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)

Recently we generated a mathematical model (Bentele, M., Lavrik, I., Ulrich, M., Stosser, S., Heermann, D. W., Kalthoff, H., Krammer, P. H., and Eils, R. (2004) J. Cell Biol. 166, 839-851) of signaling in CD95(Fas/APO-1)-mediated apoptosis. Mathematical modeling in combination with experimental data provided new insights into CD95-mediated apoptosis and allowed us to establish a threshold mechanism of life and death. Here, we further assessed the predictability of the model experimentally by a detailed analysis of the threshold behavior of CD95 signaling. Using the model predictions for the mechanism of the threshold behavior we found that the CD95 DISC (death-inducing signaling complex) is formed at the cell membrane upon stimulation with low concentrations of agonistic anti-APO-1 monoclonal antibodies; however, activation of procaspase-8 at the DISC is blocked due to high cellular FLICE-inhibitory protein recruitment into the DISC. Given that death signaling does not occur upon CD95 stimulation at low (threshold) anti-APO-1 concentrations, we also analyzed survival signaling, focusing on mitogen-activated protein kinase activation. Interestingly, we found that mitogen-activated protein kinase activation takes place under threshold conditions. These findings show that triggering of CD95 can signal both life or death, depending on the strength of the stimulus.
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PMID:Analysis of CD95 threshold signaling: triggering of CD95 (FAS/APO-1) at low concentrations primarily results in survival signaling. 1734 43

Nuclear factor-kappa B (NF-kappaB) inhibits cell death through suppression of the caspase cascade, the c-Jun N-terminal kinase (JNK) pathway, and reactive oxygen species (ROS) accumulation. To suppress this antiapoptotic function of NF-kappaB might be a promising strategy to increase susceptibility of tumor cells to stress-induced cell death. We have recently shown that tumor necrosis factor (TNF)alpha induces caspase-dependent and -independent JNK activation and ROS accumulation in cellular FLICE-inhibitory protein (c-Flip)(-/-) murine embryonic fibroblasts (MEFs). To apply this observation to tumor therapy, we knocked down c-FLIP by RNA interference in various tumor cells. Consistent with the results using c-Flip(-/-) MEFs, we found that TNFalpha stimulation induced caspase-dependent prolonged JNK activation and ROS accumulation, followed by apoptotic and necrotic cell death in various tumor cells. Furthermore, TNFalpha and Fas induced the cleavage of mitogen-activated protein kinase/ERK kinase kinase (MEKK)1, resulting in generation of a constitutive active form of MEKK1 leading to JNK activation in c-FLIP knockdown cells. Given that ROS accumulation and necrotic cell death enhance inflammation followed by compensatory proliferation of tumor cells, selective suppression of caspase-dependent ROS accumulation will be an alternative strategy to protect cells from ROS-dependent DNA damage and compensatory tumor progression.
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PMID:Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells. 1759 41

Tumor necrosis factor-alpha (TNF-alpha)-activated neutrophils phagocytose and eliminate bacteria by using such oxidants as hydrogen peroxide (H(2)O(2)) and hypochlorous acid (HOCl), which is produced from H(2)O(2) by myeloperoxidase (MPO). Thereafter, neutrophils eventually undergo apoptosis to prevent excessive inflammation. However, it is unclear how this process is regulated. Here, we show that cotreatment of TNF-alpha-resistant neutrophilic HL-60 cells with taurine chloramine (TauCl), a detoxified form of HOCl, and TNF-alpha renders them susceptible to apoptosis, mostly by preventing nuclear factor-kappaB (NF-kappaB) activation. Of several NF-kappaB target genes tested, FLICE inhibitory protein short form (FLIP(S)) was specifically down-regulated by TauCl. TNF-alpha/TauCl cotreatment-induced apoptosis was largely blocked by stable expression of FLIP(S). Cotreatment with TNF-alpha and H(2)O(2) promoted apoptotic signaling via MPO activation and subsequent attenuation of FLIP(S) expression. TNF-alpha priming with H(2)O(2) or bacteria caused MPO-dependent apoptosis in human neutrophils. However, FLIP(S) knock-down by siRNA did not affect the viability of cells treated with TNF-alpha, implying that TauCl may affect another pathway in TNF-alpha-driven apoptosis. Indeed, oxidization of thioredoxin-1 (Trx-1) by TauCl induced the activation of apoptosis signal-regulating kinase 1 (ASK1) and cJun N-terminal kinase (JNK), thereby triggering TNF-alpha-mediated apoptosis. Taken together, these results indicate that the antiapoptotic signaling induced by TNF-alpha via NF-kappaB activation can be altered to promote apoptosis via H(2)O(2)-MPO-mediated FLIP(S) down-regulation and JNK activation.
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PMID:Apoptosis triggered by phagocytosis-related oxidative stress through FLIPS down-regulation and JNK activation. 1770 1

