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)

To clarify the effects of silica and silicates on cellular features of lymphocytes, a human T-lymphotropic virus type-1-immortalized polyclonal T-cell line, MT-2, was exposed to various concentrations of chrysotile-A, an asbestos classified as silicate. MT-2 cells underwent apoptosis in a dose- and time-dependent manner. The mitochondrial apoptotic pathway was activated during chrysotile-A-induced apoptosis of MT-2 cells, because of the phosphorylation of JNK and p38, increase of BAX and release of cytochrome-c from mitochondria to cytoplasma. In addition, anti-oxidants such as hydroxyl-radical excluders and capturers of superoxide and inhibitors of superoxide production effectively reduced the size of the apoptotic fraction in MT-2 cells cultured with chrysotile-A. These results indicate that the activation of reactive oxygen species may play a central role in asbestos-induced T-cell apoptosis, and anti-oxidants may help to prevent complications of pneumoconiosis.
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PMID:Inhibitory effects of anti-oxidants on apoptosis of a human polyclonal T-cell line, MT-2, induced by an asbestos, chrysotile-A. 1588 36

Kupffer cells become activated in response to elevated levels of LPS during ethanol feeding, but the role of ethanol in the molecular processes of activation remains unclear. Because cytochrome P4502E1 (CYP2E1) is upregulated in Kupffer cells after ethanol, we hypothesized that this effect primes Kupffer cells, sensitizing them to increase TNF-alpha production in response to LPS. However, cultured Kupffer cells rapidly lose their CYP2E1. This difficulty was overcome by transfecting CYP2E1 to RAW 264.7 macrophages. Macrophages with stable increased CYP2E1 expression (E2) displayed increased levels of CD14/Toll-like receptor 4, NADPH oxidase and H2O2, accompanied by activation of ERK1/2, p38, and NF-kappaB. These increases primed E2 cells, sensitizing them to LPS stimuli, with amplification of LPS signaling, resulting in increased TNF-alpha production. Diphenyleneiodonium, a NADPH oxidase inhibitor, and diallyl sulfide, a CYP2E1 inhibitor, decreased approximately equally H2O2 levels in E2 cells, suggesting that NADPH oxidase and CYP2E1 contribute equally to H2O2 generation. Because CYP2E1 expression also enhanced the levels of the membrane localized NADPH oxidase subunits p47phox and p67phox, thereby contributing to the oxidase activation, it may augment H2O2 generation via this mechanism. H2O2, derived in part from NADPH and CYP2E1, activated ERK1/2 and p38. ERK1/2 stimulated TNF-alpha production via activation of NF-kappaB, whereas p38 promoted TNF-alpha production by stabilizing TNF-alpha mRNA. Oxidant generation after CYP2E1 overexpression appears to be central to macrophage priming and their sensitization to LPS. Accordingly, CYP2E1 priming could explain the sensitization of Kupffer cells to LPS activation by ethanol, a critical early step in alcoholic liver disease.
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PMID:Cytochrome P4502E1 primes macrophages to increase TNF-alpha production in response to lipopolysaccharide. 1596 86

The potential use of low dose chemotherapy has been appealing since lower dosages are more attainable during cancer therapy and cause less toxicity in patients. Combination therapy of Taxol, a promising frontline chemotherapy agent, with natural anti-tumor agents that are considerably less toxic with a capability of activating additional apoptotic signals or inhibiting survival signals may provide a rational molecular basis for novel chemotherapeutic strategies. Esculetin, a well-known lipoxygenase inhibitor, showed an inhibitory effect on the cell cycle progression of HL-60 cells in our previous study. In this report, the effects of a concomitant administration of esculetin and Taxol were investigated in human hepatoma HepG2 cells. Firstly, esculetin alone could exert an antiproliferation effect together with an inhibitory effect on the activation of ERKs and p38 MAPK. As compared to the treatment with Taxol only, a co-administration with esculetin and Taxol could result in a further enhancement of apoptosis as revealed by DNA fragmentation assay and Annexin-V-based assay. Meanwhile, immunoblotting analysis also showed that the co-administration of esculetin and Taxol could increase the expression of Bax and the cytosolic release of cytochrome C and enhance the expression of Fas and Fas ligand while the activation of caspase-8 and caspase-3 was also increased. Finally, the ERK cascade was proven to be involved in the enhancement of esculetin on the Taxol-induced apoptosis.
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PMID:Enhancement of esculetin on Taxol-induced apoptosis in human hepatoma HepG2 cells. 1605 Dec 89

