Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide(NO) induces apoptosis in human osteoblasts. Treatment with exogenous NO donors, SNAP (S-Nitroso-N-acetylpenicillamine) and SNP (sodium nitroprusside), to MG-63 osteoblasts resulted in apoptotic morphological changes, as shown by a bright blue-fluorescent condensed nuclei and chromatin fragmentation by fluorescence microscope of Hoechst 33258-staining. The activities of caspase-9 and the subsequent caspase-3-like cysteine proteases were increased during NO-induced cell death. Pretreatment with Z-VAD-FMK (a pan-caspase inhibitor) or Ac-DEVD-CHO (a specific caspase-3 inhibitor) abrogated the NO-induced cell death. The NO donor markedly activated JNK, a stress-activated protein kinase in the human osteoblasts. This study showed that the inhibition of the JNK pathway markedly reduced NO-induced cell death. But neither PD98059 (MEK inhibitor) nor SB203580 (p38 MAPK inhibitor) had any effect on NO-induced death. Taken together, these results suggest that JNK/SAPK may be related to NO-induced apoptosis in MG-63 human osteoblasts.
 ...
PMID:JNK/SAPK is required in nitric oxide-induced apoptosis in osteoblasts. 1466 60

Dietary phytochemicals have been shown to be protective against various types of cancers. However, the precise underlying protective mechanisms are poorly understood. In the present study, we report that treatment of A549 cells with quercetin resulted in a dose-dependent reduction in cell viability and DNA synthesis with the rate of apoptosis equivalent to 1.2 +/- 0.8, 6.3 +/- 0.9, 16.5 +/- 1.5, 36.4 +/- 2.6 and 42.5 +/- 5.8% on treatment with 0.1% dimethylsulfoxide, 14.5, 29.0, 43.5 and 58.0 micro M quercetin, respectively. Concomitantly, quercetin treatments led to a 1.1-, 1.1-, 2.5- and 3.5-fold increase in Bax. Similar elevations were also observed in Bad, which increased 1.1-, 2.1-, 2.2- and 2.3-fold, respectively, as compared with control. While Bcl-2 was decreased by 30%, Bcl-x(L) was elevated in a dose-dependent fashion. Quercetin also induced the cleavage of caspase-3, caspase-7 and PARP (poly ADP-ribose polymerase). While Akt-1 and phosphorylated Akt-1 were inhibited, the extracellular signal-regulated kinase (ERK) was phosphorylated following quercetin treatment in a dose-dependent fashion. Phosphorylation of ERK and c-Jun occurred at 3 h and was sustained over 14 h. Phosphorylation of MEK1/2 was increased in concordance with ERK activation. Quercetin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and cleavage of caspase-3 occurred 6 h after quercetin exposure and before cleavage of caspase-7 and PARP was detected. Inhibition of MEK1/2 but not PI-3 kinase, p38 kinase or JNK abolished quercetin-induced phosphorylation of c-Jun, cleavage of caspase-3 and -7, cleavage of PARP and apoptosis. Inhibition of caspase activation completely blocked quercetin-induced apoptosis. Expression of constitutively activated MEK1 in A549 cells led to activation of caspase-3 and apoptosis. The results suggest that in addition to inactivation of Akt-1 and alteration in the expression of the Bcl-2 family of proteins, activation of MEK-ERK is required for quercetin-induced apoptosis in A549 lung carcinoma cells.
 ...
PMID:The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. 1468 22

