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 investigate the protective mechanism of FTY720 in small-for-size liver grafts, we applied a rat orthotopic liver transplantation model using 40% of liver grafts. FTY720 was administered (1 mg/kg, i.v.) at 20 min before graft harvesting in the donor, immediately before total hepatectomy and immediately after graft reperfusion in the recipient. The 7-day graft survival rates in the FTY720 group were significantly improved compared with the control group [100% (6/6) vs. 40% (4/10), p = 0.034]. FTY720 significantly reduced serum ALT and AST levels at 24 h after liver transplantation. The cell-survival Akt signaling pathway was activated in FTY720 groups by phosphorylation of Glycogen Synthase Kinase-3beta, Bad and Forkhead Transcription Factor at 6 and 24 h after liver transplantation. The cleaved-caspases 3, 7 and 9 were down-regulated, accompanied with less apoptotic nuclei after FTY720 treatment. Acute-phase inflammatory MAPK pathway was down-regulated by dephosphorylation of c-Raf, Mek and Erk in the treatment groups. A20 and endothelial nitric oxide synthase were up-regulated together with down-regulation of iNOS. Hepatic sinusoids were well preserved in the FTY720 group but disrupted in the control group. In conclusion, FTY720 attenuates small-for-size liver graft injury by activation of cell-survival Akt signaling and down-regulation of the MAPK pathway.
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PMID:Attenuation of small-for-size liver graft injury by FTY720: significance of cell-survival Akt signaling pathway. 1530 27

Tumor necrosis factor-alpha (TNFalpha) activates both cell death and cell survival pathways, which render most cancer cells resistant to its cytotoxicity. In this study, we found that pretreatment with luteolin, a plant flavonoid, greatly sensitized TNFalpha-induced apoptotic cell death in a number of human cancer cell lines; including colorectal cancer COLO205, HCT116 cells and cervical cancer HeLa cells. In the search of the molecular mechanisms responsible for the sensitization effect of luteolin, we discovered that luteolin inhibited TNFalpha-induced activation of nuclear transcription factor-kappa B (NF-kappaB), the main survival factor in TNFalpha signaling. As a result, luteolin suppressed the expression of NF-kappaB-targeted antiapoptotic genes, including A20 and cellular inhibitor of apoptosis protein-1 (c-IAP1). The role of A20 and c-IAP1 was further confirmed by ectopic expression of these two genes, which significantly protected cell death induced by luteolin followed by TNFalpha. In addition, inhibition of NF-kappaB by luteolin led to augmentation and prolongation of c-Jun N-terminal kinase (JNK) activation induced by TNFalpha. Suppression of JNK activation, either by a synthetic JNK inhibitor (SP600125) or by overexpression of the dominant negative forms of JNK kinase 1 (JNKK1) and JNK kinase 2 (JNKK2), conferred significant protection against apoptotic cell death induced by luteolin and TNFalpha, suggesting that NF-kappaB and JNK are closely associated with the sensitization effect of luteolin. Data from this study reveal a novel function of luteolin and enhance the value of luteolin as an anticancer agent.
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PMID:Luteolin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells. 1533 63

Rhotekin (RTKN), the gene coding for the Rho effector, RTKN, was shown to be overexpressed in human gastric cancer (GC). In this study, we further showed that RTKN is expressed at a low level in normal cells and is overexpressed in many cancer-derived cell lines. The function of RTKN as an effector protein in Rho GTPase-mediated pathways regulating apoptosis was investigated. By transfection and expression of RTKN in cells that expressed endogenous RTKN at a low basal level, we showed that RTKN overexpression conferred cell resistance to apoptosis induced by serum deprivation or treatment with sodium butyrate, and the increased resistance correlated to the level of RTKN. Conversely, reducing RTKN expression by small interfering RNAs greatly sensitized cells to apoptosis. The RTKN-mediated antiapoptotic effect was blocked by the nuclear factor-kappaB (NF-kappaB) inhibitors, curcumin or parthenolide, but not by the phosphatidylinositol 3'-OH-kinase inhibitor, LY294002, or the MAP kinase inhibitor, PD98059. Reporter gene assays and electrophoretic mobility shift assay confirmed that RTKN overexpression led to constitutive activation of NF-kappaB through the phosphorylation of IkappaB by IKKbeta. By using the RTKN truncation mutants, we showed that RTKN mediated Rho activity eliciting signaling pathway to activate NF-kappaB, with a concomitant induction of expression of the NF-kappaB antiapoptotic genes, cIAP-2, BCl-xL, A1, and A20. Consistent with these data, RTKN-expressing cells showed increased chemoresistance to 5-fluorouracil and paclitaxol, and the resistance was greatly attenuated by NF-kappaB inhibitor. In conclusion, overactivated Rho/RTKN/NF-kappaB signaling pathway through overexpression of RTKN may play a key role in gastric tumorigenesis by conferring cells resistance to apoptosis, and this signaling pathway may serve as an important target for novel therapeutic approaches to the treatment of human GC.
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PMID:Rho/Rhotekin-mediated NF-kappaB activation confers resistance to apoptosis. 1548 Apr 28