Proteasome inhibitors can resensitize cells that are resistant to tumor necrosis factor-related apoptotic-inducing ligand (TRAIL)-mediated apoptosis. However, the underlying mechanisms of this effect are unclear. To characterize the mechanisms of interaction between proteasome inhibitors and TRAIL protein, we evaluated the effects of combined treatment with the proteasome inhibitors bortezomib and MG132 and TRAIL protein on two TRAIL-resistant human colon cancer cell lines, DLD1-TRAIL/R and LOVO-TRAIL/R. Both bortezomib and MG132 in combination with TRAIL enhanced apoptotosis induction in these cells, as evidenced by enhanced cleavage of caspases 8, 9, and 3, Bid, poly(ADP-ribose) polymerase and by the release of cytochrome C and Smac. Subsequent studies showed that combined treatment with bortezomib or MG132 resulted in an increase of death receptor (DR) 5 and Bik at protein levels but had no effects on protein levels of DR4, Bax, Bak, Bcl-2, Bcl-XL or Flice-inhibitory protein (FLIP). Moreover, c-Jun N-terminal kinase (JNK) is activated by these proteasome inhibitors. Blocking JNK activation with the JNK inhibitor SP600125 attenuated DR5 increase, but enhancement of apoptosis induction and increase of Bik protein were not affected. However, bortezomib-mediated TRAIL sensitization was partially blocked by using siRNA to knockdown Bik. Thus, our data suggests that accumulation of Bik may be critical for proteasome inhibitor-mediated resensitization of TRAIL.
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PMID:Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. 1608 82

Glucocorticoids have successfully been used in the treatment of rheumatoid arthritis. Data suggest that 7alpha-hydroxy-dehydroepiandrosterone (7alpha-OH-DHEA), an immunostimulating metabolite of dehydroepiandrosterone, can block glucocorticoid-induced immune suppression. Formation of 7alpha-OH-DHEA is catalyzed by activity of cytochrome p450 enzyme 7b (Cyp7b). Recently, we reported that tumour necrosis factor (TNF)-alpha, IL-1alpha, IL-1beta and IL-17 enhance Cyp7b mRNA expression and induce a concomitant increase in the formation of 7alpha-OH-DHEA by fibroblast-like synoviocytes (FLS) from rheumatoid arthritis patients. The aim of this study was to elucidate which signal transduction pathway is involved in the TNF-alpha-mediated induction of Cyp7b activity in FLS. We studied the effects of inhibitors of different signal transduction pathways on Cyp7b activity in FLS by measuring Cyp7b mRNA expression using reverse transcription PCR and by measuring the formation of 7alpha-OH-DHEA. We applied SN50, an inhibitor of nuclear translocation of transcription factors (i.e. activator protein-1 [AP-1] and nuclear factor-kappaB [NF-kappaB]); PSI, a proteasome inhibitor that prevents IkappaB degradation and thereby NF-kappaB release; SP600125, a c-Jun N-terminal kinase (JNK) inhibitor; and the mitogen-activated protein kinase inhibitors PD98059 (extracellular signal-regulated kinase) and SB203580 (p38). Cyp7b is constitutively expressed in RA FLS and can be activated in response to TNF-alpha. SN50 and PSI prevented the TNF-alpha-induced increase in Cyp7b activity, whereas the mitogen-activated protein kinase inhibitors PD98059 and SB203580 had no effect. In addition, inhibition of Cyp7b mRNA expression and activity was observed with SN50, PSI and SP600125, suggesting that NF-kappaB and AP-1 induce Cyp7b transcription. These findings suggest that NF-kappaB and AP-1 are involved in the TNF-alpha-enhanced formation of the dehydroepiandrosterone metabolite 7alpha-OH-DHEA. Our results are in accordance with presence of AP-1 and NF-kappaB binding sites in the Cyp7b promoter.
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PMID:Tumour necrosis factor-alpha stimulates dehydroepiandrosterone metabolism in human fibroblast-like synoviocytes: a role for nuclear factor-kappaB and activator protein-1 in the regulation of expression of cytochrome p450 enzyme 7b. 1627 80

