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)

Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3- induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.
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PMID:Mitogen-activated protein kinase kinase antagonized fas-associated death domain protein-mediated apoptosis by induced FLICE-inhibitory protein expression. 981 57

We have previously reported on the death effector domain containing E8 gene product from equine herpesvirus-2, designated FLICE inhibitory protein (v-FLIP), and on its cellular homologue, c-FLIP, which inhibit the activation of caspase-8 by death receptors. Here we report on the structure and function of the E10 gene product of equine herpesvirus-2, designated v-CARMEN, and on its cellular homologue, c-CARMEN, which contain a caspase-recruiting domain (CARD) motif. c-CARMEN is highly homologous to the viral protein in its N-terminal CARD motif but differs in its C-terminal extension. v-CARMEN and c-CARMEN interact directly in a CARD-dependent manner yet reveal different binding specificities toward members of the tumor necrosis factor receptor-associated factor (TRAF) family. v-CARMEN binds to TRAF6 and weakly to TRAF3 and, upon overexpression, potently induces the c-Jun N-terminal kinase (JNK), p38, and nuclear factor (NF)-kappaB transcriptional pathways. c-CARMEN or truncated versions thereof do not appear to induce JNK and NF-kappaB activation by themselves, nor do they affect the JNK and NF-kappaB activating potential of v-CARMEN. Thus, in contrast to the cellular homologue, v-CARMEN may have additional properties in its unique C terminus that allow for an autonomous activator effect on NF-kappaB and JNK. Through activation of NF-kappaB, v-CARMEN may regulate the expression of the cellular and viral genes important for viral replication.
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PMID:Equine herpesvirus-2 E10 gene product, but not its cellular homologue, activates NF-kappaB transcription factor and c-Jun N-terminal kinase. 1018 71

We isolated and identified an endogenous 24-kDa human basement membrane-derived inhibitor of angiogenesis and tumor growth, termed canstatin. Canstatin, a fragment of the alpha2 chain of type IV collagen, was produced as a recombinant molecule in Escherichia coli and 293 embryonic kidneys cells. Canstatin significantly inhibited human endothelial cell migration and murine endothelial cell tube formation. Additionally, canstatin potently inhibited 10% fetal bovine serum-stimulated endothelial cell proliferation and induced apoptosis, with no inhibition of proliferation or apoptosis observed on non-endothelial cells. Inhibition of endothelial proliferation was not concomitant with a change in extracellular signal-regulated kinase activation. We demonstrate that apoptosis induced by canstatin was associated with a down-regulation of the anti-apoptotic protein, FLIP. Canstatin also suppressed in vivo growth of large and small size tumors in two human xenograft mouse models with histology revealing decreased CD31-positive vasculature. Collectively, these results suggest that canstatin is a powerful therapeutic molecule for suppressing angiogenesis.
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PMID:Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. 1062 65

Casper (c-FLIP) associates with FADD and caspase-8 in signaling complexes downstream of death receptors like Fas. We generated Casper-deficient mice and cells and noted a duality in the physiological functions of this molecule. casper-/- embryos do not survive past day 10.5 of embryogenesis and exhibit impaired heart development. This phenotype is reminiscent of that reported for FADD-/- and caspase-8-/- embryos. However, unlike FADD-/- and caspase-8-/- cells, casper-/- embryonic fibroblasts are highly sensitive to FasL- or TNF-induced apoptosis and show rapid induction of caspase activities. NF-kappaB and JNK/SAPK activation is intact in TNF-stimulated casper-/- cells. These results suggest that Casper has two distinct roles: to cooperate with FADD and caspase-8 during embryonic development and to mediate cytoprotection against death factor-induced apoptosis.
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PMID:Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. 1089 63

In this study, quiescent bone marrow-derived CD34+ erythroid burst-forming units (BFU-E) were found to be resistant to the inhibitory effects of tumour necrosis factor (TNF)-alpha and -beta as well as interferon (IFN)-alpha, -beta and -gamma, in contrast to those stimulated by a combination of erytrhropoietin (Epo) plus kit ligand (KL). Unexpectedly, we found that TNF-alpha also inhibited the apoptosis of quiescent normal human CD34+ BFU-E cells. Accordingly, TNF-alpha added to CD34+ cells cultured for 2 d in serum-free medium protected clonogeneic BFU-E from undergoing serum deprivation-mediated apoptosis. Furthermore, the prosurvival effect of TNF-alpha in quiescent CD34+ cells was consistent with its ability to induce phosphorylation of mitogen-activated protein kinase (MAPK) p42/44. However, when added to CD34+ cells that were stimulated by Epo + KL, TNF-alpha induced apoptosis and inhibited proliferation of BFU-E. To explain this intriguing differential sensitivity between unstimulated CD34+ cells versus those stimulated by Epo + KL, we examined the expression of apoptosis-regulating genes (FLIP, BCL-2, BCL-XL, BAD and BAX) in these cells. Of all the genes tested, FLIP became rapidly downregulated in CD34+ cells 24 h after stimulation with Epo + KL, suggesting that it may protect quiescent CD34+ BFU-E progenitors residing in the bone marrow from the inhibitory effects of inflammatory cytokines. Thus, we hypothesize that cycling cells may become more sensitive to proapoptotic stimuli (e.g. chemotherapy, inhibitory cytokines) than quiescent ones because of the downregulation of protective FLIP.
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PMID:Quiescent CD34+ early erythroid progenitors are resistant to several erythropoietic 'inhibitory' cytokines; role of FLIP. 1451 Sep 60

