Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ultraviolet (UV) light is a strong apoptotic trigger that induces caspase-dependent biochemical changes in cells. Previously we showed that UV irradiation can activate caspase-3, and the subsequent cleavage and activation of p21(Cdc42/Rac)-activated kinase 2 (PAK2) in human epidermoid carcinoma A431 cells. In this study we demonstrate that curcumin (Cur), the yellow pigment of Curcuma longa with known anti-oxidant and anti-inflammatory properties, can prevent UV irradiation-induced apoptotic changes, including c-Jun N-terminal kinase (JNK) activation, loss of mitochondrial membrane potential (MMP), mitochondrial release of cytochrome C, caspase-3 activation, and cleavage/activation of PAK2 in A431 cells. Flow cytometric analysis using the cell permeable dye 2',7'-dichlorofluorescin diacetate (DCF-DA) as an indicator of reactive oxygen species (ROS) generation revealed that the increase in intracellular oxidative stress caused by UV irradiation could be abolished by Cur. In addition, we found that SP600125, a JNK-specific inhibitor, reduced UV irradiation-induced JNK activation as well as caspase-3 activation, indicating that JNK activity is required for UV irradiation-induced caspase activation. Collectively, our results demonstrate that Cur significantly attenuates UV irradiation-induced ROS formation, and suggest that ROS triggers JNK activation, which in turn causes MMP change, cytochrome C release, caspase activation, and subsequent apoptotic biochemical changes.
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PMID:Curcumin inhibits UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermoid carcinoma A431 cells. 1450 49

Acute treatments with MK-801, a noncompetitive antagonist of the NMDA glutamate receptor, induce spatial memory deficits in rodents. In the present study, we developed a low-dose chronic MK-801 treatment regimen that induced persistent learning deficits (determined by the Morris water maze task) after administration of the drug (0.2 mg/kg) every 12 h for 14 days. To determine the impact of such a treatment, changes in mRNA expression were investigated in the hippocampi and striata of treated animals using a cDNA membrane array followed by Western blots. Genes whose expression levels were found to be most altered included preprolactin (downregulated) and mitogen-activated protein kinase (MAP kinase 1; upregulated) in the hippocampus, and acyl-CoA synthetase (downregulated) and apolipoprotein D (upregulated) in the striatum. Furthermore, MAP kinase 1 and proteosome subunit beta precursor was found to meet selection criteria for upregulation in both the hippocampus and striatum. Among other genes found to be most changed in the hippocampus were protein kinase C beta I and II, protein tyrosine phosphatase 1beta, neuropilin I and II, adenosine receptor A1, and metabotropic glutamate receptor 2/3. The impact of some gene expression alterations on their corresponding protein levels was studied next. In the hippocampus, protein kinase C beta I and II, protein tyrosine phosphatase, neuropilin I and II, adenosine receptor A, metabotropic glutamate receptor 2/3, and in the striatum phosphatidyl inositol 4 kinase, mitogen-activated protein kinase 1, adenylyl cyclase II, dopamine receptors 1A and 2, and cytochrome C oxidase subunit Va gene and protein expression levels were found to be highly correlated. These results suggest the potential involvement of several genes and proteins in the neuropharmacological effects of MK-801 and possibly the persisting cognitive deficits induced by this repeated drug treatment.
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PMID:Gene expression profiling following chronic NMDA receptor blockade-induced learning deficits in rats. 1451 34

Over the last decade, a great deal of attention has been directed at elucidating the role of apoptosis regulators in governing survival decisions in neoplastic cells, particularly those of hematopoietic origin. A major focus of this work has involved investigation of the function of pro- and anti-apoptotic members of the BCL-2 family, and the relationship between these proteins and mitochondrial integrity. Currently, these proteins can be classified into two broad categories: those that modulate mitochondrial function and those that regulate the activation of caspases responsible for activation and execution of the apoptotic cascade. Within the first category, certain proteins (e.g., BCL-2, BCL-xL) act to preserve mitochondrial integrity by preventing loss of mitochondrial membrane potential and/or release of pro-apoptotic proteins such as cytochrome C into the cytosol. Other proapoptotic proteins (e.g., BAX, BAK, BIM) promote release of cytochrome C. These proteins are therefore primarily involved in regulation of the intrinsic, mitochondrial apoptotic pathway. Within the second category, proteins such as the inhibitors of apoptosis proteins (e.g., XIAP) or FLIP block the activation of caspases, particularly those involved in engagement of the receptor-related, extrinsic apoptotic pathway. Cross-talk between the intrinsic and extrinsic pathways exists. For example, the BH3-domain only protein BID is cleaved by the activation of pro-caspase-8 through the extrinsic pathway, and translocates to the mitochondrion to promote cytochrome C release. Apoptosis is also regulated by various signal transduction pathways, possibly through post-translational modifications in BCL-2 family proteins. For example, phosphorylation of BCL-2 through a JNK-dependent mechanism has been postulated to contribute to apoptosis induced by the taxane class of cytotoxic agents. Finally, attempts to modulate apoptotic pathways with small molecules have recently received much attention. For example, small molecule inhibitors of BCL-2 or mimetics of SMAC/DIABLO, which opposes the actions of XIAP, have recently been shown to promote the antineoplastic activity of conventional cytotoxic agents. It is likely that an improved understanding of apoptosis regulation will lead to new insights into neoplastic transformation, and may also provide important leads for the development of novel antileukemic strategies.
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PMID:Apoptosis regulators. 1476 59

