Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ASK1 activates JNK and p38 mitogen-activated protein kinases and constitutes a pivotal signaling pathway in cytokine- and stress-induced apoptosis. However, little is known about the mechanism of how ASK1 executes apoptosis. Here we investigated the roles of caspases and mitochondria in ASK1-induced apoptosis. We found that benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk), a broad-spectrum caspase inhibitor, mostly inhibited ASK1-induced cell death, suggesting that caspases are required for ASK1-induced apoptosis. Overexpression of ASK1DeltaN, a constitutively active mutant of ASK1, induced cytochrome c release from mitochondria and activation of caspase-9 and caspase-3 but not of caspase-8-like proteases. Consistently, caspase-8-deficient (Casp8 (-/-)) cells were sensitive to ASK1-induced caspase-3 activation and apoptosis, suggesting that caspase-8 is dispensable for ASK1-induced apoptosis, whereas ASK1 failed to activate caspase-3 in caspase-9-dificient (Casp9 (-/-)) cells. Moreover, mitochondrial cytochrome c release, which was not inhibited by zVAD-fmk, preceded the onset of caspase-3 activation and cell death induced by ASK1. ASK1 thus appears to execute apoptosis mainly by the mitochondria-dependent caspase activation.
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PMID:Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. 1084 26

Bovine carotid artery endothelial (BAE) cells are resistant to tumor necrosis factor-alpha (TNF), like most other cells. We examined if mitogen-activated protein (MAP) kinase and phosphatidylinositol-3 (PI3) kinase/Akt pathways are involved in this effect. In BAE cells, TNF activates MAP kinase in a MAP kinase kinase 1 (MEK1) manner and Akt in PI3-kinase-dependent manner. Pretreatment with either the MEK1 inhibitor U0126 or PI3-kinase inhibitor LY294002 sensitized BAE cells to TNF-induced apoptosis. Neither U0126 nor LY294002 pretreatment affected TNF-induced activation of NF-kappaB, suggesting that the MAP kinase or PI3-kinase/Akt-mediated anti-apoptotic effect induced by TNF was not relevant to NF-kappaB activation. Both MAP kinase and PI3-kinase/Akt -mediated signaling could prevent cytochrome c release and mitochondrial transmembrane potential (Deltapsi) decrease. PI3-kinase/Akt signaling attenuated caspase-8 activity, whereas MAP kinase signaling impaired caspase-9 activity. These results suggest that TNF-induced MAP kinase and PI3-kinase/Akt signaling play important roles in protecting BAE cells from TNF cytotoxicity.
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PMID:Inhibition of phosphatidylinositol-3 kinase/Akt or mitogen-activated protein kinase signaling sensitizes endothelial cells to TNF-alpha cytotoxicity. 1142 13

Despite the high frequency of prostate cancer, therapeutic options for advanced disease are limited to chemotherapy, radiation or hormonal therapy and eventually fail in all patients. Therefore, alternative approaches need to be developed. We previously reported that FTY720, a metabolite from Isaria sinclarii, is a unique antitumor agent for an androgen-independent prostate cancer cell line and requires caspase-3 activation in apoptosis. In our study, we have evaluated the effect of FTY720 on a family of mitogen-activated protein kinases (MAPKs), focal adhesion kinase (FAK), mitochondrial transmembrane potential, caspase-9 and caspase-8 and analyzed the expression of some cell-cycle regulator proteins in DU145 cells in order to understand the various antitumor effects of FTY720. Apoptosis was quantified by phosphatidylserine exposure. Activation of MAPKs, cleavage of caspase-9 and caspase-8, status of cyclin-dependent kinases (CDKs) and Cip1/p21, a cyclin-dependent kinase inhibitor, were evaluated by Western blot analysis, in addition to FAK and phospho-FAK immunoprecipitation and cell-cycle analysis by FACScan. We found that in DU145 cells, 40 microM FTY720 caused activation of p38 MAPK and the upstream kinase MKK3/MKK6 but not SAPK/JNK. Mitochondrial transmembrane potential, FAK and ERK1/2 were reduced while caspase-9 and caspase-8 were cleaved. The p38-specific inhibitor had no effect on apoptosis induced by FTY720, whereas z-VAD.FMK, a broad-spectrum caspase inhibitor, did not inhibit the p38 MAPK activation. An amount of 20 microM FTY720 resulted in G(1) arrest and a decrease of CDK2 as well as CDK4, whereas it induced Cip1/p21. FTY720 may exert anticarcinogenic effects against prostate cancer cells possibly involving modulation of mitogenic signaling, cell-cycle regulators, induction of G(1) arrest and apoptotic death in DU145 cells.
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PMID:Anticarcinogenic effect of FTY720 in human prostate carcinoma DU145 cells: modulation of mitogenic signaling, FAK, cell-cycle entry and apoptosis. 1185 3

