Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the significance of the activation of c-Jun N-terminal kinase (JNK) and p42/44 mitogen-activated protein kinase (MAPK) by ethanol and acetaldehyde in rat hepatocyte apoptosis. Acetaldehyde induced rapid and transient (15 min) activation of p42/44 MAPK followed by activation of JNK, which remained above control up to 1 h. Ethanol activated JNK for up to 4 h. Both ethanol and acetaldehyde caused apoptosis as determined by DNA fragmentation, caspase-3 activation and 2'[4-ethoxyphenyl]-5-[4-methyl-piperazinyl]-2,5'-bi-1H-benzimidazole (Hoechst 33342) staining. Ethanol-induced apoptosis was blocked by JNK inhibitor 1,9-pyrazoloanthrone (SP600125), indicating that JNK activation is pro-apoptotic. In contrast, acetaldehyde-induced apoptosis was not suppressed by this inhibitor. In fact, SP600125 potentiated acetaldehyde-induced apoptosis, suggesting that JNK activation is anti-apoptotic. Inhibition of p42/44 MAPK by MAPK kinase (MKK1) inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), potentiated apoptosis by acetaldehyde or ethanol, suggesting anti-apoptotic role of p42/44 MAPK. The activation of JNK by ethanol or acetaldehyde was insensitive to the genistein (tyrosine kinase inhibitor), GF109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide, protein kinase C [PKC] inhibitor) and N-acetylcysteine (N-AC) (antioxidant), whereas p42/44 MAPK activation by acetaldehyde was inhibited by genistein and GF109203X. Furthermore, p42/44 MAPK activation is not necessary for the JNK activation. In summary, transient activation of JNK by acetaldehyde is anti-apoptotic, whereas sustained activation of JNK by ethanol is pro-apoptotic. The activation of p42/44 MAPK appears to be anti-apoptotic for both ethanol and acetaldehyde. Thus, JNK activation by ethanol and acetaldehyde can be both pro- and anti-apoptotic in hepatocytes.
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PMID:Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes. 1568 Feb 52

We have shown previously that LPPs (lipid phosphate phosphatases) reduce the stimulation of the p42/p44 MAPK (p42/p44 mitogen-activated protein kinase) pathway by the GPCR (G-protein-coupled receptor) agonists S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) in serum-deprived HEK-293 cells [Alderton, Darroch, Sambi, McKie, Ahmed, N. J. Pyne and S. Pyne (2001) J. Biol. Chem. 276, 13452-13460]. In the present study, we now show that this can be blocked by pretreating HEK-293 cells with the caspase 3/7 inhibitor, Ac-DEVD-CHO [N-acetyl-Asp-Glu-Val-Asp-CHO (aldehyde)]. Therefore LPP2 and LPP3 appear to regulate the apoptotic status of serum-deprived HEK-293 cells. This was supported further by: (i) caspase 3/7-catalysed cleavage of PARP [poly(ADP-ribose) polymerase] was increased in serum-deprived LPP2-overexpressing compared with vector-transfected HEK-293 cells; and (ii) serum-deprived LPP2- and LPP3-overexpressing cells exhibited limited intranucleosomal DNA laddering, which was absent in vector-transfected cells. Moreover, LPP2 reduced basal intracellular phosphatidic acid levels, whereas LPP3 decreased intracellular S1P in serum-deprived HEK-293 cells. LPP2 and LPP3 are constitutively co-localized with SK1 (sphingosine kinase 1) in cytoplasmic vesicles in HEK-293 cells. Moreover, LPP2 but not LPP3 prevents SK1 from being recruited to a perinuclear compartment upon induction of PLD1 (phospholipase D1) in CHO (Chinese-hamster ovary) cells. Taken together, these data are consistent with an important role for LPP2 and LPP3 in regulating an intracellular pool of PA and S1P respectively, that may govern the apoptotic status of the cell upon serum deprivation.
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PMID:Regulation of cell survival by lipid phosphate phosphatases involves the modulation of intracellular phosphatidic acid and sphingosine 1-phosphate pools. 1596 Jun 10

