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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukotriene B4 (LTB4) is a potent chemoattractant and activator for granulocytes and macrophages and is considered to be an inflammatory mediator. Two G-protein-coupled receptors for LTB4, BLT1 and BLT2, have been cloned from human and shown to be high and low affinity LTB4 receptors, respectively. To reveal the biological roles of BLT2 using mouse disease models, we cloned and characterized mouse BLT2. Chinese hamster ovary cells stably expressing mouse BLT2 exhibited specific binding to LTB4, LTB4-induced calcium mobilization, inhibition of adenylyl cyclase, and phosphorylation of extracellular signal-regulated kinase. We found that Compound A (4'-{[pentanoyl (phenyl) amino] methyl}-1, 1'-biphenyl-2-carboxylic acid) was a BLT2-selective agonist and induced Ca(2+) mobilization and phosphorylation of extracellular signal-regulated kinase through BLT2, whereas it had no effect on BLT1. 12-epi LTB4 exhibited a partial agonistic activity against mBLT1 and mBLT2, whereas 6-trans-12-epi LTB4 did not. Northern blot analysis showed that mouse BLT2 is expressed highly in small intestine and skin in contrast to the ubiquitous expression of human BLT2. By in situ hybridization and the reverse transcriptase polymerase chain reaction, we demonstrated that mouse BLT2 is expressed in follicular and interfollicular keratinocytes. Compound A, LTB4, and 12-epi LTB4 all induced phosphorylation of extracellular signal-regulated kinase in primary mouse keratinocytes. Furthermore, Compound A and LTB4 induced chemotaxis in primary mouse keratinocytes. These data suggest the presence of functional BLT2 in primary keratinocytes.
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PMID:Characterization of a mouse second leukotriene B4 receptor, mBLT2: BLT2-dependent ERK activation and cell migration of primary mouse keratinocytes. 1586 83

Interleukin (IL)-8 plays a central role in the initiation and maintenance of inflammatory responses in the inflammatory bowel disease. The proinflammatory cytokine-mediated production of IL-8 requires activation of various kinases, which leads to the I kappa B degradation and NF-kappa B activation. We investigated the role of 18 beta-glycyrrhetinic acid (GA), a saponin isolated from licorice roots, on TNF-alpha-induced IL-8 production in human colonic epithelial cells. HT29 cells were stimulated with TNF-alpha in the presence or absence of GA (1, 5 or 10 microM). IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction analysis, and the mitogen-activated protein kinases (MAPKs) activation and I kappa B alpha degradation were determined by Western blot analysis. GA suppressed TNF-alpha-induced IL-8 production in a concentration-dependent manner. In addition, GA inhibited TNF-alpha-induced phosphorylation of p38 MAPK and extracellular-regulated kinases (ERK), I kappa B alpha degradation, and NF-kappa B activation. These results suggest that GA has the inhibitory effects on TNF-alpha-induced IL-8 production in the intestinal epithelial cells through blockade in the phosphorylation of MAPKs, following I kappa B alpha degradation and NF-kappa B activation.
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PMID:Inhibition of interleukin-8 production in the human colonic epithelial cell line HT-29 by 18 beta-glycyrrhetinic acid. 1587 Sep 3

