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)

X-linked inhibitor of apoptosis protein (XIAP) is a potent suppressor of apoptotic cell death, which functions by directly inhibiting caspases, the principal effectors of apoptosis. Here we report that XIAP can also function as a cofactor in the regulation of gene expression by transforming growth factor-beta (TGF-beta). XIAP, but not the related proteins c-IAP1 or c-IAP2, associated with several members of the type I class of the TGF-beta receptor superfamily and potentiated TGF-beta-induced signaling. Although XIAP-mediated activation of c-Jun N-terminal kinase and nuclear factor kappa B was found to require the TGF-beta signaling intermediate Smad4, the ability of XIAP to suppress apoptosis was found to be Smad4-independent. These data implicate a role for XIAP in TGF-beta-mediated signaling that is distinct from its anti-apoptotic functions.
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PMID:X-linked inhibitor of apoptosis protein functions as a cofactor in transforming growth factor-beta signaling. 1135 28

TNF-alpha transduces signals of survival or death via its two receptors, R1/p55/p60 and RII/p80/p75. The role of caspases as effectors of cell death is universally accepted, although caspase inhibitors may potentiate TNF cytotoxicity in some instances. In conditions when macromolecular synthesis is blocked, caspases are part of the machinery that executes TNF-triggered apoptotic death in U937, a human myelomonocyte cell line, and in the Jurkat T cell line. However, inhibition of p38 mitogen-activated protein kinase (p38 MAPK) triggered TNF cytotoxicity in U937 cells and murine splenic macrophages, but not the Jurkat cell line. TNF induced expression of the antiapoptotic protein c-IAP2 (cytoplasmic inhibitor of apoptosis protein 2), and was blocked in the presence of a p38 MAPK inhibitor, which also induced caspase-dependent, TNF-mediated apoptosis in U937 cells. Thus, inhibition of p38 MAPK resulted in the activation of caspase 9 and cleavage of the adaptor molecule BH3 interacting domain death agonist, and blocked NF-kappaB-mediated transactivation, without affecting the nuclear translocation of NF-kappaB. Collectively, these data show that activation of p38 MAPK is critical to cell survival by TNF in U937 cells, and demonstrate lineage-specific regulation of TNF-triggered signals of activation or apoptosis.
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PMID:Inhibition of p38 kinase reveals a TNF-alpha-mediated, caspase-dependent, apoptotic death pathway in a human myelomonocyte cell line. 1135 9

The single layer of epithelial cells lining the intestine that serves as an important physical and functional barrier regulating the uptake of nutrients and the exclusion of various environmental antigens is disrupted in inflammatory bowel diseases. A central cytokine in the pathogenesis of inflammatory bowel disease is tumor necrosis factor (TNF), which increases apoptosis in a number of cell types. However, details determining the fate of intestinal cells exposed to high levels of TNF are lacking. Our laboratory reported that kinase suppressor of Ras (KSR) regulates TNF activation of the Raf/mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase/ERK signaling cassette by threonine phosphorylation of Raf-1, regulating proliferation and differentiation pathways. In the present study, we expressed a dominant-negative kinase-inactive KSR and determined the survival of young adult mouse colon cells exposed to TNF. Our data show that inhibition of KSR signaling decreases survival and increases apoptosis of TNF-treated cells. Antiapoptotic pathways including nuclear factor kappa B activation and one of its transcriptional targets, cIAP2 (c inhibitor of apoptosis protein 2) gene expression, and ERK/MAP kinase activation are all inhibited in TNF-treated kinase-inactive KSR-expressing young adult mouse colon cells. These antiapoptotic pathways are also inhibited by antisense-mediated down-regulation of KSR. However, TNF activation of p38 or stress-activated protein kinase/c-Jun NH(2)-terminal kinase is not inhibited by disruption of KSR signaling. Furthermore, inhibitors of both ERK and nuclear factor kappa B activation synergistically enhance apoptosis of cells treated with TNF. These findings demonstrate that KSR plays a novel regulatory role in intestinal epithelial cells exposed to TNF by activating cell survival pathways.
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PMID:Kinase suppressor of Ras determines survival of intestinal epithelial cells exposed to tumor necrosis factor. 1175 83