To study the effect of growth factors on iatrogenic apoptosis, we examined the influence of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) on staurosporine-induced apoptosis in primary cultures of human umbilical vein endothelial cells (HUVEC). Apoptosis was evaluated by a cell viability test, the TUNEL-POD assay and the activation of the pro-apoptotic caspase-3. Staurosporine (10-100nM) caused the activation of caspase-3. This effect was manifest after 2hr of incubation and reached its maximum after 5hr. Severe loss of viability followed within 18hr. VEGF or EGF (10-100ng/mL) added together with staurosporine decreased the activation of caspase-3. The loss of viability was 24hr delayed. The action of growth factors was observed at 1% serum concentration but also at concentration optimal for HUVEC survival (10%, v/v). Furthermore, the inhibition of PI-3 kinase (PI-3K) by wortmannin or LY294002 as well as the inhibition of MEK by PD098059 or U0126 prevented the protective effect of VEGF and EGF. Western blotting analysis showed that after 3hr of incubation with staurosporine the level of the anti-apoptotic protein Mcl-1 decreased and this effect was reverted by VEGF. It is concluded that VEGF and EGF antagonize the pro-apoptotic action of staurosporine by the combined signalling of PI-3K and ERKs pathways.
 ...
PMID:Effect of vascular endothelial growth factor and epidermal growth factor on iatrogenic apoptosis in human endothelial cells. 1469 40

The insulin like growth factor-1 (IGF-1) receptor (R) induced PI3K/Akt signal transduction cascade has critical roles in prevention of apoptosis and regulation of cell cycle progression. Here, we discuss the effects of IGF-1R-mediated signal transduction on hematopoietic cells which normally require interleukin-3 (IL-3) for growth and prevention of apoptosis. Cytokine-dependent FDC-P1 hematopoietic cells were conditionally transformed to grow in response to overexpression of IGF-1R in the presence of IGF-1. When these cells were deprived of IL-3 or IGF-1 for 24 hrs, they exited the cell cycle, activated caspase 3 and underwent apoptosis. The effects of inhibitors which targeted the PI3K/Akt and Raf/MEK/ERK pathways were determined. When the cells were cultured with IGF-1 and either PI3K or MEK inhibitors, cell cycle progression and DNA synthesis were inhibited and caspase 3 activity and apoptosis were induced. Coinhibition of both pathways synergized to prevent cell cycle progression, inhibit DNA synthesis and induce apoptosis. These inhibitors had more apoptotic inducing effects when the cells were grown in response to IGF-1 than IL-3, indicating that IL-3 can induce additional anti-apoptotic pathways. These results demonstrate that the PI3K/Akt and Raf/MEK/ERK pathways are intimately involved in IGF-1R-mediated cell cycle progression and prevention of apoptosis in hematopoietic cells.
 ...
PMID:Synergy between PI3K/Akt and Raf/MEK/ERK pathways in IGF-1R mediated cell cycle progression and prevention of apoptosis in hematopoietic cells. 1472 97

Prostanoids can suppress vascular smooth muscle cell (VSMC) proliferation, but the mechanism through which this is mediated has not been identified. In this study, we show rat aortic VSMCs to express the EP1, EP2, EP3, EP4, and IP receptors. The EP4 receptor-specific agonist, 11-deoxy-PGE1, induced a time-dependent phosphorylation of protein kinase C and extracellular signal-regulated kinase (ERK) 1/2 in serum-depleted (0.1%) VSMCs, whereas the EP2 receptor agonist, butaprost, was without effect. PGI2 or iloprost at the IP receptor inhibited basal ERK phosphorylation with IC50 values of 10 nmol/L. Iloprost also attenuated the sustained activation of ERK induced by endothelin-1 or basic fibroblast growth factor (bFGF). Endothelin-1 or bFGF significantly increased the number of VSMCs counted 24 hours later compared with basal, and both responses were blocked by the MEK inhibitor, U0126, or iloprost. Under basal conditions, U0126 or iloprost reduced the number of viable cells and increased caspase-3 activity, which could be reversed by coapplication with endothelin-1, bFGF, or the adenylate cyclase inhibitor, SQ22536. Endothelin-1, bFGF, or SQ22536 prevented the depression to below basal levels of ERK phosphorylation induced by iloprost. Forskolin activated caspase-3 and attenuated basal ERK phosphorylation, which were prevented by SQ22536, endothelin-1, or bFGF. These data suggest that iloprost induces apoptosis via a cAMP-mediated suppression of ERK activity. In turn, this apoptotic response can be blocked by a mitogenic stimulus that re-establishes ERK activity back to basal levels, but at the expense of any concomitant proliferative activity. However, ERK stimulation by a selective EP4 receptor agonist, suggests that prostanoids may have diverse and complex roles in VSMC physiology.
 ...
PMID:Prostacyclin induces apoptosis of vascular smooth muscle cells by a cAMP-mediated inhibition of extracellular signal-regulated kinase activity and can counteract the mitogenic activity of endothelin-1 or basic fibroblast growth factor. 1496 6