The development of osteoarthritis (OA) has recently been implicated as a result of immune-mediated damage of chondrocytes and their supporting matrixes. Pro-inflammatory cytokines like interleukin (IL)-1 and tumor necrosis factor alpha (TNF-alpha) play pivotal roles in immunopathogenesis of OA. Because vitamins preserving anti-oxidative effects are suggested to provide protection in OA patients from joint damage, in the present study, we examined the effects and mechanisms of all-trans retinoic acid (t-RA) in suppressing pro-inflammatory cytokine-induced matrix metalloproteinases (MMPs) production in human chondrocytes. Chondrocytes were prepared from cartilage specimens of OA patients receiving total hip or total knee replacement. The protein concentration was measured by ELISA, the mRNA expression by reverse transcriptase-polymerase chain reaction, the protein expression by Western blotting, the transcription factor DNA-binding activity by electrophoretic mobility shift assay and the protein kinase activity by kinase assay. We showed that both MMP-1 and MMP-13 mRNA expression, protein production and enzyme activity induced by either IL-1 or TNF-alpha were suppressed by t-RA or different retinoid derivatives. The molecular investigation revealed that the t-RA-mediated suppression was likely through blocking p38 kinase and c-Jun N-terminal kinase-activator protein-1 signaling pathways. In contrast, t-RA had no effect on extracellular signal-regulated kinase activity, nuclear factor (kappa)B (NF-(kappa)B) DNA-binding activity and I(kappa)B(alpha) degradation. Furthermore, we showed that t-RA could reduce IL-1-induced TNF-alpha production in chondrocytes. Our results suggest that vitamin A may protect OA patients from pro-inflammatory cytokine-mediated damage of chondrocytes and their supporting matrixes.
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PMID:Retinoic acid blocks pro-inflammatory cytokine-induced matrix metalloproteinase production by down-regulating JNK-AP-1 signaling in human chondrocytes. 1594 54

Blastocyst formation, as a critical period during development, is an effective indicator of embryonic health and reproductive efficiency. Out of a number of mechanisms underlying blastocyst formation, highly conserved mitogen-activated protein kinase (MAPK) signaling has emerged as a major mechanism involved in regulating murine preimplantation embryo development. The objective of our study was to ascertain the role of MAPK signaling in regulating bovine development to the blastocyst stage. Using reverse transcriptase PCR and immunohistochemical staining procedures we have demonstrated that mRNA transcripts and polypeptides encoding p38 MAPK pathway constituents are detectable in preimplantation bovine embryos from the one-cell to the blastocyst stage. Further, the effects on bovine embryo development following inhibition of p38 alpha/beta and extracellular signal-regulated kinase (ERK) signaling by treatment with SB220025 and U0126, respectively, were investigated. Eight-cell bovine embryos (50 per group; three replicates) were placed into treatments consisting of synthetic oviductal fluid (SOF) medium: SOF + SB202474 (inactive analogue), SOF + SB220025, SOF + U0124 (inactive analogue), SOF + U0126, and SOF + SB220025 + U0126. Inhibition of p38 MAPK or ERK signaling individually did not affect development to the blastocyst stage. However, when both pathways were blocked simultaneously there was a significant reduction (P < 0.05) in blastocyst formation, cell number and immunofluorescence of phosphorylated downstream pathway constituents. We have determined that, in variance to what was observed during murine preimplantation development, bovine early embryos progress at normal frequencies to the blastocyst stage in the presence of p38 MAPK inhibitors.
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PMID:Mitogen-activated protein kinase (MAPK) blockade of bovine preimplantation embryogenesis requires inhibition of both p38 and extracellular signal-regulated kinase (ERK) pathways. 1598 30

