antagonist does not attenuate the activation of ERK by 15d-PGJ2. 15d-PGJ2-mediated ERK activation is however blocked by the MEK inhibitor PD 098059, appears to require phosphatidylinositol-3 kinase, but is independent of protein kinase C activation. These results demonstrate a novel effect of 15d-PGJ2 to induce ERK in human mesangial cells independently of PPARgamma.
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PMID:A cyclopentenone prostaglandin activates mesangial MAP kinase independently of PPARgamma. 1117 60

Estrogen biosynthesis from C(19) steroids is catalyzed by aromatase cytochrome P450. Aromatase is expressed in breast adipose tissue through the use of a distal, cytokine-responsive promoter (promoter I.4). Breast tumors, however, secrete soluble factors that stimulate aromatase expression through an alternative proximal promoter, promoter II. In other estrogenic tissues such as ovaries, transcription from promoter II requires the presence of the Ftz-F1 homologue steroidogenic factor-1 (SF-1); adipose tissue, however, does not express SF-1. We have explored the hypothesis that in adipose tissue, an alternative Ftz-F1 family member, liver receptor homologue-1 (LRH-1), substitutes for SF-1 in driving transcription from promoter II. In transient transfection assays using 3T3-L1 preadipocytes, promoter II reporter constructs were modestly (2-3-fold) stimulated by either treatment with activators of protein kinases A or C (PKA/C) or by cotransfection with LRH-1. In combination, these treatments synergistically activated promoter II (>30-fold). Induction by LRH-1 (but not by PKA/C) required an AGGTCA motif at -130 base pairs, to which LRH-1 bound in gel shift assays. Activity of GAL4-LRH-1 fusion proteins was not altered by activators of PKA or PKC. Quantitative real-time PCR revealed that LRH-1 (but not SF-1) is expressed in the preadipocyte fraction of human adipose tissue at levels comparable with that of liver. Differentiation of cultured human preadipocytes into mature adipocytes was associated with a time-dependent induction of peroxisome proliferator-activated receptor-gamma (PPARgamma), and rapid loss of LRH-1 and aromatase expression. We conclude that LRH-1 is a preadipocyte-specific nuclear receptor that regulates expression of aromatase in adipose tissue. Alterations in LRH-1 expression and/or activity in adipose tissue could therefore have considerable effects on local estrogen production and breast cancer development.
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PMID:Liver receptor homologue-1 (LRH-1) regulates expression of aromatase in preadipocytes. 1192 88

Glucose concentration may be an important factor in breast cancer cell proliferation, and the prevalence of breast cancer is high in diabetic patients. Leptin may also be an important factor since plasma levels of leptin correlated with TNM staging for breast cancer patients. The effects of glucose and leptin on breast cancer cell proliferation were evaluated by examining cell doubling time, DNA synthesis, levels of cell cycle related proteins, protein kinase C (PKC) isozyme expression, and peroxisome proliferator-activated receptor (PPAR) subtypes were determined following glucose exposure at normal (5.5 mM) and high (25 mM) concentrations with/without leptin in MCF-7 human breast cancer cells. In MCF-7 cells, leptin and high glucose stimulated cell proliferation as demonstrated by the increases in DNA synthesis and expression of cdk2 and cyclin D1. PKC-alpha, PPARgamma, and PPARalpha protein levels were up-regulated following leptin and high glucose treatment in drug-sensitive MCF-7 cells. However, there was no significant effect of leptin and high glucose on cell proliferation, DNA synthesis, levels of cell cycle proteins, PKC isozymes, or PPAR subtypes in multidrug-resistant human breast cancer NCI/ADR-RES cells. These results suggested that hyperglycemia and hyperleptinemia increase breast cancer cell proliferation through accelerated cell cycle progression with up-regulation of cdk2 and cyclin D1 levels. This suggests the involvement of PKC-alpha, PPARalpha, and PPARgamma.
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PMID:Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-alpha and PPAR expression. 1237 72

Endothelin is a potent vasoconstrictor peptide isolated from endothelial cells and it induces smooth muscle cell proliferation. Endothelin-1 secretion is increased in atheroma and induces deleterious effects such as vasospasm and atherosclerosis. Oxidized low-density lipoproteins (LDLs) induce atherosclerosis in the vascular wall, as well as endothelin-1 secretion in endothelial cells and are activators of both peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma. PPAR-alpha (fibric acids) and PPAR-gamma (glitazones) activators are used to treat dyslipoproteinemias and type 2 diabetes, respectively. Furthermore, these drugs induce numerous pleiotropic effects, such as inhibiting thrombin-induced endothelin-1 secretion in endothelial cells. This study shows that both PPAR-alpha (Wy 14643) and PPAR-gamma activation (rosiglitazone) partially inhibit oxidized LDL-induced protein kinase C activity and endothelin-1 secretion in endothelial cells at the transcriptional levels and suggests that synthetic PPAR activators are stronger PPAR activators than oxidized LDL. This study also suggests that fibrate and glitazone treatments should have beneficial effects on the vascular wall by reducing endothelin-1 secretion and the resulting vasospasm and atherosclerosis.
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PMID:Peroxisome proliferator-activated receptor activators inhibit oxidized low-density lipoprotein-induced endothelin-1 secretion in endothelial cells. 1245 15


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