In culture, cerebellar granule neurons die of apoptosis in serum-free media containing a physiologic level of K(+) but survive in a depolarizing concentration of K(+) or when insulin-like growth factor 1 (IGF-1) is added. Both Akt/PKB activation and caspase-3 inhibition were implicated as the underlying neuroprotective mechanisms. The duration of high K(+), however, induced survival effects that outlasted its transient activation of Akt, and granule neurons derived from caspase-3 knockout mice died to the same extent as did those from wild-type mice, suggesting that additional mechanisms are involved. To delineate these survival mechanisms, we compared the activities of two major survival pathways after high K(+)-induced depolarization or IGF-1 stimulation. Although IGF-1 promoted neuronal survival by activating its tyrosine kinase receptor, high K(+) depolarization provided the same effect by increasing the Ca(2+) influx through the L Ca(2+) channel. Moreover, high K(+)-induced depolarization resulted in sustained activation of MAP kinase, whereas IGF-1 activated Akt in 4 hr. Inhibition of MEK (MAP kinase kinase) by either PD98059 or UO126 abolished the protective effect of high K(+)-induced depolarization, but not that of IGF-1, suggesting that activation of the MAP kinase pathway is necessary for high K(+) neuroprotective effects. We demonstrated also that high K(+)-induced depolarization, but not IGF-1, increased phosphorylation of cAMP-response element-binding protein (CREB) and protein synthesis, both of which can be blocked by UO126. Overall, our findings suggested that high K(+)-induced depolarization, unlike IGF-1, promoted neuronal survival via activating MAP kinase, possibly by increasing CREB-dependent transcriptional activation of specific proteins that promote neuronal survival.
 ...
PMID:High K+ and IGF-1 protect cerebellar granule neurons via distinct signaling pathways. 1499 40

Endoplasmic reticulum (ER) stress has increasingly come into focus as a factor contributing to neuronal injury. Although caspase-dependent mechanisms have been implicated in ER stress, the signaling pathways involved remain unclear. In this study, we examined the role of the extracellular signal-regulated kinase (ERK), a mitogen-activated protein (MAP) kinase pathway that is highly conserved in many systems for balancing cell survival and death. Prolonged treatment of the human neuroblastoma cell line SH-SY5Y with thapsigargin, an inducer of ER stress, increased cell death over 24-48 h, as measured by LDH release. Caspases were involved; increased levels of active caspase-3 and cleaved caspase substrate PARP were detected, and treatment with Z-VAD-FMK reduced thapsigargin-induced cytotoxicity. In contrast, inhibition of calpain was not protective, although calpain was activated following thapsigargin treatment. An early and transient phosphorylation of ERK1/2 occurred after thapsigargin-induced ER stress, and targeting this pathway with the MEK inhibitors U0126 or PD98059 significantly reduced cell death. Similar cytoprotection was obtained against brefeldin A, another ER stress agent. However, protection against ER stress via ERK inhibition was not accompanied by amelioration of caspase-3 activation, PARP cleavage, or DNA laddering. These data indicate that ERK may contribute to non-caspase-dependent pathways of injury after ER stress.
 ...
PMID:Involvement of ERK MAP kinase in endoplasmic reticulum stress in SH-SY5Y human neuroblastoma cells. 1503 Apr 7