Kaposi's sarcoma-associated herpesvirus (KSHV) in vitro target cell infection is characterized by the expression of the latency-associated genes ORF 73 (LANA-1), ORF 72, and K13 and by the transient expression of a very limited number of lytic genes such as lytic cycle switch gene ORF 50 (RTA) and the immediate early (IE) lytic K5, K8, and v-IRF2 genes. During the early stages of infection, several overlapping multistep complex events precede the initiation of viral gene expression. KSHV envelope glycoprotein gB induces the FAK-Src-PI3K-RhoGTPase (where FAK is focal adhesion kinase) signaling pathway. As early as 5 min postinfection (p.i.), KSHV induced the extracellular signal-regulated kinase 1 and 2 (ERK1/2) via the PI3K-PKCzeta-MEK pathway. In addition, KSHV modulated the transcription of several host genes of primary human dermal microvascular endothelial cells (HMVEC-d) and fibroblast (HFF) cells by 2 h and 4 h p.i. Neutralization of virus entry and infection by PI-3K and other cellular tyrosine kinase inhibitors suggested a critical role for signaling molecules in KSHV infection of target cells. Here we investigated the induction of ERK1/2 by KSHV and KSHV envelope glycoproteins gB and gpK8.1A and the role of induced ERK in viral and host gene expression. Early during infection, significant ERK1/2 induction was observed even with low multiplicity of infection of live and UV-inactivated KSHV in serum-starved cells as well as in the presence of serum. Entry of UV-inactivated virus and the absence of viral gene expression suggested that ERK1/2 induction is mediated by the initial signal cascade induced by KSHV binding and entry. Purified soluble gpK8.1A induced the MEK1/2 dependent ERK1/2 but not ERK5 and p38 mitogen-activated protein kinase (MAPK) in HMVEC-d and HFF. Moderate ERK induction with soluble gB was seen only in HMVEC-d. Preincubation of gpK8.1A with heparin or anti-gpK8.1A antibodies inhibited the ERK induction. U0126, a selective inhibitor for MEK/ERK blocked the gpK8.1A- and KSHV-induced ERK activation. ERK1/2 inhibition did not block viral DNA internalization and had no significant effect on nuclear delivery of KSHV DNA during de novo infection. Analyses of viral gene expression by quantitative real-time reverse transcriptase PCR revealed that pretreatment of cells with U0126 for 1 h and during the 2-h infection with KSHV significantly inhibited the expression of ORF 73, ORF 50 (RTA), and the IE-K8 and v-IRF2 genes. However, the expression of lytic IE-K5 gene was not affected significantly. Expression of ORF 73 in BCBL-1 cells was also significantly inhibited by preincubation with U0126. Inhibition of ERK1/2 also inhibited the transcription of some of the vital host genes such as DUSP5 (dual specificity phosphatase 5), ICAM-1 (intercellular adhesion molecule 1), heparin binding epidermal growth factor, and vascular endothelial growth factor that were up-regulated early during KSHV infection. Several MAPK-regulated host transcription factors such as c-Jun, STAT1alpha, MEF2, c-Myc, ATF-2 and c-Fos were induced early during infection, and ERK inhibition significantly blocked the c-Fos, c-Jun, c-Myc, and STAT1alpha activation in the infected cells. AP1 transcription factors binding to the RTA promoter in electrophoretic mobility shift assays were readily detected in the infected cell nuclear extracts which were significantly reduced by ERK inhibition. Together, these results suggest that very early during de novo infection, KSHV induces the ERK1/2 to modulate the initiation of viral gene expression and host cell genes, which further supports our hypothesis that beside the conduit for viral DNA delivery into the cytoplasm, KSHV interactions with host cell receptor(s) create an appropriate intracellular environment facilitating infection.
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PMID:ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. 1605 24

The majority of ovarian cancer patients are treated with platinum-based chemotherapy, but the emergence of resistance to such chemotherapy severely limits its overall effectiveness. We have shown that development of resistance to this treatment can modify cell signaling responses in a model system wherein cisplatin treatment has altered cell responsiveness to ligands of the erbB receptor family. A cisplatin-resistant ovarian carcinoma cell line PE01CDDP was derived from the parent PE01 line by exposure to increasing concentrations of cisplatin, eventually obtaining a 20-fold level of resistance. Whereas PE01 cells were growth stimulated by the erbB receptor-activating ligands, such as transforming growth factor-alpha (TGFalpha), NRG1alpha, and NRG1beta, the PE01CDDP line was growth inhibited by TGFalpha and NRG1beta but unaffected by NRG1alpha. TGFalpha increased apoptosis in PE01CDDP cells but decreased apoptosis in PE01 cells. Differences in extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling were also found, which may be implicated in the altered cell response to ligands. Microarray analysis revealed 51 genes whose mRNA increased by at least 2-fold in PE01CDDP cells relative to PE01 (including FRA1, ETV4, MCM2, AXL, MT3, TRAP1, and FANCG), whereas 36 genes (including IGFBP3, TRAM1, and KRT4 and KRT19) decreased by a similar amount. Differential display reverse transcriptase-PCR identified altered mRNA expression for TCP1, SLP1, proliferating cell nuclear antigen, and ZXDA. Small interfering RNA inhibition of FRA1, TCP1, and MCM2 expression was associated with reduced growth and FRA1 inhibition with enhanced cisplatin sensitivity. Altered expression of these genes by cytotoxic exposure may provide survival advantages to cells including deregulation of signaling pathways, which may be critical in the development of drug resistance.
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PMID:Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. 1606 61

