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)

Human and rat primary sub-cultured vascular smooth muscle cells (VSMCs) showed clear expression of the death receptors TRAIL-R1 and TRAIL-R2; however, recombinant soluble TRAIL did not induce cell death when added to these cells. TRAIL tended to protect rat VSMCs from apoptosis induced either by inflammatory cytokines tumor necrosis factor-alpha + interleukin-1beta + interferon-gamma or by prolonged serum withdrawal, and promoted a significant increase in VSMC proliferation and migration. Of note, all the biological effects induced by TRAIL were significantly inhibited by pharmacological inhibitors of the ERK pathway. Western blot analysis consistently showed that TRAIL induced a significant activation of ERK1/2, and a much weaker phosphorylation of Akt, while it did not affect the p38/MAPK pathway. Taken together, these data strengthen the notion that the TRAIL/TRAIL-R system likely plays a role in the biology of the vascular system by affecting the survival, migration and proliferation of VSMCs.
 ...
PMID:TRAIL promotes the survival, migration and proliferation of vascular smooth muscle cells. 1528 37

RAS oncogenes play a major role in cancer development by activating an array of signaling pathways, most notably mitogen-activated protein kinases, resulting in aberrant proliferation and inhibition of apoptotic signaling cascades, rendering transformed cells resistant to extrinsic death stimuli. However, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill specific tumor cells through the engagement of its receptors, death receptor 4 (DR4) and death receptor 5 (DR5), and the activation of apoptotic pathways, providing promising targets for anticancer therapies. In this study, we show that TRAIL induces cell death in human colon adenocarcinoma cells in a MEK-dependent manner. We also report a prolonged MEK-dependent activation of ERK1/2 and increased c-FOS expression induced by TRAIL in this system. Our study reveals that transformation of the colon cell line Caco-2 by Ki- and mainly by Ha-ras oncogenes sensitizes these cells to TRAIL-induced apoptosis by causing specific MEK-dependent up-regulation of DR4 and DR5. These observations taken together reveal that RAS-MEK-ERK1/2 signaling pathway can sensitize cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5 and overall imply that TRAIL-based therapeutic strategies using TRAIL agonists could be used in cases of human colon cancers bearing RAS mutations.
 ...
PMID:Transformation by oncogenic RAS sensitizes human colon cells to TRAIL-induced apoptosis by up-regulating death receptor 4 and death receptor 5 through a MEK-dependent pathway. 1575 91

The pathway of interferon gamma (IFN-gamma-induced suppression in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated endothelial cell apoptosis was investigated. rTRAIL triggered apoptosis of human umbilical vein endothelial cells (HUVECs) in a type II cell death manner. IFN-gamma pretreatment significantly suppressed the expression of death receptor 4 (DR4) and DR5 on HUVECs, and inhibited apoptosis in response to TRAIL. IFN-gamma rapidly phosphorylated signal transducers and activators of transcription 1 (STAT1) and STAT6 but did not enhance phosphorylation of STAT3, Akt and extracellular signal-regulated kinase (ERK) and nuclear translocation of NF-kappaB p65. Janus kinase (JAK)-induced phosphorylation of STAT1/6 appeared to be crucial since chemical inhibition of JAK abolished phosphorylation of STAT1/6, down-regulation of DR4/DR5 expression and IFN-gamma-induced inhibition of TRAIL-mediated apoptosis. IFN-gamma/JAK/STAT-induced suppression was regulated by cycloheximide (CHX)-sensitive mechanism since the use of CHX mimicked the action of chemical inhibition of JAK in regard to DR4/DR5 expression as well as TRAIL-mediated endothelial cell apoptosis. We have not yet clarified precise mechanism, however, the present data provide a novel finding that IFN-gamma/JAK/STAT pathway elicits inhibition of TRAIL-mediated endothelial cell apoptosis through CHX-sensitive suppression of DR4/DR5.
 ...
PMID:IFN-gamma/JAK/STAT pathway-induced inhibition of DR4 and DR5 expression on endothelial cells is cancelled by cycloheximide-sensitive mechanism: novel finding of cycloheximide-regulating death receptor expression. 1580 6

Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) mainly activates programmed cell death through caspases. By contrast, TNF primarily induces gene transcription through the inhibitor of kappaB kinase (IKK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. Apo2L/TRAIL also can stimulate these kinases, albeit less strongly; however, the underlying mechanisms of this stimulation and its relation to apoptosis are not well understood. Here we show that Apo2L/TRAIL activates kinase pathways by promoting the association of a secondary signaling complex, subsequent to assembly of a primary, death-inducing signaling complex (DISC). The secondary complex retained the DISC components FADD and caspase-8, but recruited several factors involved in kinase activation by TNF, namely, RIP1, TRAF2, and NEMO/IKKgamma. Secondary complex formation required Fas-associated death domain (FADD), as well as caspase-8 activity. Apo2L/TRAIL stimulation of JNK and p38 further depended on RIP1 and TRAF2, whereas IKK activation required NEMO. Apo2L/TRAIL induced secretion of interleukin-8 and monocyte chemoattractant protein-1, augmenting macrophage migration. Thus, Apo2L/TRAIL and TNF organize common molecular determinants in distinct signaling complexes to stimulate similar kinase pathways. One function of kinase stimulation by Apo2L/TRAIL may be to promote phagocytic engulfment of apoptotic cells.
 ...
PMID:Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand. 1622 29

The mammalian extrinsic apoptosis pathway is triggered by Fas ligand (FasL) and Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL). Ligand binding to cognate receptors activates initiator caspases directly in a death-inducing signaling complex. In Drosophila, TNF ligand binding activates initiator caspases indirectly, through JNK. We characterized the extrinsic pathway in zebrafish to determine how it operates in a nonmammalian vertebrate. We identified homologs of FasL and Apo2L/TRAIL, their receptors, and other components of the cell death machinery. Studies with three Apo2L/TRAIL homologs demonstrated that they bind the receptors zHDR (previously linked to hematopoiesis) and ovarian TNFR (zOTR). Ectopic expression of these ligands during embryogenesis induced apoptosis in erythroblasts and notochord cells. Inhibition of zHDR, zOTR, the adaptor zFADD, or caspase-8-like proteases blocked ligand-induced apoptosis, as did antiapoptotic Bcl-2 family members. Thus, the extrinsic apoptosis pathway in zebrafish closely resembles its mammalian counterpart and cooperates with the intrinsic pathway to trigger tissue-specific apoptosis during embryogenesis in response to ectopic Apo2L/TRAIL expression.
 ...
PMID:Delineation of the cell-extrinsic apoptosis pathway in the zebrafish. 1688 47

AP-1/cJun, NF-kappaB and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-kappaB and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio- and chemotherapy. In the present study, we observed strong effects of sodium arsenite treatment on upregulation of TRAIL-mediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-kappaB by sodium arsenite resulted in upregulation of the endogenous TRAIL and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAIL-induced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via downregulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anticancer treatment.
 ...
PMID:Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression. 1707 May 20