Fibroblast growth factor-2 (FGF-2) is an important molecule that controls bone formation through activation of osteoblastic cell replication and differentiation. The role of FGF-2 on human osteoblast survival and the signaling pathway that mediates its effect are not known. We studied the effect of FGF-2 on apoptosis induced by low serum concentration and the signal transduction pathway involved in this effect in human primary calvaria osteoblasts and immortalized osteoblastic cells. Treatment with FGF-2 for 24-48 h protected against osteoblast apoptosis induced by low serum concentration, through specific inhibition of caspase-2 and caspase-3 activity. Pharmacological inhibition of MEK-1 and p38 MAPK had no effect on the inhibition of caspases-2 and -3 induced by FGF-2. In contrast, inhibition of PI3K with LY294002 abolished the FGF-2-induced inhibition of caspases-2 and -3. FGF-2 increased PI3K activity but did not induce phosphorylation of Akt or the downstream effector p70 S6 kinase. FGF-2 also induced GSK-3alpha and beta phosphorylation in osteoblastic cells, which however did not result in beta-catenin accumulation or Lef/Tcf transcriptional activity. In contrast, lithium induced beta-catenin accumulation, Lef/Tcf transcriptional activation and increased caspase-2 and -3 activity. The results indicate that the immediate protective effect of FGF-2 on human osteoblastic cell apoptosis involves PI3K and inhibition of downstream caspases, independently of GSK-3 and beta-catenin-Lef/Tcf-mediated transcription.
 ...
PMID:Fibroblast growth factor-2 induces osteoblast survival through a phosphatidylinositol 3-kinase-dependent, -beta-catenin-independent signaling pathway. 1519 39

The molecular mechanisms underlying H(2)O(2)-induced toxicity were characterized in rat oligodendrocyte cultures. While progenitor cells were more sensitive than mature oligodendrocytes to H(2)O(2), the antioxidant, N-acetyl-L-cysteine, blocked toxicity at both stages of development. Differentiated oligodendrocytes contained more glutathione than did progenitors and were less susceptible to decreases in glutathione concentration induced by H(2)O(2) stress. As free radicals have been considered to serve as second messengers, we examined the effect of H(2)O(2) on activation of the mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinases (ERK) 1/2 and p38. H(2)O(2) caused a time- and concentration-dependent increase in MAPK phosphorylation, an effect that was totally blocked by N-acetyl-L-cysteine. Further exploration of potential mechanisms involved in oligodendrocyte cell death showed that H(2)O(2) treatment caused DNA condensation and fragmentation at both stages of development, whereas caspase 3 activation and poly (ADP-ribose) polymerase cleavage were significantly increased only in oligodendrocyte progenitors. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone, blocked DNA fragmentation in progenitors and produced a small but significant level of protection from H(2)O(2) toxicity in progenitors and mature oligodendrocytes. In contrast, inhibitors of both p38 and MEK reduced H(2)O(2)-induced death most significantly in oligodendrocytes. The poly (ADP-ribose) polymerase inhibitor, PJ34, reduced H(2)O(2)-induced toxicity on its own but was most effective when combined with benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone or PD169316. The finding that molecular mechanisms conferring resistance to reactive oxygen species toxicity are regulated during oligodendrocyte differentiation may be of importance in designing therapies for certain neurological diseases affecting white matter.
 ...
PMID:Developmental differences in HO-induced oligodendrocyte cell death: role of glutathione, mitogen-activated protein kinases and caspase 3. 1522 96

Mitogen-activated protein kinase (MAPK) cascades are membrane-to-nucleus signaling modules that recently have been implicated as mediators of cellular injury. In this study, we investigated the involvement of the MAP kinase p44/p42 (extracellular signal-regulated kinase [ERK1/2]) in traumatic brain injury (TBI) in rats. There was a strong increase in activated, phosphorylated ERK 1/2 (p-ERK 1/2) protein at 10 min up to 24 h after the injury. Expression of p-ERK occurred in cells identified as neurons, astrocytes, and microglia. Most of the cells expressing p-ERK were TUNEL positive at later time points. Treatment with the MEK inhibitor U0126 or the free radical scavenger S-PBN, both with neuroprotective properties in TBI, attenuated the early activation of ERK and resulted in less activation of caspase-3 and subsequent DNA fragmentation. Post-treatment with U0126 resulted in a significant decrease (-60%) in cortical cavity size and cortical atrophy at 2 weeks after trauma. Overall, the results suggest that ERK activation is initiated by increased oxygen radical activity and that overactivation of ERK sets off secondary cell death mechanisms in TBI. Clinical studies are warranted to evaluate the concept of MEK inhibition in head-injured patients.
 ...
PMID:Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury. 1545 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>