Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Applying the recently developed DNA array technique to a murine stroke model, we found that the gene coding for RhoB, a member of the family of GTPases that regulate a variety of signal transduction pathways, is upregulated in ischemia-damaged neurons. RhoB immunoreactivity precedes DNA single-strand breaks and heralds the evolving infarct, making it an early predictor of neuronal death. Expression of RhoB colocalized with drastic rearrangement of the actin cytoarchitecture indicates a role for Rho in postischemic morphological changes. Apoptosis in a murine hippocampal cell line was also associated with an early increase in RhoB protein. Activation of caspase-3, a crucial step in apoptosis, could be inhibited by cytochalasin D, a substance that counteracts the actin-modulating activity of Rho GTPases, indicating that Rho proteins may have impact on injury-initiated neuronal signal transduction. Our findings make Rho GTPases potential targets for the development of drugs aimed at limiting neuronal death following brain damage.
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PMID:GTPase RhoB: an early predictor of neuronal death after transient focal ischemia in mice. 1135 85

Rho family GTPases are critical molecular switches that regulate the actin cytoskeleton and cell function. In the current study, we investigated the involvement of Rho GTPases in regulating neuronal survival using primary cerebellar granule neurons. Clostridium difficile toxin B, a specific inhibitor of Rho, Rac, and Cdc42, induced apoptosis of granule neurons characterized by c-Jun phosphorylation, caspase-3 activation, and nuclear condensation. Serum and depolarization-dependent survival signals could not compensate for the loss of GTPase function. Unlike trophic factor withdrawal, toxin B did not affect the antiapoptotic kinase Akt or its target glycogen synthase kinase-3beta. The proapoptotic effects of toxin B were mimicked by Clostridium sordellii lethal toxin, a selective inhibitor of Rac/Cdc42. Although Rac/Cdc42 GTPase inhibition led to F-actin disruption, direct cytoskeletal disassembly with Clostridium botulinum C2 toxin was insufficient to induce c-Jun phosphorylation or apoptosis. Granule neurons expressed high basal JNK and low p38 mitogen-activated protein kinase activities that were unaffected by toxin B. However, pyridyl imidazole inhibitors of JNK/p38 attenuated c-Jun phosphorylation. Moreover, both pyridyl imidazoles and adenoviral dominant-negative c-Jun attenuated apoptosis, suggesting that JNK/c-Jun signaling was required for cell death. The results indicate that Rac/Cdc42 GTPases, in addition to trophic factors, are critical for survival of cerebellar granule neurons.
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PMID:An essential role for Rac/Cdc42 GTPases in cerebellar granule neuron survival. 1150 62

Daunorubicin, an anti-cancer drug, is known to induce apoptosis in HL-60 cells in a dose-dependent manner through the activation of caspase-3 (CPP32). Caspase-3 selective inhibitor, Ac-DEVD-CHO, prevented both the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). D4-GDI is a GDP dissociation inhibitor for the Ras-related Rho family GTPase in hematopoietic cells. Here we report that D4-GDI is a substrate for the caspase-3. D4-GDI was cleaved to a 23 kDa fragment by daunorubicin treatment in HL-60 cells with kinetics that parallel the onset of apoptosis. D4-GDI cleavage as well as DNA fragmentation was inhibited by treatment with Ac-DEVD-CHO but not with Ac-YVAD-CHO, a caspase-1 inhibitor. These data suggest that D4-GDI of Rho family GTPase may be regulated during apoptosis through the caspase-3 mediated cleavage of the GDI protein.
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PMID:D4-GDI is cleaved by caspase-3 during daunorubicin-induced apoptosis in HL-60 cells. 1198 76