Mutations in p53 are the most common genetic abnormality in cancers. Arsenic trioxide (ATO) is an effective chemotherapeutic agent for the treatment of acute promyelocytic leukemia (APL) and is being tested in phase II studies in various types of cancers. We have shown that ATO is a potent inducer of apoptosis in multiple myeloma cells, engaging primarily the intrinsic apoptotic pathway in cells expressing w.t. p53 and the extrinsic apoptotic pathway in cells expressing mutant p53. To further establish the differential apoptotic signals of ATO in relation to p53 functional status we studied the activation of the intrinsic and the extrinsic apoptotic pathways in IM9 myeloma cells expressing w.t. p53 following silencing of p53 and p21 with the corresponding SiRNAs-GFP constructs. In untransfected cells or in cells transfected with GFP-empty vector construct we observed weak apoptosis concomitant with mild depolarization of mitochondrial membrane, depletion of reduced glutathione and release of cytochrome c. Following silencing of p53 or p21 we observed extensive apoptosis concomitant with extensive depolarization of mitochondrial membrane and depletion of reduced glutathione. We also observed in these cells activation of the extrinsic apoptotic pathway through upregulation of APO2/TRAIL and APO2/TRAIL-R2, activation of caspase 8, degradation of FLIP-L and release of apoptosis inducing factors from mitochondria, instead of cytochrome c. In addition, we observed marked activation of the MAP kinase pathway and dephosphorylation of Akt in p53 or p21 silenced cells. Hence, silencing of p53 or p21 in IM9 myeloma cells results in diversion of apoptosis to the extrinsic pathway and sensitization of myeloma cells to ATO.
 ...
PMID:Arsenic trioxide induces p53-dependent apoptotic signals in myeloma cells with SiRNA-silenced p53: MAP kinase pathway is preferentially activated in cells expressing inactivated p53. 1733 40

The TNF-related apoptosis-inducing ligand, TRAIL, has been shown to selectively kill tumour cells. This property has made TRAIL and agonistic antibodies against its death inducing receptors (TRAIL-R1 and TRAIL-R2) to some of the most promising novel biotherapeutic agents for cancer therapy. Here we review the signalling pathways initiated by the apoptosis- as well as the non-apoptosis-inducing receptors, TRAIL-R3 and TRAIL-R4. The TRAIL "death-inducing signalling complex" (DISC) transmits the apoptotic signal. DISC formation leads to activation of a protease cascade, finally resulting in cell death. The TRAIL death receptor-mediated "extrinsic" pathway and the "intrinsic" pathway, which is controlled by the interaction of members of the Bcl-2 family, interact with each other in the decision about life or death of a cell. Apoptotic and non-apoptotic signalling is influenced by the NF-kappaB, PKB/Akt and the MAPK signalling pathways. In this review we intend to summarise the most important findings on the TRAIL signalling network and the interplay in the decisions between life and death of a tumor cell.
 ...
PMID:TRAIL signalling: decisions between life and death. 1740 12

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) mRNA was induced preferentially by interferon (IFN)-beta but not IFN-alpha in human fibrosarcoma and primary fibroblast cells. To characterize the signaling components mediating the IFN subtype-specific induction of this gene, we used mutant cell lines lacking individual components involved in signaling by type I IFNs. TRAIL was not induced by IFN-beta in mutant cell lines U2A, U3A, U4A, U5A, and U6A, which lack, respectively, IFN regulatory factor-9 (IRF-9), Stat1, Jak1, IFNAR-2.2, and Stat2, indicating transcription factor IFN-stimulated gene factor 3 (ISGF3) was essential for the induction of this gene. TRAIL was not induced by IFN-beta in U1A (Tyk2 null) or U1A.R930 cells (that express a kinase-deficient point mutant of Tyk2) but was induced in U1A.wt-5 cells (U1A cells expressing wild-type Tyk2), indicating that Tyk2 protein and kinase activity were both required for induction of the gene. Biochemical and genetic analyses revealed the requirement of transcription factor NF-kappa B and phosphoinositide 3-kinase (PI3K) but not extracellular signal-regulated kinase (ERK) for the induction of TRAIL by IFN-beta. Furthermore, the antiproliferative but not antiviral effects of IFN-beta required catalytically active Tyk2, suggesting that expression of genes, such as TRAIL, may play an important role in mediating the biologic effects of IFNs.
 ...
PMID:Requirement of catalytically active Tyk2 and accessory signals for the induction of TRAIL mRNA by IFN-beta. 1789 98

Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-kappaB that control the expression of antiapoptotic genes, including cFLIP and Bcl-xL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-kappaB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while gamma-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by gamma-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.
 ...
PMID:Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression. 1822 23


<< Previous 1 2 3 4 5 Next >>