Since Fas-induced apoptosis is major pathway to eliminate unwanted or uncontrolled cells, many types of human cancer cells develop tactful mechanisms to get resistance against the apoptosis. One of the resistant mechanisms in human cancer is overexpression of FLICE-inhibitory protein (c-FLIP), human homolog of viral protein v-FLIP. c-FLIP has multiple splice variants at transcriptional level or two isoforms at protein level, a long (c-FLIP(L)) and a short form of c-FLIP (c-FLIP(S)). However, functional differences between these variants are not fully understood. In this study, we show that c-FLIP(L) but not c-FLIP(S) physically binds to Daxx through interaction between C-terminal domain of c-FLIP(L) and Fas-binding domain of Daxx, an alternative Fas signaling adaptor. Fas-induced cell death and JNK activation are sensitive to Fas stimulation in cell lines carrying undetectable level of c-FLIP(L). To support this, overexpression of c-FLIP(L) but not of c-FLIP(S) renders the cells resistant to Fas-induced cell death and to JNK activation. In signaling context, the interaction of c-FLIP(L) with Daxx is likely to inhibit JNK activation by preventing the normal interaction of Daxx and Fas, which is known to lead to apoptosis via JNK activation. This study implies that through this new mechanism, c-FLIP(L), acting at both FADD- and Daxx-mediated signaling pathways, may be involved in complete inhibition of Fas-induced cell death and may provide an answer to why c-FLIP(L) is more abundant and effective than c-FLIP(S).
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PMID:Long form of cellular FLICE-inhibitory protein interacts with Daxx and prevents Fas-induced JNK activation. 1463 55

GnRH agonist therapy is known to reduce uterine leiomyoma volume, although the molecular mechanisms responsible for this effect remain poorly understood. In this study, we have investigated the molecular mechanisms involved in the anti-proliferative effect of a GnRH agonist, leuprolide acetate (LA), in uterine leiomyomas obtained from six patients treated with LA for 3 months before surgery (group B), compared with tumours from six untreated patients (group A). To this end, we have evaluated the expression and the activity of molecules involved in the regulation of cell survival and proliferation. In group B, the total activity of PI3K was reduced by 60% compared with control samples. Furthermore, LA caused a reduction of PKB activation of approximately 50%, measured as serine 473 phosphorylation. In parallel with PKB reduction in LA samples, we observed a 60% reduction in the phosphorylation of its substrate BAD. While Bcl-xL/BAD association was not significantly modified in LA-treated leiomyomas, BAD/14.3.3 interaction was reduced, due to a 50% decreased 14.3.3 expression. In addition, LA was able to reduce the expression of the antiapoptotic proteins FLIP and PED/PEA15 by 70 and 50% respectively, compared with control samples. We next evaluated the activation of MAP kinases in leiomyomas. Activation of p42 and p44 MAP kinase isoforms was increased by 30% in group B. However, the phosphorylation of the transcription factor Elk1 was not increased in a similar fashion in LA-treated leiomyomas compared with group A. Thus, these data suggest that LA reduction of leiomyoma volume is mediated at least in part by a decreased activation of the PI3K/PKB survival pathway and by the suppression of antiapoptotic factors.
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PMID:Molecular mechanisms involved in GnRH analogue-related apoptosis for uterine leiomyomas. 1466 5