Clostridium difficile toxin B (TcdB) inactivates the small GTPases Rho, Rac and Cdc42 during intoxication of mammalian cells. In the current work, we show that TcdB has the potential to stimulate caspase-dependent and caspase-independent apoptosis. The apoptotic pathways became evident when caspase-3-processed-vimentin was detected in TcdB-treated HeLa cells. Caspase-3 activation was subsequently confirmed in TcdB-intoxicated HeLa cells. Interestingly, caspase inhibitor delayed TcdB-induced cell death, but did not alter the time-course of cytopathic effects. A similar effect was also observed in MCF-7 cells, which are deficient in caspase-3 activity. The time-course to cell death was almost identical between cells treated with TcdB plus caspase inhibitor and cells intoxicated with the TcdB enzymatic domain (TcdB1-556). Unlike TcdB treated cells, intoxication with TcdB1-556 or expression of TcdB1-556 in a transfected cell line, did not stimulate caspase-3 activation yet cells exhibited cytopathic effects and cell death. Although TcdB1-556 treated cells did not demonstrate caspase-3 activation these cells were apoptotic as determined by differential annexin-V/propidium iodide staining and nucleosomal DNA fragmentation. These data indicate TcdB triggers caspase-independent apoptosis as a result of substrate inactivation and may evoke caspase-dependent apoptosis due to a second, yet undefined, activity of TcdB. This is the first example of a bacterial virulence factor with the potential to stimulate multiple apoptotic pathways in host cells.
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PMID:Clostridium difficile toxin B activates dual caspase-dependent and caspase-independent apoptosis in intoxicated cells. 1210 88

Ectopic expression of ROCK II (Rho kinase II or ROKalpha), an effector of Rho GTPase, induces membrane blebbing and chromatin condensation. ROCK II can induce membrane blebbing in the presence of the caspase inhibitor z-VAD-fmk or in caspase-3-deficient MCF-7 cells, indicating that the activation of caspases is not required. ROCK-II-induced membrane blebbing, however, is reversed by the myosin light chain kinase inhibitor ML-7 or cytochalasin D. In addition, the expression of a constitutively activated form of cofilin (S3A-cofilin) suppresses both membrane blebbing and chromatin condensation in ROCK II expressing cells. These findings suggest that the activation of actin-myosin contractility is responsible for membrane blebbing and chromatin condensation and implicate ROCK II as a potential mediator of the morphological changes associated with apoptosis.
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PMID:ROCK-II-induced membrane blebbing and chromatin condensation require actin cytoskeleton. 1212 56

The signaling pathways that lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) use to activate Akt in ovarian cancer cells are investigated here. We show for the first time, with the use of both pharmacological and genetic inhibitors, that the kinase activity and S473 phosphorylation of Akt induced by LPA and S1P requires both mitogen-activated protein (MAP) kinase kinase (MEK) and p38 MAP kinase, and MEK is likely to be upstream of p38, in HEY ovarian cancer cells. The requirement for both MEK and p38 is cell type- and stimulus-specific. Among 12 cell lines that we tested, 11 respond to LPA and S1P and all of the responsive cell lines require p38 but only nine of them require MEK. Among different stimuli tested, platelet-derived growth factor stimulates S473 phosphorylation of Akt in a MEK- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1-stimulated Akt S473 phosphorylation require p38 but not MEK. Insulin, on the other hand, stimulates Akt S473 phosphorylation independent of both MEK and p38 in HEY cells. T308 phosphorylation stimulated by LPA/S1P requires MEK but not p38 activation. MEK and p38 activation were sufficient for Akt S473 but not T308 phosphorylation in HEY cells. In contrast to S1P and PDGF, LPA requires Rho for Akt S473 phosphorylation, and Rho is upstream of phosphatidylinositol 3-kinase (PI3-K). LPA/S1P-induced Akt activation may be involved in cell survival, because LPA and S1P treatment in HEY ovarian cancer cells results in a decrease in paclitaxel-induced caspase-3 activity in a PI3-K/MEK/p38-dependent manner.
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PMID:Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific. 1218 43