We investigated intracellular signalling pathways for apoptosis induced by epigallocatechin-3-gallate (EGCG) as compared with those induced by a toxic chemical substance (etoposide, VP16) or the death receptor ligand [tumour necrosis factor (TNF)]. EGCG as well as VP16 and TNF induced activation of two apoptosis-regulating mitogen-activated protein (MAP) kinases, namely c-Jun N-terminal kinase (JNK) and p38 MAP kinase, in both human leukaemic U937 and OCI-AML1a cells. In U937 cells, the apoptosis and activation of caspases-3 and -9 induced by EGCG but not VP16 and TNF were inhibited with SB203580, a specific inhibitor of p38, while those induced by EGCG and VP16 but not TNF were inhibited with SB202190, a rather broad inhibitor of JNK and p38. In contrast, the EGCG-induced apoptosis in OCI-AML1a cells was resistant to SB203580 but not to SB202190. Unlike TNF, EGCG did not induce the activation of nuclear factor-kappaB but rather induced the primary activation of caspase-9. N -Acetyl-L-cysteine (NAC) almost completely abolished apoptosis induced by EGCG under conditions in which the apoptosis induced by VP16 or TNF was not affected. The JNK/p38 activation by EGCG was also potently inhibited by NAC, whereas those by VP16 and TNF were either not or only minimally affected by NAC. In addition, dithiothreitol also suppressed both apoptosis and JNK/p38 activation by EGCG, and EGCG-induced activation of MAP kinase kinase (MKK) 3/6, MKK4 and apoptosis-regulating kinase 1 (ASK1) was suppressed by NAC. Dominant negative ASK1, MKK6, MKK4 and JNK1 potently inhibited EGCG-induced cell death. EGCG induced an intracellular increase in reactive oxygen species and GSSG, both of which were also inhibited by NAC, and the decreased synthesis of glutathione rendered the cell susceptible to EGCG-induced apoptosis. Taken together these results strongly suggest that EGCG executed apoptotic cell death via an ASK1, MKK and JNK/p38 cascade which is triggered by NAC-sensitive intracellular oxidative events in a manner distinct from chemically induced or receptor-mediated apoptosis.
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PMID:Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis. 1220 15

EB1089, a novel vitamin D3 analog, has been shown to have cytotoxic and antiproliferative properties in a variety of malignant cells. However, its potential as a treatment for B-cell chronic lymphocytic leukemia (B-CLL) has not been evaluated. EB1089 induced apoptosis in all of the 102 B-CLL samples tested with a mean LD(50) (the concentration of EB1089 required to kill 50% of cells) value (+/- SD) of 2.1 x 10(-8) M (+/- 1.4 x 10(-8) M). Furthermore, no significant difference was found in the cytotoxicity of EB1089 in B-CLL samples from previously treated and untreated patients (P =.1637). Induction of apoptosis was associated with a reduction in Bcl-2 and Mcl-1 protein expression, but this was evident only in the apoptotic cells. In contrast, the expression of Bax, p21, and p53 was not altered in the viable or apoptotic cells from either B- or T-lymphocyte lineages. EB1089-induced apoptosis was preceded by activation of p38 mitogen-activated protein (MAP) kinase and suppression of extracellular signal-regulated kinase (ERK) activity, and this was associated with downstream activation of caspase-3. The pancaspase inhibitor (Z-VAD-FMK) and the caspase-9 inhibitor (Z-LEHD-FMK) were able to partially abrogate the apoptotic effects of EB1089 but did not affect the phosphorylation of p38 MAP kinase or the suppression of ERK. The B-CLL cells in the study were shown to highly express vitamin D receptor, but an additional receptor-independent mechanism of cell killing cannot be ruled out at this stage. These findings show that EB1089 is a potent apoptosis-inducing agent in B-CLL cells and may be useful in the treatment of B-CLL patients, particularly those with p53 mutations or drug-resistant disease.
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PMID:The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. 1244 53