The hierarchy of events accompanying induction of apoptosis by the microtubule inhibitor docetaxel was investigated in HL-60 human leukemia cells. Treatment of HL-60 cells with docetaxel resulted in the production of reactive oxygen species (ROS), activation of caspase-3 (-like) protease, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activation, bcl-2 phosphorylation and apoptosis. Docetaxel elicited ROS production from NADPH oxidase as demonstrated by specific oxidase inhibitor diphenylene iodonium (DPI). ROS mediated the caspase-3 activation and apoptosis in HL-60 cells. The caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO) effectively inhibited JNK/SAPK activation, bcl-2 phosphorylation and partially attenuated the ROS production induced by docetaxel. Docetaxel-induced bcl-2 phosphorylation was completely blocked by expression of dominant negative JNK or the JNK/SAPK inhibitor SP600125. Overexpression of bcl-2 partially prevented docetaxel-mediated ROS production and subsequent caspase-3 activation, thereby inhibiting apoptotic cell death. It is thus conferred that such sequent events as ROS production, caspase activation, JNK/SAPK activation, bcl-2 phosphorylation and the further generation of ROS should be parts of an amplification loop to increase caspase activity, thereby facilitating the apoptotic cell death process.
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PMID:Amplification loop cascade for increasing caspase activity induced by docetaxel. 1614 76

4-Hydroxynonenal (4-HNE) is a peroxidation product of omega-6-poly-unsaturated fatty acids and exerts growth modifying as well as cytotoxic activities. This aldehyde component of oxidized lipid is increased during the aging process. In this study, to characterize the potential role of the lipid peroxidation product in aging, we studied the effects of 4-HNE on cell proliferation and activation of cell-cycle machinery and the mitogen-activated protein kinase signaling pathway. 4-HNE-treated smooth muscle cells (SMCs) have shown a different cell proliferation rate depending on 4-HNE's incubation time and concentration. Interestingly, a prolonged treatment of 0.1 microM 4-HNE (36 h) resulted in an increase of cell growth in young SMCs but displayed cytotoxicity in aged SMCs. Treatment with 4-HNE enhanced cyclin D1 expression and activation of the extracellular signal-regulated kinase (ERK) signaling pathway, which were stronger in young SMCs compared with aged SMCs. Moreover, 4-HNE-induced cell proliferation and cyclin D1 expression were significantly attenuated by PD98059, the ERK inhibitor, in young SMCs. These data clearly indicate that increased cell proliferation was associated with the induction of cyclin D1 expression which was regulated by ERK in 4-HNE-treated young SMCs for 36 h. In contrast, we found that the cytotoxicity of aged SMCs to 4-HNE was partly related to generation of ROS and that pretreatment with N-acetyl-L-cysteine prevented 4-HNE-induced cell death in aged SMCs. These results suggest that the prolonged treatment of 0.1 microM 4-HNE-induced cell growth inhibition was caused by generation of ROS. Collectively, the age-related different growth rates and responses to 4-HNE are related to the expression level of cyclin D1, activation of the ERK signaling pathway, and regulation of ROS generation in SMCs.
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PMID:Age-related differential growth rate and response to 4-hydroxynonenal in mouse aortic smooth muscle cells. 1632 8

Acetaldehyde, the major metabolite of ethanol, which is far more toxic and reactive than ethanol, may be responsible for alcohol-induced cardiac damage. This study was designed to examine the impact of facilitated acetaldehyde metabolism using transfection of human aldehyde dehydrogenase-2 (ALDH2) transgene on acetaldehyde- and ethanol-induced cell injury. Fetal human cardiac myocytes were transfected with ALDH2, the efficacy of which was verified by flow cytometry, Western blot and ALDH2 activity assays. Generation of reactive oxygen species (ROS) was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride (DAPI) fluorescence microscopy, quantitative DNA fragmentation ELISA and caspase 3 activity. Acetaldehyde and ethanol elicited overt ROS generation and apoptosis in human cardiac myocytes following 24-48 h of incubation. Immunostaining revealed activation of the MAP kinase cascades ERK1/2, SAPK/JNK and p38 MAP kinase in acetaldehyde-treated myocytes. Interestingly, ALDH2 transgene significantly attenuated acetaldehyde-induced ROS generation, apoptosis and phosphorylation of ERK1/2 and SAPK/JNK. Time-dependent response (0-12 h) revealed ROS accumulation and activation of MAP kinases prior to acetaldehyde-induced apoptosis. In addition, acetaldehyde-induced ROS generation and apoptosis were antagonized by non-enzymatic antioxidants. Our results suggested that ALDH2 transgene overexpression may effectively alleviate acetaldehyde-elicited cell injury through an ERK1/2 and SPAK/JNK-dependent mechanism. Our data are consistent with the notion of acetaldehyde as a contributor to alcoholic cardiomyopathy and implicate the therapeutic potential of ALDH2 enzyme in alcoholic complications.
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PMID:Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene in human cardiac myocytes: role of MAP kinase signaling. 1640 13

Lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4 agonist, causes airway hyperreactivity through nuclear factor-kappaB (NF-kappaB). Because NF-kappaB induces cyclooxygenase-2 (COX-2) to increase synthesis of prostaglandins (PGs), including the potent airway anti-inflammatory and smooth muscle relaxant PGE(2), we investigated whether LPS causes short-term PGE(2)-dependent relaxation of mouse isolated trachea. In rings of trachea contracted submaximally with carbachol, LPS caused slowly developing, epithelium-dependent relaxations that reached a maximum within 60 min. Fluorescence immunohistochemistry revealed TLR4-like immunoreactivity localized predominantly to the epithelium. The LPS antagonist polymixin B; the nonselective COX inhibitor indomethacin; the selective COX-1 and COX-2 inhibitors 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC560) and 4-[5-(4-chlorophenyl)-1-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide (SC236), respectively; the transcription inhibitor actinomycin D; the translation inhibitor cycloheximide; the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imadazole (SB203580); and a combination of the mixed DP/EP1/EP2 receptor antagonist 6-isopropoxy-9-xanthone-2-carboxylic acid (AH6809) and the EP4 receptor antagonist 4'-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1-5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide (L-161982) all abolished relaxation to LPS, giving instead slowly developing, small contractions over 60 min. The cytosolic phospholipase A(2) (cPLA(2)) inhibitor 1,1,1-trifluoro-6Z,9Z, 12Z,15Z-heneicosateraen-2-one significantly (p < 0.05) inhibited the relaxation to LPS, whereas the NF-kappaB proteasomal inhibitor Z-Leu-Leu-Leu-aldehyde (MG-132) had no affect on the relaxation in the first 20 min, after which it reversed the response to a contraction. In conclusion, our data indicate that LPS activates airway epithelial TLR4 to cause release of PGE(2) and subsequent EP2 and EP4 receptor-dependent smooth muscle relaxation. Activation of both COX-1 and COX-2 seems to be essential for this novel response to LPS, which also involves cPLA(2), p38 MAPK, NF-kappaB, and an unidentified NF-kappaB-independent, labile regulatory protein.
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PMID:Lipopolysaccharide induces epithelium- and prostaglandin E(2)-dependent relaxation of mouse isolated trachea through activation of cyclooxygenase (COX)-1 and COX-2. 1646 66

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde that is present in cigarette smoke. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by various such electrophilic compounds. In this study, the regulatory effects of acrolein upon the expression of HO-1 were investigated in endothelial cells (ECs). We demonstrate that acrolein induces the elevation of HO-1 protein levels, and subsequent enzyme activity, at non-cytotoxic concentrations. An additional alpha,beta-unsaturated aldehyde, cinnamaldehyde, was also found to increase HO-1 expression and have less cytotoxicity than acrolein. Moreover, acrolein-mediated HO-1 induction is abrogated in the presence of actinomycin D and cycloheximide. Nrf2 is a transcription factor involved in the induction of HO-1 through an antioxidant response element (ARE) in the promoter region of the HO-1 gene. We show that acrolein induces Nrf2 translocation and ARE-luciferase reporter activity. Acrolein was also found to induce the production of both superoxide and H2O2 at levels greater than 100 microM. However, with the exception of NAC, no antioxidant generated any effect upon acrolein-dependent HO-1 expression in ECs. Our present findings suggest that reactive oxygen species (ROS) may not be a major modulator for HO-1 induction. Using buthionine sulfoximine to deplete the intracellular GSH levels further enhanced the effects of acrolein. We also found that cellular GSH level was rapidly reduced after both 10 and 100 microM acrolein treatment. However, after 6 h of exposure to ECs, only 10 microM acrolein treatment increases GSH level. In addition, only the JNK inhibitor SP600125 and tyrosine kinase inhibitor genistein had any significant inhibitory impact upon the upregulation of HO-1 by acrolein. Pretreatment with a range of other PI3 kinase inhibitors, including wortmannin and LY294002, showed no effects. Hence, we show in our current experiments that a sublethal concentration of acrolein is in fact a novel HO-1 inducer, and we further identify the principal underlying mechanisms involved in this process.
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PMID:Upregulation of endothelial heme oxygenase-1 expression through the activation of the JNK pathway by sublethal concentrations of acrolein. 1648 Jul 51