We have shown that carbon monoxide (CO) generated by heme oxygenase-1 (HO-1) protects endothelial cells (EC) from tumor necrosis alpha (TNF-alpha)-mediated apoptosis. This effect relies on the activation of p38 MAPK. We now demonstrate that HO-1/CO requires the activation of the transcription factor NF-kappaB to exert this anti-apoptotic effect. Our data suggest that EC have basal levels of NF-kappaB activity that sustain the expression of NF-kappaB-dependent anti-apoptotic genes required to support the anti-apoptotic effect of HO-1/CO. Over-expression of the inhibitor of NF-kappaB alpha (IkappaBalpha) suppresses the anti-apoptotic action of HO-1/CO. Reconstitution of NF-kappaB activity, by co-expression of IkappaBalpha with different members of the NF-kappaB family, i.e. p65/RelA or p65/RelA plus c-Rel, restores the anti-apoptotic effect of HO-1/CO. Expression of the NF-kappaB family members p65/RelA or p65/RelA with p50 or c-Rel up-regulates the expression of the anti-apoptotic genes A1, A20, c-IAP2, and manganese superoxide dismutase (MnSOD). Inhibition of NF-kappaB activity by over-expression of IkappaBalpha suppresses the expression of some of these anti-apoptotic genes, i.e. c-IAP2. Under inhibition of NF-kappaB, co-expression of some of these anti-apoptotic genes, i.e. c-IAP2 and A1, restores the anti-apoptotic action of HO-1/CO, whereas expression of A20 or MnSOD cannot. The ability of c-IAP2 and/or A1 to restore the anti-apoptotic action of HO-1/CO is abolished when p38 MAPK activation is blocked by over-expression of a p38 MAPK dominant negative mutant. In conclusion, we demonstrate that HO-1/CO cooperates with NF-kappaB-dependent anti-apoptotic genes, i.e. c-IAP2 and A1, to protect EC from TNF-alpha-mediated apoptosis. This effect is dependent on the ability of HO-1/CO to activate the p38 MAPK signal transduction pathway.
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PMID:Heme oxygenase-1-derived carbon monoxide requires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosis factor-alpha-mediated apoptosis. 1188 Mar 64

Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory mediator that exerts its biological functions by binding two TNF receptors (TNF-RI and TNF-RII), which initiate biological responses by interacting with adaptor and signalling proteins. Among the signalling components that associate with TNF receptors are members of the TNF-R-associated factor (TRAF) family. TRAF2 is required for TNF-alpha-mediated activation of c-Jun N-terminal kinase (JNK), contributes to activation of NF-kappaB, and mediates anti-apoptotic signals,. TNF-RI and TNF-RII signalling complexes also contain the anti-apoptotic ('inhibitor of apoptosis') molecules c-IAP1 and c-IAP2 (refs 5, 6), which also have RING domain-dependent ubiquitin protein ligase (E3) activity. The function of IAPs in TNF-R signalling is unknown. Here we show that binding of TNF-alpha to TNF-RII induces ubiquitination and proteasomal degradation of TRAF2. Although c-IAP1 bound TRAF2 and TRAF1 in vitro, it ubiquitinated only TRAF2. Expression of wild-type c-IAP1, but not an E3-defective mutant, resulted in TRAF2 ubiquitination and degradation. Moreover, E3-defective c-IAP1 prevented TNF-alpha-induced TRAF2 degradation and inhibited apoptosis. These findings identify a physiologic role for c-IAP1 and define a mechanism by which TNF-RII-regulated ubiquitin protein ligase activity can potentiate TNF-induced apoptosis.
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PMID:TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. 1190 83