One of the characteristic features of the pathogenesis of rheumatoid arthritis is synovial hyperplasia. We have reported previously that metastatic lymph node 51 (MLN51) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are involved in the proliferation of fibroblast-like synoviocytes in the pathogenesis of rheumatoid arthritis. In this study, we have found that: (1) GM-CSF-mediated MLN51 upregulation is attributable to both transcriptional and post-translational control in rheumatoid arthritis fibroblast-like synoviocytes; (2) p38 mitogen-activated protein kinase plays a key role in the upregulation of MLN51; and (3) FLICE-inhibitory protein is upregulated downstream of MLN51 in response to GM-CSF, resulting in the proliferation of fibroblast-like synoviocytes. These results imply that GM-CSF signaling activates mitogen-activated protein kinase, followed by the upregulation of MLN51 and FLICE-inhibitory protein, resulting in fibroblast-like synoviocyte hyperplasia in rheumatoid arthritis.
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PMID:FLIP and MAPK play crucial roles in the MLN51-mediated hyperproliferation of fibroblast-like synoviocytes in the pathogenesis of rheumatoid arthritis. 1851 26

The cyclic AMP (cAMP) signaling pathway has been reported to either promote or suppress apoptosis, in a cell context-dependent manner. Our previous study has shown that cAMP, by protein kinase A (PKA)-cAMP response element-binding protein (CREB)-dynein light chain (DLC) pathway, negatively regulates mitogen-activated protein kinase p38 activation, thereby contributing to tumor necrosis factor (TNF)-alpha-induced apoptosis in certain types of cells. However, it remains largely unknown how cAMP suppresses apoptosis. Here we report that cAMP antagonized UV-induced apoptosis in Rat-1 and NIH 3T3 cells. Despite that cAMP significantly suppressed UV-induced p38 activation, inhibition of p38 activity showed no significant effect on UV-induced cell death in both cell lines. Further studies revealed that cAMP antagonized UV-induced apoptosis by inhibition of c-Jun N-terminal protein kinase (JNK) activation. The induction of the long form of cellular FLICE-inhibitory protein (c-FLIP(L)) and mitogen-activated protein kinase phosphatase-1 (MKP-1), but not DLC and p21(WAF1) by CREB was required for cAMP-mediated inhibition of JNK activation. The suppression by cAMP of UV-induced apoptosis was reversed by c-FLIP(L) small-interfering RNA (siRNA) or MKP-1 siRNA, which released the inhibition of JNK activation by cAMP. Thus, our results provide a molecular mechanism by which cAMP suppresses JNK activation and antagonizes apoptosis.
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PMID:Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIP(L) and MKP-1, thereby antagonizing UV-induced apoptosis. 1856 5