The relationship of cytokine production and reactive oxygen species (ROS) generated in mast cells has not been reported yet. This study aimed to examine the signal pathway in the production of cytokines [interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha)] by ROS generated from phorbol myristate acetate (PMA)-stimulated human mast cell line-1 cells (HMC-1). HMC-1 cells were stimulated with 25 ng/ml of PMA. The ROS generation and production of cytokines (IL-8 and TNF-alpha) were measured by fluorescence-activated cell sorter and enzyme-linked immunosorbent assay method, respectively. Phosphorylation of mitogen-activated protein kinase family (extracellular signal-regulated kinase, p38 and c-Jun N-terminal kinase) was detected by the Western blotting method. The expression of cytokine's mRNA was measured by reverse transcriptase--polymerase chain reaction, and the DNA-binding activity of the transcription factors [nuclear factor-kappaB (NF-kappaB) and activator protein-1] was detected by electrophoretic mobility shift assay. PMA-stimulated HMC-1 cells immediately generated ROS, and the generated ROS was inhibited by 1,3-dimethyl-2-thiourea (DMTU), but partially inhibited by catalase or N-acetyl-L-cysteine. The production of cytokines in PMA-stimulated HMC-1 cells reached the maximum at 3-5 h and was inhibited by DMTU and specific kinase inhibitor for p38, SB203580. DMTU and SB203580 also inhibited the expressed cytokine's mRNA level and the increased DNA-binding activity of transcription factors, NF-kappaB in PMA-stimulated HMC-1 cells. These data suggest that intracellular ROS generated from PMA-stimulated HMC-1 cells contributes to the production of inflammatory cytokines via p38 kinase/NF-kappaB.
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PMID:Signal pathway of cytokines produced by reactive oxygen species generated from phorbol myristate acetate-stimulated HMC-1 cells. 1609 Nov 23

Rituximab (chimeric anti-CD20 monoclonal antibodies) is currently being used in the treatment of B non-Hodgkin's lymphoma (NHL). We have recently reported that rituximab triggers and modifies various intracellular signaling pathways in NHL B-cell lines, resulting in reverting the chemoresistant phenotype to a sensitive phenotype. This study investigated whether rituximab also modifies intracellular signaling pathways resulting in the sensitization of NHL cells to Fas-induced apoptosis. Treatment of the Fas-resistant NHL cell lines (2F7, Ramos and Raji) with rituximab sensitized the cells to CH-11 (FasL agonist mAb)-induced apoptosis and synergy was achieved. Fas expression was upregulated by rituximab as early as 6 h post-treatment as determined by flow cytometry, reverse transcriptase-polymerase chain reaction and Western blot. Rituximab inhibited both the expression and activity of the transcription repressor Yin-Yang 1 (YY1) that negatively regulates Fas transcription. Inhibition of YY1 resulted in the upregulation of Fas expression and sensitization of the tumor cells to CH-11-induced apoptosis. The downregulation of YY1 expression was the result of rituximab-induced inhibition of both the p38 mitogen-activated protein kinase (MAPK) signaling pathway and constitutive nuclear factor kappa of B cells (NF-kappaB) activity. The involvement of NF-kappaB and YY1 in the regulation of Fas expression was corroborated by the use of Ramos cells with a dominant-active inhibitor of NF-kappaB (Ramos IkappaB-estrogen receptor (ER) mutant) and by silencing YY1 with YY1 siRNA, respectively. Further, the role of rituximab-mediated inhibition of the p38 MAPK/NF-kappaB/YY1 pathway in the regulation of Fas and sensitization to CH-11-induced apoptosis was validated by the use of specific chemical inhibitors of this pathway and which mimicked rituximab-mediated effects. These findings provide a novel mechanism of rituximab-mediated activity by sensitizing NHL cells to Fas-induced apoptosis.
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PMID:Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced apoptosis. 1610 77