We recently identified TL1A, an endothelium-derived T cell costimulator and a ligand for tumor necrosis factor receptor superfamily members DR3 and decoy receptor 3. To elucidate the signaling events triggered by TL1A-DR3 interaction and to understand the molecular mechanisms regulating DR3-mediated apoptosis, we have studied the effect of TL1A and an agonistic DR3 monoclonal antibody in human erythroleukemic TF-1 cells, which express DR3 endogenously. TL1A induced the formation of a DR3 signaling complex containing TRADD, TRAF2, and RIP and activated the NF-kappaB and the ERK, JNK, and p38 mitogen-activated protein kinase pathways. However, TL1A or an agonistic DR3 monoclonal antibody did not induce apoptosis in these cells nor were there detectable levels of FADD or procaspase-8 seen in the signaling complex. Interestingly, DR3-mediated apoptosis was induced in TF-1 cells in the presence of a NF-kappaB pathway-specific inhibitor but not in the presence of mitogen-activated protein kinase inhibitors, either alone or in combination, suggesting that DR3-induced NF-kappaB activation was responsible for resistance to apoptosis in these cells. Consistent with this, we found that TL1A significantly increased the production of c-IAP2, a known NF-kappaB-dependent anti-apoptotic protein, and that the NF-kappaB inhibitor or cycloheximide prevented its synthesis. Furthermore, inhibition of c-IAP2 production by RNA interference significantly sensitized TF-1 cells to TL1A-induced apoptosis. Our study identifies a molecular mechanism by which TL1A and DR3 regulate cell fate in TF-1 cells.
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PMID:TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells. 1288 79

Bcr-Abl tyrosine kinase, a chimeric oncoprotein responsible for chronic myelogenous leukemia, constitutively activates several signal transduction pathways that stimulate cell proliferation and prevent apoptosis in hematopoietic cells. The antiapoptotic function of Bcr-Abl is necessary for hematopoietic transformation, and also contributes to leukemogenesis. Herein, we show for the first time that cell transformation induced by Bcr-Abl leads to increased expression and kinase activity of MEK kinase 1 (MEKK1), which acts upstream of the c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK) and NF-kappaB signaling pathways. Inhibition of MEKK1 activity using a dominant-negative MEKK1 mutant (MEKK1km) diminished the ability of Bcr-Abl to protect cells from genotoxin-induced apoptosis, but had no effect on the proliferation of Bcr-Abl-transformed cells. Expression of MEKK1km also reduced NF-kappaB activation, and inhibited antiapoptotic c-IAP1 and c-IAP2 mRNA expression in response to the genotoxin. By contrast, neither JNK nor ERK activation was affected. These results indicate that MEKK1 is a downstream target of Bcr-Abl, and that the antiapoptotic effect of Bcr-Abl in chronic myelogenous leukemia cells is mediated via the MEKK1-NF-kappaB pathway.
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PMID:MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-kappaB activation. 1458 3

Both heme oxygenase-1 (HO-1) and p21(WAF1/Cip1) (p21) are involved in the pathogenesis of human cancer and their functions are closely associated with apoptosis. However, how these two molecules regulate apoptosis in human gastric cancer is unknown. In this study, we studied how HO-1 and p21 were regulated in two gastric cancer cell lines, MKN-45 with wild p53 and MKN-28 with mutant p53. The cells were treated with hemin and cadmium to induce HO-1. The result showed that HO-1 protein was significantly induced by hemin and cadmium in both cells tested. Following the HO-1 expression, p21 level was also markedly induced. The cells with increased HO-1 and p21 showed obviously resistantance to apoptotic stimuli. The levels of HO-1 and p21 induced were significantly inhibited by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) and extracellular-regulated kinase (ERK) inhibitor (PD098059). Parallel to decreased HO-1 and p21 expression, the kinase inhibitors also significantly attenuated the resistance of the cells to apoptosis. The elevated HO-1 and p21 was further found to be associated with increase activity of the nuclear NF-kappaB and the inhibition of NF-kappaB led to the block of their induction. The elevated HO-1 and p21 were also demonstrated to be related to increased cellular inhibitor of caspase inbitory protein-2 (c-IAP2) and decreased caspapse-3 activity. It was noted that the above changes observed were not different between MKN-45 and MKN-28 cells, suggesting the functions of HO-1 and p21 were irrespective of the status of p53. In conclusion, we demonstrate that the resistance to apoptosis in gastric cancer cells with elevated HO-1 and p21 is independent of p53 status in a p38 MAPK- and ERK-mediated pathway with elevated c-IAP2 and decreased caspase-3 activity and that this pathway is sensitive to the inhibition of NF-kappaB.
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PMID:Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells. 1464 39