Hepatic ischemia-reperfusion injury is an inevitable consequence during liver surgery. The outcome is particularly poor in cirrhotic livers, which are more prone to hepatic ischemia-reperfusion injury. We aim to study whether FTY720 could attenuate hepatic ischemia-reperfusion injury both in normal and in cirrhotic livers. We applied a 70% liver-ischemia (60 min) model in rats with normal or cirrhotic livers. FTY720 was given 20 min before ischemia and 10 min before reperfusion (1 mg/kg, i.v.). Liver tissues and blood were sampled at 20 min, 60 min, 90 min, 6 h and 24 h after reperfusion for detection of MAPK-Egr-1, Akt pathways and caspase cascade. Hepatic ultrastructure and apoptosis were also compared. FTY720 significantly improved liver function in the rats with normal and cirrhotic livers. Akt pathway was activated at 6 and 24 h after reperfusion. FTY720 significantly down-regulated Egr-1, ET-1, iNOS and MIP-2 accompanied with up-regulation of A20, IL-10, HO-1 and Hsp70. MAPK (Raf-MEK-Erk) pathway was down-regulated. Hepatic ultrastructure was well maintained and fewer apoptotic liver cells were found in the FTY720 groups. In conclusion, FTY720 attenuates ischemia-reperfusion injury in both normal and cirrhotic livers by activation of cell survival Akt signaling and down-regulation of Egr-1 via Raf-MEK-Erk pathway.
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PMID:FTY720 attenuates hepatic ischemia-reperfusion injury in normal and cirrhotic livers. 2824 Aug 25

Macrophages respond to infection with pathogenic Yersinia species by activating MAPK- and NF-kappaB-signaling pathways. To counteract this response, Yersiniae secrete a protease (Yersinia outer protein J (YopJ)) that is delivered into macrophages, deactivates MAPK- and NF-kappaB-signaling pathways, and induces apoptosis. NF-kappaB promotes cell survival by up-regulating expression of several apoptosis inhibitor genes. Previous studies show that deactivation of the NF-kappaB pathway by YopJ is important for Yersinia-induced apoptosis. To determine whether deactivation of the NF-kappaB pathway is sufficient for Yersinia-induced apoptosis, two inhibitors of the NF-kappaB pathway, IkappaBalpha superrepressor or A20, were expressed in macrophages. Macrophages expressing these proteins were infected with Yersinia pseudotuberculosis strains that secrete functionally active or inactive forms of YopJ. Apoptosis levels were substantially higher (5- to 10-fold) when active YopJ was delivered into macrophages expressing IkappaBalpha superrepressor or A20, suggesting that deactivation of the NF-kappaB pathway is not sufficient for rapid Yersinia-induced apoptosis. When macrophages expressing A20 were treated with specific inhibitors of MAPKs, similar levels of apoptosis (within approximately 2-fold) were observed when active or inactive YopJ were delivered during infection. These results suggest that MAPK and NF-kappaB pathways function together to up-regulate apoptosis inhibitor gene expression in macrophages in response to Yersinia infection and that YopJ deactivates both pathways to promote rapid apoptosis. In addition, treating macrophages with a proteasome inhibitor results in higher levels of infection-induced apoptosis than can be achieved by blocking NF-kappaB function alone, suggesting that proapoptotic proteins are stabilized when proteasome function is blocked in macrophages.
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PMID:Inhibition of MAPK and NF-kappa B pathways is necessary for rapid apoptosis in macrophages infected with Yersinia. 1594

The SH2 domain-containing inositol polyphosphate 5-phosphatase (SHIP) is known to play an important role in the negative regulation by FcgammaRIIB of PI3K-dependent signaling cascades activated by the B cell antigen receptor (BCR) as well as several tyrosine-kinase coupled cytokine receptors. However, to date the role of SHIP in the regulation of PI3K-dependent signals elicited by G-protein-coupled receptors (GPCR) such as chemokine receptors has not been investigated. In this study, we report that ligation of the G-protein-coupled chemokine receptor CXCR4 by SDF-1/CXCL12 has no effect on the tyrosine phosphorylation of SHIP in the murine B cell lymphoma A20. However, co-ligation of the B cell antigen receptor and FcgammaRIIB inhibits the PI3K-dependent phosphorylation of PKB and ERK1/2 in response to CXCL12. We have also utilised a constitutively active membrane-localised SHIP mutant expressed in the Jurkat leukaemic T cell line (which do not normally express SHIP), in order to investigate the effect of this mutant on CXCL12 stimulated PI3K-dependent signaling events. Experiments have revealed that CXCL12-mediated PKB phosphorylation, chemotaxis and lipid accumulation are inhibited in the presence of this SHIP mutant. Thus, it appears that heterologous activation of SHIP by non-G-protein-coupled receptor-mediated routes can impinge on PI3K-dependent signaling pathways activated by independently ligated G-protein-coupled chemokine receptors.
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PMID:Heterologous regulation of chemokine receptor signaling by the lipid phosphatase SHIP in lymphocytes. 1603 94