Tubular atrophy resulting from epithelial cell loss is one of the characteristic features in the development of chronic renal interstitial fibrosis. Although the trigger(s) and mechanism for tubular cell loss remain undefined, the hyperactive transforming growth factor (TGF)-beta1 signaling has long been suspected to play an active role. Here we demonstrate that although TGF-beta1 did not induce cell death per se, it dramatically potentiated renal tubular cell apoptosis initiated by other death cues in vitro. Pre-incubation of human kidney epithelial cells (HKC) with TGF-beta1 markedly promoted staurosporine-induced cell death in a time- and dose-dependent manner. TGF-beta1 dramatically accelerated the cleavage and activation of pro-caspase-9, but not pro-caspase-8, in HKC cells. This event was followed by an accelerated activation of pro-caspase-3. To elucidate the mechanism underlying TGF-beta1 promotion of tubular cell death, we investigated the signaling pathways activated by TGF-beta1. Both Smad-2 and p38 mitogen-activated protein (MAP) kinase were rapidly activated by TGF-beta1, as demonstrated by the early induction of phosphorylated Smad-2 and p38 MAP kinase, respectively. We found that overexpression of inhibitory Smad-7 completely abolished Smad-2 phosphorylation and activation induced by TGF-beta1 but did not inhibit TGF-beta1-induced apoptosis. However, suppression of p38 MAP kinase with chemical inhibitor SC68376 not only abolished p38 MAP kinase phosphorylation but also obliterated apoptosis induced by TGF-beta1. These results suggest that hyperactive TGF-beta1 signaling potentiates renal tubular epithelial cell apoptosis by a Smad-independent, p38 MAP kinase-dependent mechanism.
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PMID:Transforming growth factor-beta1 potentiates renal tubular epithelial cell death by a mechanism independent of Smad signaling. 1256 Mar 23

Therapy with high oxygen concentrations (hyperoxia) is often necessary to treat patients with respiratory failure. However, hyperoxia may exacerbate the development of acute lung injury, perhaps by increasing lung epithelial cell death. Therefore, interrupting lung epithelial cell death is an important protective and therapeutic strategy. In the present study, hyperoxia (95% O(2)) results in murine lung epithelium cell death by DNA-laddering, terminal deoxynucleotidyltransferase dUTP nick end labeling, and Annexin V-fluorescein isothiocyanate flow cytometry assay. We show that hyperoxia increases superoxide production, as assessed by nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity and flow cytometric assay, and increases phospho-extracellular signal-regulated kinase (ERK)1/2 by Western blot analysis. These processes are inhibited by a reactive oxygen species inhibitor, diphenylene iodonium (DPI), and by an inhibitor of the mitogen-activated protein (MAP) or ERK kinase (MEK)/ERK1/2 pathway, PD98059. ERK1/2 activation in hyperoxia is also inhibited by DPI. Hyperoxia-induced cell death is associated with cytochrome c release, subsequent caspase 9 and 3 activation, and poly (ADP-ribosyl) polymerase cleavage, which can all be suppressed by DPI and PD98059. However, the broad caspase inhibitor z-VAD-FMK protects cells from death without affecting superoxide generation and ERK1/2 activation. Taken together, our data suggest that hyperoxia, by virtue of activating NADPH oxidase, generates reactive oxygen species (ROS), which mediates cell death of lung epithelium via ERK1/2 MAPK activation, and functions upstream of caspase activation in lung epithelial cells.
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PMID:Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia-induced cell death in lung epithelium. 1259 56