Rats treated with the alkylating agent methylnitrosourea (MNU) develop multiple, hormonally dependent mammary tumors. Roughly 50% of the tumors have Ha-ras mutation, whereas 50% do not. The MNU-induced rat mammary tumor model was employed to examine the therapeutic efficacy of the farnesyltransferase inhibitor (FTI), R115777, and to examine the use of genomics in identifying susceptible tumors as well as identifying genes whose expression are modulated by FTI treatment. In animals bearing palpable mammary tumors (< 7 mm diameter), we performed a surgical biopsy, and 3 days following the biopsy, rats were treated with R115777 (50 mg/kg body wt/day) by gavage. Tumors with Ha-ras mutations underwent profound regression, with nearly 90% showing complete regressions within 4 weeks. In contrast, the non-Ha-ras mutation-bearing tumors yielded a more variable response, although roughly half of the non-Ha-ras mutation tumors underwent significant regression. These results show that although all tumors appear to respond to the FTI inhibitor the tumors with Ha-ras mutations were exquisitely sensitive. We employed a microarray approach to define potential targets and the mechanism of action of R115777 in Ha-ras mutant or wildtype tumors following treatment with FTI. In addition, we determined whether gene expression prior to FTI treatment can be used to differentiate highly sensitive tumors (Ha-ras mutant) and tumors with variable sensitivity (Ha-ras wildtype). Untreated or FTI-treated (4 days at 50 mg/kg body wt) tumors (Ha-ras mutant or wildtype) were examined using oligonucleotide arrays. A significant number of genes were differentially expressed in control rat mammary tumors with or without an activated Ha-ras mutation, suggesting that a microarray analysis might differentiate highly sensitive and variably sensitive tumors. Most of the genes whose expressions were modulated by FTI in tumors were independent of Ha-ras status and were presumably modulated by effects on farnesylation of proteins other than Ha-ras. However, treatment of Ha-ras-mutated mammary tumors with R155777 results in preferential modulation of genes involved in ras-MAP kinase signal transduction pathway and in decreased expression of many genes involved with cell proliferation. In contrast, several classes of genes are altered in rat mammary tumors without a mutated Ha-ras, suggesting that non-ras targets are involved. Ras pathway related genes, p53, WT1 and PCNA, were preferentially modulated in Ha-ras-mutated tumors, whereas modulation of genes in the G-protein pathway, various cytochrome p450s and RB1 are involved in Ha-ras wildtype tumors. Elucidation of gene expression changes in FTI-treated or control rat mammary adenocarcinomas will help in identifying potential pharmacodynamic markers of FTI treatment as well as potential molecular targets of R115777 and other FTIs.
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PMID:Efficacy of the farnesyltransferase inhibitor R115777 in a rat mammary tumor model: role of Ha-ras mutations and use of microarray analysis in identifying potential targets. 1640 72

Recent data showed that epidermal growth factor receptor (EGFR) inhibitors, such as ZD1839, alone or in combination with chemotherapeutic agents for androgen-independent prostate cancer (AIPC) did not produce promising results in clinical settings. More effective regimens involving novel stronger inhibitor of EGFR and better combinations are needed. The anti-tumor activity of PD168393, an irreversible EGFR inhibitor, with or without chemotherapeutic agents for the treatment of AIPC was investigated in vitro. In results, both the androgen-independent cell lines PC-3 and DU145 expressed higher levels of EGFR than the androgen-dependent MDA PCa 2b and androgen-responsive LNCaP cells by Western blotting. DU145 was much more sensitive to PD168393 and ZD1839 than MDA PCa 2b. PD168393, but not ZD1839, significantly potentiated paclitaxel cytotoxicity against DU145 by MTT assay and median-effect analysis. The combination of PD168393 or ZD1839 with other cytotoxic agents including docetaxel and 5-fluorouracil, however, was either additive or antagonistic. Compared to paclitaxel alone, PD168393 significantly enhanced paclitaxel-induced DNA fragmentation, sub-G1 fraction accumulation, mitochondrial membrane dysfunction, cytochrome C release, caspase-3 activation and eventually apoptosis. These molecular events were accompanied by Bad up-regulation, p53 and p21Waf1/Cip1 induction, ERK1/2 inactivation and inhibition of EGFR phosphorylation in the presence of PD168393. These effects did not involve significant alteration in the Akt1/2 and STAT3 signaling pathway. In conclusion, the combination of paclitaxel and PD168393 produced a profound synergistic growth inhibition of AIPC cells. Combining PD168393 with paclitaxel may have clinical benefits and warrants further investigation.
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PMID:Epidermal growth factor receptor inhibitor (PD168393) potentiates cytotoxic effects of paclitaxel against androgen-independent prostate cancer cells. 1641 5