The flexible heteroarotinoid, SHetA2, is a novel compound with apoptosis-inducing and anticancer activities in vitro and in vivo. Our previous research showed that up-regulation of death receptor 5 plays a critical role in the mechanism of SHetA2-induced apoptosis in human lung cancer cells. The hypothesis of this study was that the mechanism of SHetA2-induced apoptosis requires modulation of additional proteins critical for regulation of apoptosis, including cellular FLICE-inhibitory protein (c-FLIP), survivin, X-linked inhibitor of apoptosis, Bcl-2, Bcl-X(L), Bax, and Bim. Western blot analysis showed that c-FLIP and survivin were substantially reduced in all of the tested cell lines exposed to SHetA2 compared with other proteins that were reduced only in a subset of the cell lines tested. Strikingly, overexpression of c-FLIP, but not survivin, protected cells from SHetA2-induced apoptosis and enhancement of TRAIL-initiated apoptosis, although knockdown of endogenous survivin did slightly sensitize cells to SHetA2-induced apoptosis. Consistent with these results, small interfering RNA-mediated reduction of c-FLIP was more effective than survivin down-regulation in triggering apoptosis in these cell lines. SHetA2 increased ubiquitination of c-FLIP and the consequent degradation was abrogated by the proteasome inhibitor MG132. Although SHetA2 treatment led to increased c-Jun phosphorylation, the JNK inhibitor SP600125 did not prevent c-FLIP down-regulation by SHetA2. Thus, it appears that SHetA2 down-regulates c-FLIP levels by facilitating its ubiquitin/proteasome-mediated degradation independent of JNK activation. Collectively, the present study indicates that, in addition to death receptor 5 up-regulation, c-FLIP down-regulation is another important component of flexible heteroarotinoid (SHetA2)-induced apoptosis as well as enhancement of TRAIL-induced apoptosis.
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PMID:Involvement of c-FLIP and survivin down-regulation in flexible heteroarotinoid-induced apoptosis and enhancement of TRAIL-initiated apoptosis in lung cancer cells. 1900 38

Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on clarifying the mechanism(s) by which glutathione S-transferase (GST)-MDA-7 altered cell survival of human renal carcinoma cells in vitro. GST-MDA-7 caused plasma membrane clustering of CD95 and the association of CD95 with procaspase-8. GST-MDA-7 lethality was suppressed by inhibition of caspase-8 or by overexpression of short-form cellular FLICE inhibitory protein, but only weakly by inhibition of cathepsin proteases. GST-MDA-7-induced CD95 clustering (and apoptosis) was blocked by knockdown of acidic sphingomyelinase or, to a greater extent, ceramide synthase-6 expression. GST-MDA-7 killing was, in parallel, dependent on inactivation of extracellular signal-regulated kinase 1/2 and on CD95-induced p38 mitogen-activated protein kinase and c-jun NH(2)-terminal kinase-1/2 signaling. Knockdown of CD95 expression abolished GST-MDA-7-induced phosphorylation of protein kinase R-like endoplasmic reticulum kinase. GST-MDA-7 lethality was suppressed by knockout or expression of a dominant negative protein kinase R-like endoplasmic reticulum kinase that correlated with reduced c-jun NH(2)-terminal kinase-1/2 and p38 mitogen-activated protein kinase signaling and maintained extracellular signal-regulated kinase-1/2 phosphorylation. GST-MDA-7 caused vacuolization of LC3 through a mechanism that was largely CD95 dependent and whose formation was suppressed by knockdown of ATG5 expression. Knockdown of ATG5 suppressed GST-MDA-7 toxicity. Our data show that in kidney cancer cells GST-MDA-7 induces ceramide-dependent activation of CD95, which is causal in promoting an endoplasmic reticulum stress response that activates multiple proapoptotic pathways to decrease survival.
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PMID:MDA-7/IL-24-induced cell killing in malignant renal carcinoma cells occurs by a ceramide/CD95/PERK-dependent mechanism. 1941 61

Chronic intake of alcohol results in multiple organ damage including brain. This study was designed to examine the impact of facilitated acetaldehyde breakdown via transgenic overexpression of mitochondrial aldehyde dehydrogenase-2 (ALDH2) on alcohol-induced cerebral cortical injury. ALDH2 transgenic mice were produced using the chicken beta-actin promoter. Wild-type FVB and ALDH2 mice were placed on a 4% alcohol or control diet for 12 weeks. Protein damage and apoptosis were evaluated with carbonyl formation, caspase and TUNEL assays. Western blot was performed to examine expression (or its activation) of ALDH2, the pro- and anti-apoptotic proteins caspase-8, Bax, Bcl-2, Omi/HtrA2, apoptosis repressor with caspase recruitment domain (ARC), FLICE-like inhibitory protein (FLIP), X-linked inhibitor of apoptosis protein (XIAP), Akt, glycogen synthase kinase-3beta (GSK-3beta), p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Chronic alcohol intake led to elevated apoptosis in the absence of overt protein damage, the effect of which was ablated by the overexpression of ALDH2 transgene. Consistently, ALDH2 transgene significantly attenuated alcohol-induced upregulation of Bax, Omi/HtrA2 and XIAP as well as downregulation of Bcl-2 and ARC without affecting alcohol-induced increase of FLIP in cerebral cortex. Phosphorylation of Akt and GSK-3beta was dampened while total/phosphorylated JNK and p38 phosphorylation were elevated following chronic alcohol intake, the effects of which were abrogated by ALDH2 transgene. Expression of total Akt, GSK-3beta, p38 and ERK (total or phosphorylated) was not affected by either chronic alcohol intake or ALDH2 transgene. Our results suggested that transgenic overexpression of ALDH2 rescues chronic alcoholism-elicited cerebral injury possibly via a mechanism associated with Akt, GSK-3beta, p38 and JNK signaling.
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PMID:Aldehyde dehydrogenase-2 transgene ameliorates chronic alcohol ingestion-induced apoptosis in cerebral cortex. 1942 58