In response to certain cytokines and inflammatory mediators, the activity of the neutrophil NADPH oxidase enzyme is primed for enhanced superoxide production when the cells receive a subsequent oxidase-activating stimulus. The relative role of p38 MAPK in the priming and activation processes is incompletely understood. We have developed a 2-step assay that allows the relative contributions of p38 MAPK activity in priming to be distinguished from those involved in oxidase activation. Using this assay, together with in vitro kinase assays and immunochemical studies, we report that p38 MAPK plays a critical role in TNFalpha priming of the human and porcine NADPH oxidase for superoxide production in response to complement-opsonized zymosan (OpZ), but little, if any, role in neutrophil priming by platelet-activating factor (PAF) for OpZ-dependent responses. The OpZ-mediated activation process per se is independent of p38 MAPK activity, in contrast to oxidase activation by fMLP, where 70% of the response is eliminated by p38 MAPK inhibitors regardless of the priming agent. We further report that incubation of neutrophils with TNFalpha results in the p38 MAPK-dependent phosphorylation of a subpopulation of p47(phox) and p67(phox) molecules, whereas PAF priming results in phosphorylation only of p67(phox). Despite these phosphorylations, TNFalpha priming does not result in significant association of either of these oxidase subunits with neutrophil membranes, demonstrating that the molecular basis for priming does not appear to involve preassembly of the NADPH oxidase holoenzyme/cytochrome complex prior to oxidase activation.
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PMID:Distinct ligand-dependent roles for p38 MAPK in priming and activation of the neutrophil NADPH oxidase. 1510 56

Sequential conversion of estradiol to catecholestradiols and methoxyestradiols by cytochrome-P(450) (CYP450) and catechol-O-methyltransferase (COMT), respectively, contributes to the antimitogenic effects of estradiol on vascular smooth muscle cell (SMC) growth via estrogen receptor-independent mechanisms. Because catecholamines are also substrates for COMT, we hypothesize that catecholamines may abrogate the vasoprotective effects of estradiol by competing for COMT and inhibiting methoxyestradiol formation. To test this hypothesis, we investigated the antimitogenic/inhibitory effects of estradiol on human coronary artery SMC growth (cell number, DNA synthesis, collagen synthesis, and SMC migration) and ERK1/2 phosphorylation in the presence and absence of catecholamines. Norepinephrine, epinephrine, isoproterenol, and OR486 (COMT inhibitor) abrogated the inhibitory effects of estradiol on SMC growth and ERK1/2 phosphorylation. The interaction of catecholamines with estradiol was not affected by phentolamine or propanolol, alpha- and beta-adrenoceptor antagonists, respectively. The antimitogenic effects of 2-hydroxy-estradiol, but not 2-methoxyestradiol, were abrogated by epinephrine, isoproterenol, and OR486. Catecholamines inhibited the conversion of both estradiol and 2-hydroxy-estradiol to 2-methoxyestradiol, and SMCs expressed CYP1A1 and CYP1B1. Our findings suggest that catecholamines within the coronary arteries may abrogate the antivasoocclusive effects of estradiol by blocking the conversion of catecholestradiols to methoxyestradiols. The interaction between catecholamines and estradiol metabolism may importantly define the cardiovascular effects of estradiol therapy in postmenopausal women.
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PMID:Catecholamines block the antimitogenic effect of estradiol on human coronary artery smooth muscle cells. 1529 28