Among other cellular responses, tumor necrosis factor (TNF) induces different forms of cell death and the activation of the p38 mitogen-activated protein kinase (MAPK). The influence of p38 MAPK activation on TNF-induced apoptosis or necrosis is controversially discussed. Here, we demonstrate that pharmacological inhibition of p38 MAPK enhances TNF-induced cell death in murine fibroblast cell lines L929 and NIH3T3. Furthermore, overexpression of dominant-negative versions of p38 MAPK or its upstream kinase MKK6 led to increased cell death in L929 cells. While overexpression of the p38 isoforms alpha and beta did not protect L929 cells from TNF-induced toxicity, overexpression of constitutively active MKK6 decreased TNF-induced cell death. Although the used inhibitors of p38 MAPK decreased the phosphorylation of the survival kinase PKB/Akt, this effect could be ruled out as cause of the observed sensitization to TNF-induced cytotoxicity. Finally, we demonstrate that the nuclear factor kappaB (NF-kappaB)-dependent gene expression, shown as an example for the anti-apoptotic gene cellular inhibitor of apoptosis (c-IAP2), was reduced by p38 MAPK inhibition. In consequence, we found that inhibition of p38 MAPK led to the activation of the executioner caspase-3.
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PMID:Inhibition of p38 mitogen-activated protein kinase reduces TNF-induced activation of NF-kappaB, elicits caspase activity, and enhances cytotoxicity. 1472 57

We recently reported that cAMP suppresses apoptosis in colon cancer cells and induces cellular inhibitor of apoptosis protein-2 (c-IAP2) via a cAMP-responsive element (CRE), suggesting a mechanism for chemoprevention of colon cancer by non-steroidal anti-inflammatory drugs. In this study, we used T84 human colon cancer cells to define the pathway by which increases in cAMP induce c-IAP2 expression. Treatment with several different cAMP agonists stimulated phosphorylation of CRE-binding protein (CREB) and activated expression of c-IAP2 in a CREB-dependent manner. Studies with pharmacological inhibitors revealed that cAMP-dependent phosphorylation of CREB required activation of ERK1/2 and p38 MAPK but was largely independent of protein kinase A. Immunoblots and transcriptional reporter assays using specific inhibitors, as well as expression of constitutively active forms of MEK1 and MKK3, showed that c-IAP2 induction by cAMP is regulated predominantly through ERK1/2 and p38 MAPK and suggested involvement of p90 ribosomal protein S6 kinase and mitogen and stress response kinase-1 as well. Consistent with those results, we found that cAMP-dependent suppression of apoptosis was blocked by treatment with inhibitors of ERK1/2 and p38 MAPK. We conclude that cAMP can induce c-IAP2 expression in colon cancer cells through CREB phosphorylation and CRE-dependent transcription in a manner that involves activation of ERK1/2 and p38 MAPK. These results emphasize that activation of kinases other than protein kinase A can mediate the actions of agents that increase cAMP, particularly in the regulation of CREB-dependent events.
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PMID:Cyclic AMP promotes cAMP-responsive element-binding protein-dependent induction of cellular inhibitor of apoptosis protein-2 and suppresses apoptosis of colon cancer cells through ERK1/2 and p38 MAPK. 1507 90


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