Trichosanthin (TCS) is a type I ribosome-inactivating protein possessing multiple biological and pharmacological activities. One of its major actions is inhibition of human immunodeficiency virus (HIV) replication. The mechanism is still not clear. It is generally believed that this action is mediated via ribosome inactivation. Recently, we found that some TCS mutants with full ribosome inactivating activity were devoid of anti-HIV-1 effect. This suggested that there might be other mechanisms contributing to the anti-HIV-1 action. This study showed that a commonly used c-Jun N-terminal kinases inhibitor (CEP-11004) could counteract the antiviral action of TCS in C8166 cells. CEP-11004 alone had no effect on HIV-1 replication and TCS alone significantly inhibited this process. When CEP-11004 was used together with TCS, the antiviral action of TCS was much reduced. Two methods were used to assess viral replication. (1) By measuring the HIV-1 reverse transcriptase, TCS on the average reduced viral replication to 52+/-4%. With CEP-11004 pretreatment, TCS appeared to lose the HIV-1 inhibitory activity with viral replication stood at 101+/-7%. (2) By measuring HIV-1 p24, TCS reduced viral replication to 68+/-4%. With CEP-11004 pretreatment, TCS again seemed to lose its anti-HIV-1 activity with HIV-1 replication rose back to 101+/-4%. Both indexes indicated that CEP-11004 counteracted the antiviral action of TCS. Phosphorylation of JNK on the other hand was only slightly elevated by 1.5-fold by TCS and CEP-11004 inhibited this elevation. These results suggested that the anti-HIV-1 effect of TCS may be related to the MAPK signal process downstream from the point of CEP inhibition.
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PMID:An inhibitor of c-Jun N-terminal kinases (CEP-11004) counteracts the anti-HIV-1 action of trichosanthin. 1628

Telomerase is essential for immortalization of most human cancer cells. Expression of the core telomerase RNA (hTR) and reverse transcriptase (hTERT) subunits is mainly regulated by transcription. However, hTR transcriptional regulation remains poorly understood. We previously showed that the core hTR promoter is activated by Sp1 and is repressed by Sp3. Here, we show that the mitogen-activated protein kinase kinase kinase 1 (MEKK1)/c-Jun-NH(2)-kinase (JNK) pathway represses hTR expression by a mechanism that involves Sp1 and Sp3. Promoter activity was induced by the JNK inhibitor SP600125 and was repressed by activated MEKK1. Repression by MEKK1 was blocked by SP600125 or enhanced by coexpression of wild-type but not phosphoacceptor mutated JNK. SP600125 treatment also increased levels of endogenous hTR. Mutations in the hTR promoter Sp1/Sp3 binding sites attenuated SP600125-mediated promoter induction, whereas coexpression of MEKK1 with Sp3 enhanced hTR promoter repression. Chromatin immunoprecipitation showed that levels of immunoreactive Sp1 associated with the hTR promoter were low in comparison with Sp3 in control cells but increased after JNK inhibition with a reciprocal decrease in Sp3 levels. No corresponding changes in Sp1/Sp3 protein levels were detected. Thus, JNK represses hTR promoter activity and expression, apparently by enhancing repression through Sp3.
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PMID:Transcriptional repression of telomerase RNA gene expression by c-Jun-NH2-kinase and Sp1/Sp3. 1645 90


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