We investigated the mechanism of the pan-caspase inhibitor z-VAD-fmk's augmentation of TNFalpha-induced L929 cell death and found this mechanism differs from that of TNFalpha-induced L929 cell death. In the presence of 20 ng/ml TNFalpha, z-VAD-fmk initiated apoptosis and necrosis in the majority of L929 cells as measured by an agarose gel electrophoresis and lactate dehydrogenase(LDH)activity based assay. Mitochondrial permeability transition (MPT) inhibitor (cyclosporine A) effectively inhibited z-VAD-fmk-augmented cell death. In addition, z-VAD-fmk plus TNFalpha increased Bax expression without affecting Bcl-2 and cytochrome expression. Western-blot analysis showed that z-VAD-fmk plus TNFalpha caused persistent JNK activation and ERK inactivation. Poly(ADP-ribose) polymerase (PARP) inhibitor (DPQ) effectively reversed the cell death which was augmented by z-VAD-fmk, and z-VAD-fmk plus TNFalpha also caused PARP cleavage to an 85 KDa fragment. These results indicate that in the presence of TNFalpha, z-VAD-fmk further augments cell death which requires the mitochondrial permeability transition and the JNK activation. However, we did not detect the changes in cytochrome c expression and the participation of caspase-9 in this process, suggesting that there might exist an unknown signal pathway(s) from the mitochondria to the downstream protein PARP, which is cleaved in a caspase-independent manner.
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PMID:The augmentation of TNFalpha-induced cell death in murine L929 fibrosarcoma by the pan-caspase inhibitor Z-VAD-fmk through pre-mitochondrial and MAPK-dependent pathways. 1641 68

Platelet-derived growth factor (PDGF)-BB and PDGF-DD mediate mesangial cell proliferation in vitro and in vivo. While PDGF-BB is a ligand for the PDGF alpha- and beta-receptor chains, PDGF-DD binds more selectively to the beta-chain, suggesting potential differences in the biological activities. Signal transduction and regulation of gene expression induced by PDGF-BB and -DD were compared in primary human mesangial cells (HMCs), which expressed PDGF alpha- and beta-receptor subunits. The growth factor concentrations used were chosen based on their equipotency in inducing HMCs proliferation and binding to the betabeta-receptor. Both growth factors, albeit at different concentrations induced phosphorylation and activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2. In addition, PDGFs led to the phosphorylation and activation of signal transducers and activators of transcription 1 (STAT1) and STAT3. HMCs proliferation induced by either PDGF-BB or -DD could be blocked by signal transduction inhibitors of the mitogen-activated protein kinase-, Janus kinase (JAK)/STAT-, or phosphatidyl-inositol 3-kinase pathways. Using a gene chip array and subsequent verification by real-time reverse transcriptase (RT)-polymerase chain reaction, we found that in HMC genes for matrix metalloproteinase 13 (MMP-13) and MMP-14 and, to a low extent, cytochrome B5 and cathepsin L were exclusively regulated by PDGF-BB, whereas no exclusive gene regulation was detected by PDGF-DD. However, at the protein level, both MMP-13 and -14 were equally induced by PDGF-BB and -DD. PDGF-BB and -DD effect similar biological responses in HMCs albeit at different potencies. Rare apparently differential gene regulation did not result in different protein expression, suggesting that in HMCs both PDGFs exert their biological activity almost exclusively via the PDGF beta-receptor.
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PMID:Biological responses to PDGF-BB versus PDGF-DD in human mesangial cells. 1655 24

It is reported that matrine, one of the major effective compounds isolated from the root of Sophora flavescens Ait., has anti-leukemia activity. In this study, we find that the treatment of leukemia U937 cells with matrine results in induction of apoptosis. Analysis of the mechanism underling this apoptotic event showed activation of caspases-9, -3, and -7, and release of cytochrome C from mitochondria to cytosol, and cleavage of poly(ADP-ribose) polymerase. Matrine did not alter the level of bcl-2 and bcl-xL as well as bax. In addition, no correlation was found between matrine administration and activation of the three major MAPK subfamilies (Erk1/2, p38, JNK/SAPK). The results indicate that matrine induces apoptosis in U937 cells via a cytochrome C-triggered caspase activation pathway.
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PMID:Matrine-induced apoptosis in leukemia U937 cells: involvement of caspases activation and MAPK-independent pathways. 1677 33


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