Chemoprevention is a cancer preventive strategy to inhibit, delay or reverse carcinogenesis using naturally occurring or synthetic chemical agents. Numerous epidemiological studies as well as experimental animal studies clearly demonstrate that high intake of cruciferous vegetables protects against tumorigenesis. Thus, cruciferous vegetables have been of great interest for potential use in the chemoprevention of cancer. Cruciferous vegetables are rich source of glucosinolates, which are degraded into isothiocyanates by enzymatic action of plant-specific myrosinase or intestinal flora in the body. It appears that significant portion of the chemopreventive effects of isothiocyanates may be associated with the inhibition of the metabolic activation of carcinogens by cytochrome P450s (Phase I), coupled with strong induction of Phase II detoxifying and cellular defensive enzymes. Inductions of Phase II cellular enzymes are largely mediated by the antioxidant responsive element (ARE), which is regulated by the transcriptional factor, Nrf2. Additional potent regulatory mechanisms of Nrf2 include the different signaling kinase pathways (MAPK, PI3K, PKC and PERK) as well as other non-kinase dependent mechanisms. Moreover, apoptosis and cell cycle perturbations appear to be yet another potential chemopreventive mechanisms elicited by isothiocyanates, especially with respect to the effects on pre-initiated or initiated tumor cells. Finally, modulation of other critical signaling mediators, including the NF-kappaB and AP-1 by a wide array of chemopreventive agents including isothiocyanates may also contribute to the overall chemopreventive mechanisms.
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PMID:Chemoprevention by isothiocyanates and their underlying molecular signaling mechanisms. 1547 60

Cholesterol metabolism to pregnenolone is dependent on the steroidogenic acute regulatory protein (StAR), which activates mitochondrial transfer of cholesterol to cytochrome CYP450scc. In mouse Y-1 adrenal cells and testis MA10 cells stimulation by 8-Bromo-cAMP (Br-cAMP) is augmented by a novel signaling initiated by low concentrations of arsenite (3-20 microM) and anisomycin (0.2 microM), a more selective stress agent. Each elevated StAR mRNA (three-fold after 6 h treatment) even with simultaneous stimulation by Br-cAMP. Arsenite produced parallel increases in StAR protein expression and cholesterol metabolism, but not for P450scc-mediated metabolism of 20alpha-hydroxycholesterol. Although arsenite and anisomycin each stimulated the phosphorylation of p38, the p38 inhibitor SB203580 (SB) produced additive increases in StAR expression. Cholesterol metabolism increased in parallel but without the increased StAR protein phosphorylation produced by Br-cAMP. Arsenite and anisomycin each elevated StAR mRNA but preferentially increased the 3.5 kb form relative to the 1.6 kb form. Arsenite and anisomycin each enhanced the stability of the more labile 3.5 kb mRNA which contains AU-rich elements that control mRNA stability. Although there were increases in both forms of StAR mRNA, arsenite did not stimulate a StAR promoter-reporter that exhibited a typical three-fold response to Br-cAMP. Arsenite and anisomycin may therefore activate a novel SB-independent MAP kinase which in part increases StAR expression through stabilizing the 3.5 kb mRNA but which may also activate a mechanism that by-passes transcription factors detected by the reporter. SB stimulation, which was completely blocked by a MEK inhibitor, was also selective towards the 3.5 kb StAR mRNA suggesting a second pathway for mRNA stabilization. These activations contrast with inhibition of StAR expression by arsenite at higher concentrations or longer incubation times.
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PMID:Novel signaling stimulated by arsenite increases cholesterol metabolism through increases in unphosphorylated steroidogenic acute regulatory (StAR) protein. 1571 39

Liver injury is a clinical prognostic indicator in acute pancreatitis (AP). We have demonstrated that Kupffer cell-derived FasL mediates liver injury during AP and sought to determine its role in AP-induced hepatocyte apoptosis. AP was induced in National Institutes of Health (NIH) Swiss mice, C57/C57, and Fas-/-, FasL-/- mice by a choline-deficient ethionine-supplement diet. Liver Fas, FasL, p38-mitogen activated phosphokinase (p38-MAPK), poly-ADP ribose polymerase (PARP), and cytochrome C were measured by immunoblotting. Apoptosis was assessed by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and DNA fragmentation (ELISA). AP upregulated liver FasL (4280 +/- 580 vs. 733 +/- 336), Fas (2866 +/- 595 vs. 649 +/- 111), cytochrome C (6980 +/- 237 vs. 903 +/- 156), and PARP (6393 +/- 591 vs. 466 +/- 261) as well as increased TUNEL staining (40 +/- 2 vs. 14 +/- 1) and DNA fragmentation (all P < 0.03 vs. control). In FasL-/- and Fas-/- mice, AP-induced upregulation of p38-MAPK, PARP, and cytochrome C was significantly attenuated (all P < 0.01 compared to C57/C57 control). In addition, AP-induced DNA fragmentation was reduced 60% in Fas-/- and FasL-/- mice (P < 0.01 vs. C57/C57). AP induces apoptosis by transcriptional activation of Fas/FasL. AP-induced apoptosis was significantly reduced in Fas and FasL knockout mice along with downregulation of p38-MAPK, PARP, and cytochrome C, thereby suggesting a central role for Fas/FasL in hepatocyte apoptosis. The manipulation of interactions between Kupffer cell-derived FasL and hepatocytes may have important therapeutic implications.
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PMID:Fas/FasL play a central role in pancreatitis-induced hepatocyte apoptosis. 1579 25