It is widely known that death receptor Fas-dependent apoptotic signals are associated with development of prostate cancer, but the key pathways involved in sensitivity to the apoptosis remain unclear. Here we investigated the molecular mechanism by which 2-methoxyestradiol (2-ME) effectively sensitizes a human prostate cancer cell line, PC3, to Fas-mediated apoptosis. 2-ME significantly inhibited nuclear factor-kappaB (NF-kappaB) activation and downregulated Fas-associated death domain (FADD) protein interluekin-1beta-converting enzyme inhibitory protein (FLIP). Overexpression of the dominant negative mutant form of IkappaBalpha (d/n IkappaBalpha) or treatment with Ikappa kinase-specific inhibitor Bay117082 gave the same results, although the sensitizing effect was not as pronounced. A selective inhibitor of Akt phosphorylation, LY294002, accelerated formation of the death-inducing signaling complex (DISC) not only by FLIP reduction but also by enhancement of recruitment of the FADD to Fas, thereby sensitizing PC3 cells to apoptosis similar to the case with 2-ME stimulation. Moreover, we found that inhibition of 2-ME-induced extracellular signal-regulated kinase (ERK) activation by the upstream kinase inhibitor PD98059 significantly enhanced 2-ME-mediated suppression of Akt activation, resulting in much greater sensitization to apoptosis. Taken together, the present findings indicate that 2-ME suppresses NF-kappaB/FLIP signaling and enhances DISC formation through inhibition of Akt, and that PC3 cells thereby are being sensitized to Fas-mediated apoptosis and by a process closely associated with ERK.
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PMID:The molecular mechanism of sensitization to Fas-mediated apoptosis by 2-methoxyestradiol in PC3 prostate cancer cells. 1469 42

Over the last decade, a great deal of attention has been directed at elucidating the role of apoptosis regulators in governing survival decisions in neoplastic cells, particularly those of hematopoietic origin. A major focus of this work has involved investigation of the function of pro- and anti-apoptotic members of the BCL-2 family, and the relationship between these proteins and mitochondrial integrity. Currently, these proteins can be classified into two broad categories: those that modulate mitochondrial function and those that regulate the activation of caspases responsible for activation and execution of the apoptotic cascade. Within the first category, certain proteins (e.g., BCL-2, BCL-xL) act to preserve mitochondrial integrity by preventing loss of mitochondrial membrane potential and/or release of pro-apoptotic proteins such as cytochrome C into the cytosol. Other proapoptotic proteins (e.g., BAX, BAK, BIM) promote release of cytochrome C. These proteins are therefore primarily involved in regulation of the intrinsic, mitochondrial apoptotic pathway. Within the second category, proteins such as the inhibitors of apoptosis proteins (e.g., XIAP) or FLIP block the activation of caspases, particularly those involved in engagement of the receptor-related, extrinsic apoptotic pathway. Cross-talk between the intrinsic and extrinsic pathways exists. For example, the BH3-domain only protein BID is cleaved by the activation of pro-caspase-8 through the extrinsic pathway, and translocates to the mitochondrion to promote cytochrome C release. Apoptosis is also regulated by various signal transduction pathways, possibly through post-translational modifications in BCL-2 family proteins. For example, phosphorylation of BCL-2 through a JNK-dependent mechanism has been postulated to contribute to apoptosis induced by the taxane class of cytotoxic agents. Finally, attempts to modulate apoptotic pathways with small molecules have recently received much attention. For example, small molecule inhibitors of BCL-2 or mimetics of SMAC/DIABLO, which opposes the actions of XIAP, have recently been shown to promote the antineoplastic activity of conventional cytotoxic agents. It is likely that an improved understanding of apoptosis regulation will lead to new insights into neoplastic transformation, and may also provide important leads for the development of novel antileukemic strategies.
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PMID:Apoptosis regulators. 1476 59

Cellular FLIP long form (c-FLIP(L)) is a caspase-defective homologue of caspase-8 that blocks apoptosis by death receptors. The expression of c-FLIP(L) in T cells can also augment extracellular signal-regulated kinase phosphorylation after TCR ligation via the association of c-FLIP(L) with Raf-1. This contributes to the hyperproliferative capacity of T cells from c-FLIP(L)-transgenic mice. In this study we show that activated CD4(+) T cells from c-FLIP(L)-transgenic mice produce increased amounts of Th2 cytokines and decreased amounts of Th1 cytokines. This correlates with increased serum concentrations of the Th2-dependent IgG1 and IgE. The Th2 bias of c-FLIP(L)-transgenic CD4(+) T cells parallels impaired NF-kappa B activity and increased levels of GATA-3, which contribute, respectively, to decreased IFN-gamma and increased Th2 cytokines. The Th2 bias of c-FLIP(L)-transgenic mice extends to an enhanced sensitivity to OVA-induced asthma. Taken together, these results show that c-FLIP(L) can influence cytokine gene expression to promote Th2-driven allergic reaction, in addition to its traditional role of blocking caspase activation induced by death receptors.
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PMID:Cellular FLIP long form-transgenic mice manifest a Th2 cytokine bias and enhanced allergic airway inflammation. 1506 48


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