In this study, we identified whether mitogen-activated protein kinases (MAPKs) mediate the effects of angiopoietin-1 (Ang-1) on endothelial cell apoptosis. Exposure of human umbilical vein endothelial cells to Ang-1 (300 ng/ml) evoked within 15-30 min a 15-fold and a 5-fold increase in phosphorylation of ERK1/2 and p38 MAPKs, respectively. Inhibitors of the PI-3 kinase pathway attenuated Ang-1-induced ERK1/2 phosphorylation at a level up-stream from Raf and MEK1/2, but these inhibitors augmented Ang-1-induced p38 phosphorylation. When serum and growth supplements were withdrawn, the percentage of endothelial apoptosis tripled over 24 h compared with control cells. The presence of Ang-1 (300 ng/ml) significantly attenuated endothelial cell apoptosis and inhibited caspase-9, -7, and -3 activation. These antiapoptotic effects were augmented when a p38 inhibitor was combined with Ang-1, whereas inhibition of ERK1/2 eliminated the antiapoptotic properties of Ang-1. We conclude that both anti- (ERK1/2) and pro- (p38) apoptotic members of MAPKs are simultaneously activated by Ang-1 in endothelial cells and that activation of ERK1/2 by Ang-1 is mediated through the PI-3 kinase pathway. The strong antiapoptotic effects of the ERK and the PI-3 kinase pathways mask the proapoptotic function of p38 MAPKs resulting in net attenuation of apoptosis by Ang-1.
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PMID:Angiopoietin-1 activates both anti- and proapoptotic mitogen-activated protein kinases. 1282 93

Norcantharidin (NCTD) is an anticancer drug routinely used against hepatoma in China. Previously, we reported that NCTD could induce mitotic arrest and apoptosis in human hepatoma HepG2 cells. However, the intracellular signaling pathways involved in NCTD-induced apoptotic cell death are still obscure. Caspase inhibitors were used to clarify the role of specific caspase in NCTD-triggered apoptotic process. Results showed that activation of caspase-9/caspase-3 cascade is required for NCTD-induced apoptotic death. To decipher the upstream signals for NCTD-induced apoptosis, we characterized the involvement of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38MAPK. The role of their downstream targets, transcription factors activating protein-1 (AP-1), and nuclear factor kappaB (NF-kappaB) in NCTD-induced apoptosis was also analyzed. Immunoblot analyses and in vitro kinase assay demonstrated that NCTD-induced apoptosis was accompanied by the elevations of the levels of phosphorylated form and kinase activity of ERK and JNK, but not p38MAPK. The inhibitor of ERK pathway (U0126 or PD98059) or JNK pathway (SP600125) markedly prevented kinase activation, and also greatly reduced NCTD-induced apoptotic cell death. Increased DNA-binding activity of AP-1 and NF-kappaB was also observed after NCTD treatment. Inhibition of NF-kappaB activation by PDTC or inhibition of AP-1 activation by curcumin drastically blocked NCTD-induced cell death. These results imply that activation of ERK and JNK, and modulation of downstream transcription factors NF-kappaB and AP-1, may be involved in NCTD-induced apoptosis.
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PMID:Norcantharidin-induced apoptosis is via the extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase signaling pathways in human hepatoma HepG2 cells. 1297 86

The heat shock response and death receptor-mediated apoptosis are both key physiological determinants of cell survival. We found that exposure to a mild heat stress rapidly sensitized Jurkat and HeLa cells to Fas-mediated apoptosis. We further demonstrate that Hsp70 and the mitogen-activated protein kinases, critical molecules involved in both stress-associated and apoptotic responses, are not responsible for the sensitization. Instead, heat stress on its own induced downregulation of FLIP and promoted caspase-8 cleavage without triggering cell death, which might be the cause of the observed sensitization. Since caspase-9 and -3 were not cleaved after heat shock, caspase-8 seemed to be the initial caspase activated in the process. These findings could help understanding the regulation of death receptor signaling during stress, fever, or inflammation.
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PMID:Heat stress downregulates FLIP and sensitizes cells to Fas receptor-mediated apoptosis. 1450 37


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