Although investigations of the transcriptional regulation of the rat cytochrome P450C24 [CYP24 (25-hydroxyvitamin D3 24-hydroxylase)] gene by 1,25D (1,25-dihydroxyvitamin D3) at either the genomic, or more recently at the non-genomic, level have provided insight into the mechanism of control of 1,25D levels, this regulation is still poorly characterized. Using HEK-293T cells (human embryonic kidney 293T cells), we reported that 1,25D induction of CYP24 requires JNK (c-Jun N-terminal kinase) but not the ERK1/2 (extracellular-signal-regulated kinase 1/2). The phenomenon of synergistic up-regulation of CYP24 expression by PMA and 1,25D is well known and was found to be protein kinase C-dependent. Whereas ERK1/2 was not activated by 1,25D alone, its activation by PMA was potentiated by 1,25D also. The importance of ERK1/2 for transcriptional synergy was demonstrated by transfection of a dominant-negative ERK1(K71R) mutant (where K71R stands for Lys71-->Arg), which resulted in a reduced level of synergy on a CYP24 promoter-luciferase construct. JNK was also shown to be required for synergy. We report, in the present study, the identification of a site located at -171/-163, about 30 bp upstream of the vitamin D response element-1 in the CYP24 proximal promoter. This sequence, 5'-TGTCGGTCA-3', is critical for 1,25D induction of CYP24 and is therefore termed the vitamin D stimulatory element. The vitamin D stimulatory element, a target for the JNK module, and an Ets-1 binding site were shown to be vital for synergy between PMA and 1,25D. This is the first report to identify the DNA binding sequences required for the synergy between PMA and 1,25D and a role for JNK on the CYP24 gene promoter.
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PMID:Molecular action of 1,25-dihydroxyvitamin D3 and phorbol ester on the activation of the rat cytochrome P450C24 (CYP24) promoter: role of MAP kinase activities and identification of an important transcription factor binding site. 1583 35

Matrix metalloproteinase (MMP)-7 (matrilysin-1) plays significant roles in the growth, invasion, and metastasis of colorectal tumors, while (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol with chemopreventive properties, has been shown to be an inhibitor of MMP-2 and MMP-9. In the present study, HT-29 human colorectal cancer cells were treated with EGCG to examine its effects on pro-MMP-7 induction and production using RT-PCR and western blot analyses. Surprisingly, EGCG (10-100 microM) treatment increased both intracellular and extracellular pro-MMP-7 protein levels (2.6-8.4-fold and 1.9-6.4-fold, respectively) in dose- and time-dependent manner, with a significant upregulation of its mRNA expression. EGCG also activated extracellular signal-regulated protein kinase (ERK)1/2, c-JUN NH2-terminal kinase (JNK)1/2 and p38 mitogen-activated protein kinase (MAPK), as previously reported. In addition, the polyphenol triggered the phosphorylation of c-JUN (Ser63 and Ser73) and induced c-JUN/c-FOS, thereby increasing the DNA binding activity of activator protein-1 (AP-1), as shown by an AP-1 luciferase reporter assay. Pharmacological blockade of MAPK activities suggested that pro-MMP-7 expression was induced via JNK1/2 activation, but not in the case of ERK1/2 or p38 MAPK. N-Acetyl-L-cysteine, superoxide (O2-) dismutase and catalase attenuated the EGCG-induced pro-MMP-7 production, suggesting an involvement of oxidative stress in these events. Conversely, EGCG spontaneously generated O2- in a cell-free system that utilized a cytochrome C reduction method. Further, (-)-epicatechin-3-gallate (25 and 100 microM) and green tea polyphenols (33 and 132 microg/ml) induced pro-MMP-7 expression, whereas (-)-epicatechin and (-)-epigallocatechin (100 microM each) did not. Induction of pro-MMP-7 expression by EGCG was also shown in another human colorectal adenocarcinoma cell line, Caco-2. Our results suggest that some green tea catechins induce pro-MMP-7 production via O2- production and the activation of JNK1/2, c-JUN, c-FOS and AP-1 in HT-29 cells.
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PMID:(-)-Epigallocatechin-3-gallate promotes pro-matrix metalloproteinase-7 production via activation of the JNK1/2 pathway in HT-29 human colorectal cancer cells. 1586 May 7


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