Enzymes of the blood coagulation pathway enhance the inflammatory response leading to endothelial dysfunction, accounting, in part, for the vascular complications occurring in sepsis and cardiovascular disease. The responses of endothelial cell activation include induction of the expression of tissue factor (TF), a membrane glycoprotein that promotes thrombosis, and of E-selectin, a cell adhesion molecule that promotes inflammation. In this report, we demonstrate synergistic interactions between the coagulation factor Xa (fXa) and the proinflammatory cytokines TNF, IL-1beta, and CD40L, leading to enhanced expression of TF and E-selectin in endothelial cells. A detailed analysis of the molecular pathways that could account for this activity of fXa showed that fXa inhibited the cytokine-induced expression of dual specificity phosphatases, MAP kinase phosphatase-L, -4, -5, and -7, blocking a negative regulatory effect on c-Jun N-terminal kinase. The synergistic interaction between fXa and TNF was also involved in the inhibition of A20 and IkappaBalpha expression in the IkappaB kinase-NF-kappaB pathway. The data indicate that inhibition of negative regulatory signaling accounts for the amplification of cytokine-induced endothelial cell activation by fXa.
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PMID:Synergistic induction of tissue factor by coagulation factor Xa and TNF: evidence for involvement of negative regulatory signaling cascades. 1610 45

B cell maturation Ag (BCMA), a member of the TNFR superfamily expressed on B cells, binds to a proliferation-inducing ligand (APRIL) and B cell-activating factor of the TNF family (BAFF) but the specific B cell responses regulated by BCMA remain unclear. This study demonstrates that ligation of A20 B cells transfected with BCMA induces the expression of CD40, CD80/B7-1, CD86/B7-2, MHC class II, and CD54/ICAM-1, which subsequently enhances the presentation of OVA peptide Ag to DO11.10 T cells. BCMA expression in murine splenic B cells can be induced with IL-4 and IL-6, allowing subsequent treatment with APRIL or agonist anti-BCMA to similarly induce Ag presentation. A comparative analysis of hybrid receptors of TNFR2 fused to the cytoplasmic domains of APRIL/BAFF receptors found that only BCMA, but not transmembrane activator and calcium-modulator and cyclophilin ligand interactor or BAFF-R, is capable of activating Ag presentation. Although all three receptors can trigger NF-kappaB signaling, only BCMA activates the JNK pathway conferring on BCMA the specific ability to activate this Ag presentation response.
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PMID:B cell maturation antigen, the receptor for a proliferation-inducing ligand and B cell-activating factor of the TNF family, induces antigen presentation in B cells. 1611 67

Curcumin, the yellow pigment in the spice turmeric, has potent chemopreventive activities that involve diverse molecular pathways. It is widely believed that curcumin pro-apoptotic properties are mediated by downregulation of NF kappa B (NFkappaB). The p65/RelA subunit of NFkappaB may influence cell death, in part by activation of NFkappaB anti-apoptotic target genes including X-linked inhibitor of apoptosis (XIAP), A20, bcl-xL and inhibition of sustained activation of c-Jun N-terminal kinase (JNK). We have shown previously that curcumin inhibits NFkappaB, activates JNK and promotes apoptosis in HCT116 colorectal cancer cells. Here, we show that forced overexpression of p65 does not affect curcumin-induced JNK activation. Indeed, overexpression of p65 enhanced curcumin-mediated apoptosis as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay and poly(ADP-ribose) polymerase (PARP) cleavage. This potentiating effect of p65 upon curcumin-mediated apoptosis was reversed by transfection of cells with an IkappaB super-repressor (DeltaNIkappaB). Curcumin treatment inhibited expression of NFkappaB anti-apoptotic target genes in mock-transfected and in p65-overexpressing HCT116 cells, although expression levels remained higher in the latter. Taken together, these results show that curcumin-mediated activation of JNK or induction of apoptosis does not require inhibition of p65. Furthermore, curcumin/p65 synergy in promotion of apoptosis cannot be attributed to active repression of NFkappaB anti-apoptotic genes.
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PMID:Overexpression of p65/RelA potentiates curcumin-induced apoptosis in HCT116 human colon cancer cells. 1649 2

The TPL-2 MEK kinase is essential for activation of the Erk MAP kinase pathway during innate immune responses. TPL-2 is found in complex with ABIN-2 (A20-binding inhibitor of NF-kappaB 2). Here, using antigen-presenting cells from ABIN-2-deficient mice, we show that ABIN-2 was required for optimal activation of Erk induced by receptors that signal via TPL-2, including Toll-like receptor 4 and tumor necrosis factor receptor 1 in macrophages, and CD40 in B cells. ABIN-2 was necessary for the maintenance of TPL-2 protein stability. In contrast, ABIN-2 deficiency did not affect agonist-induced regulation of transcription factor NF-kappaB. Stimulation of ABIN-2-deficient macrophages via Toll-like receptor 4 showed that different thresholds of Erk signaling were required for optimal induction of tumor necrosis factor and interleukin 1beta. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.
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PMID:ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses. 1663 45


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