Aldehydes are widespread environmental and industrial compounds, which cause cytotoxicity, tissue damage, mutagenicity, and carcinogenicity leading to various disease conditions such as cardiovascular, bronchial, and visual complications. We have shown earlier that aldose reductase (AR) besides reducing glucose to sorbitol, efficiently reduces various toxic lipid-derived aldehydes, generated under oxidative stress, with K(m) in the physiological range. We have identified the role of AR in the prevention of various lipid aldehyde-induced cytotoxic signals leading to apoptosis in human lens epithelial cells (HLEC). HLEC were cultured without or with AR inhibitors followed by addition of various saturated and unsaturated lipid aldehydes with a carbon chain length varying from C3 to C10. The cell viability was assessed by cell counts and MTT assay, and apoptosis was measured by evaluating nucleosomal degradation and caspase-3 activation using specific ELISA kits. Although all the aldehydes caused apoptosis of HLEC, the unsaturated aldehydes were more toxic than saturated aldehydes. Inhibition of AR by sorbinil potentiated while the over-expression of AR prevented the apoptosis induced by various lipid aldehydes. AR over-expression also prevented the lipid aldehyde-induced activation of caspase-3, MAPK, JNK and the expression of Bcl-2 family of proteins in HLEC. The results indicate that the lipid aldehydes generated under oxidative stress are cytotoxic to HLEC leading to apoptosis and that the reduction of lipid aldehydes by AR would prevent it.
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PMID:Aldose reductase prevents aldehyde toxicity in cultured human lens epithelial cells. 1663 Nov 66

To investigate the effects of sex hormones on ethanol (EtOH)-induced bone loss, female Sprague-Dawley rats were fed control or EtOH-containing diets (12 g/kg/day) by intragastric infusion. After 3 weeks, rats receiving EtOH had significant decreases in tibial trabecular and total bone mineral density, induction of receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA expression, and enhanced bone resorption, all of which were prevented by treatment with 17beta-estradiol (E(2)). The addition of progesterone did not enhance the beneficial effect of E(2) alone. Consistent with our in vivo findings, EtOH stimulated RANKL mRNA expression in cultured primary osteoblasts, and this expression was blocked by 4-methylpyrazole. Acetaldehyde also induced RANKL expression. Class 1 alcohol dehydrogenase was found to be expressed and EtOH-inducible in cultured osteoblasts, whereas CYP2E1 was undetectable. We found that EtOH induced phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducers and activators of transcription 3 (STAT3). E(2) and the mitogenactivated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked ERK and STAT3 phosphorylation and blocked RANKL induction. Moreover, E(2) completely blocked EtOH-induced osteoclastogenesis in a primary osteoblast and osteoclast precursor coculture system. The E(2) effects were estrogen receptor-mediated. Therefore, E(2) prevents EtOH-induced bone loss by opposing the induction of RANKL mRNA in osteoblasts and ethanol-induced osteoclastogenesis, through opposing effects on sustained ERK signaling.
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PMID:Estradiol protects against ethanol-induced bone loss by inhibiting up-regulation of receptor activator of nuclear factor-kappaB ligand in osteoblasts. 1697 3

4-hydroxynonenal (HNE), a lipid peroxidation end product, is produced abundantly in osteoarthritic (OA) articular tissues and was recently identified as a potent catabolic factor in OA cartilage. In this study, we provide additional evidence that HNE acts as an inflammatory mediator by elucidating the signaling cascades targeted in OA chondrocytes leading to cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) gene expression. HNE induced COX-2 protein and mRNA levels with accompanying increases in prostaglandin E2 (PGE(2)) production. In contrast, HNE had no effect on basal iNOS expression or nitric oxide (NO) release. However, HNE strongly inhibited IL-1beta-induced iNOS or NO production. Transient transfection experiments revealed that the ATF/CRE site (-58/-53) is essential for HNE-induced COX-2 promoter activation and indeed HNE induced ATF-2 and CREB-1 phosphorylation as well as ATF/CRE binding activity. Overexpression of p38 MAPK enhanced the HNE-induced ATF/CRE luciferase reporter plasmid activation, COX-2 synthesis and promoter activity. HNE abrogated IL-1beta-induced iNOS expression and promoter activity mainly through NF-kappaB site (-5,817/-5,808) possibly via suppression of IKKalpha-induced IkappaBalpha phosphorylation and NF-kappaB/p65 nuclear translocation. Upon examination of upstream signaling components, we found that IKKalpha was inactivated through HNE/IKKalpha adduct formation. Taken together, these findings illustrate the central role played by HNE in the regulation of COX-2 and iNOS in OA. The aldehyde induced selectively COX-2 expression via ATF/CRE activation and inhibited iNOS via IKKalpha inactivation.
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PMID:Differential regulation of cyclooxygenase-2 and inducible nitric oxide synthase by 4-hydroxynonenal in human osteoarthritic chondrocytes through ATF-2/CREB-1 transactivation and concomitant inhibition of NF-kappaB signaling cascade. 1703 50


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