Breast tumor cells are often resistant to tumor necrosis factor-related apoptosis-inducing ligand (tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)/APO-2 L). Here, we describe the sensitization by microtubule-interfering agents (MIAs) to TRAIL-induced apoptosis in breast tumor cells through a mitotic arrest and c-Jun N-terminal kinase (JNK)-dependent mechanism. MIA treatment resulted in BubR1-dependent mitotic arrest leading to the sustained activation of JNK and the proteasome-mediated downregulation of cellular FLICE-inhibitory protein (cFLIP) and myeloid cell leukemia-1 (Mcl-1) expression. The JNK inhibitor SP600125 abrogated MIA-induced mitotic arrest and downregulation of cFLIP and Mcl-1 and reduced the apoptosis caused by the combination of MIAs and TRAIL. Silencing of cFLIP and Mcl-1 expression by RNA interference resulted in a marked sensitization to TRAIL-induced apoptosis. Furthermore, in FLIP-overexpressing cells, MIA-induced sensitization to TRAIL-activated apoptosis was markedly reduced. In summary, our results show that mitotic arrest imposed by MIAs activates JNK and facilitates TRAIL-induced activation of an apoptotic pathway in breast tumor cells by promoting the proteasome-mediated degradation of cFLIP and Mcl-1.
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PMID:Mitotic arrest and JNK-induced proteasomal degradation of FLIP and Mcl-1 are key events in the sensitization of breast tumor cells to TRAIL by antimicrotubule agents. 1994 32

FLICE-inhibitory protein (FLIP) is an endogenous inhibitor of the signaling pathway triggered by the activation of death receptors. Here, we reveal a novel biological function for the long form of FLIP (FLIP-L) in neuronal differentiation, which can be dissociated from its antiapoptotic role. We show that FLIP-L is expressed in different regions of the mouse embryonic nervous system. Immunohistochemistry of mouse brain sections at different stages reveals that, in neurons, FLIP is expressed early during the embryonic neuronal development (embryonic day 16) and decreases at later stages (postnatal days 5-15), when its expression is essentially detected in glial cells. FLIP-L overexpression significantly enhances neurotrophin-induced neurite outgrowth in motoneurons, superior cervical ganglion neurons, and PC12 cells. Conversely, the downregulation of FLIP-L protein levels by specific RNA interference significantly reduces neurite outgrowth, even in the presence of the appropriate neurotrophin stimulus. Moreover, NGF-dependent activation of two main intracellular pathways involved in the regulation of neurite outgrowth, extracellular signal-regulated kinases (ERKs) and nuclear factor kappaB (NF-kappaB), is impaired when endogenous FLIP-L is downregulated, although TrkA remains activated. Finally, we demonstrate that FLIP-L interacts with TrkA, and not with p75(NTR), in an NGF-dependent manner, and endogenous FLIP-L interacts with TrkB in whole-brain lysates from embryonic day 15 mice embryos. Altogether, we uncover a new role for FLIP-L as an unexpected critical player in neurotrophin-induced mitogen-activated protein kinase/ERK- and NF-kappaB-mediated control of neurite growth in developing neurons.
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PMID:The death receptor antagonist FLIP-L interacts with Trk and is necessary for neurite outgrowth induced by neurotrophins. 2042 67


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