Jurkat T cells induced to undergo apoptosis by the CD95(Fas/Apo-1) pathway were investigated by proteome analysis. The most prominent differing protein spots of apoptotic and nonapoptotic cells were identified as various heterogeneous ribonuclear proteins (hnRNPs) and Rho guanin nucleotide dissociation inhibitor (GDI) 2. In apoptotic cells, four spots slightly differing in molecular mass and/or isoelectric point were identified as Rho GDI 2 with the mass and pI as expected after caspase-3 cleavage near the N-terminus. Subcellular proteome analysis revealed that Rho GDI 2 was highly enriched in the cytosolic fraction, present in minor amounts in the nuclear fraction and absent from the mitochondrial fraction. In apoptotic cells however, the spots representing processed and modified Rho GDI 2 were found in the cytosol, in the nucleus and also the mitochondria at different spot positions. In addition, twelve different hnRNPs were identified to be altered after induction of cell death of which hnRNPs A/B, D, F, H, I and L were hitherto unknown to be modified during apoptosis. Most of the hnRNP spots were found in the nucleus of nonapoptotic cells, whereas these proteins, either modified or unmodified, relocated to the cytosol and/or the mitochondria in apoptotic cells. Our results demonstrate that modification of proteins during apoptosis is often accompanied by their relocalisation between cellular compartments.
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PMID:Prediction of translocation and cleavage of heterogeneous ribonuclear proteins and Rho guanine nucleotide dissociation inhibitor 2 during apoptosis by subcellular proteome analysis. 1220 95

Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family (also known as FGF-7), is an important protective factor for epithelial cells. The receptor for KGF (also called FGFR2-IIIb), which has intrinsic tyrosine kinase activity, is expressed specifically on epithelial cells and in the lung epithelium. Administration of KGF has been shown to protect the lung from various insults, but the mechanism of protection is not well understood. To understand the mechanism by which KGF exerts protective functions on epithelial cells, we used the yeast two-hybrid assay to identify proteins that interact with the KGF receptor (KGFR). Here we show that the cytoplasmic domain of KGFR interacts with p21-activated protein kinase (PAK) 4, which is a new member of the PAK family. The PAKs are regulated by the Rho-family GTPases Rac and Cdc42. PAK4 is the most divergent member of the PAK family of proteins and may have distinct functions. However, stimuli that regulate PAK4 activity are not known. Our data show that PAK4 can associate with the KGFR, which is dependent on KGFR tyrosine kinase activity. We show that a dominant negative mutant of PAK4 blocks KGF-mediated inhibition of caspase-3 activation in epithelial cells subjected to oxidant stress. Our data demonstrate that PAK4 is an important mediator of the anti-apoptotic effects of KGF on epithelial cells.
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PMID:p21-activated protein kinase 4 (PAK4) interacts with the keratinocyte growth factor receptor and participates in keratinocyte growth factor-mediated inhibition of oxidant-induced cell death. 1252 71

The mechanism of action of farnesyltransferase inhibitors (FTIs) has not been fully clarified. We investigated the cytotoxic effects of various FTIs in chronic myeloid leukemia (CML), using LAMA cells and marrow cells from 40 CML patients in chronic phase. FTI-mediated cytotoxic effect was observed in LAMA cells and in 65% of primary CML cells, whereas marrow cells from controls were only weakly affected. Cytotoxic effects were partially related to enhanced apoptosis; however, Fas-receptor (FasR) and Fas-ligand (FasL) expression were not modified by FTIs. Susceptibility to FTI-mediated inhibition did not correlate with FasR/FasL expression in CD34+ CML cells. Moreover, intra-cellular activation of caspase-1 and -8 were not altered by FTIs, and their blockade did not reverse FTI toxicity. However, we observed FTI-induced activation of caspase-3, and its inhibition partially reverted FTI-induced apoptosis. FTIs did not modulate bcl2, bclxL, and bclxS expression, whereas they increased inducible nitric oxide (iNOS) mRNA and protein levels, resulting in higher NO production. Furthermore, C3 exoenzyme, a Rho inhibitor, significantly increased iNOS expression in CML cells, suggesting that FTIs may up-regulate NO formation at least partially through FTI-mediated inhibition of Rho. We conclude that FTIs induce selective apoptosis in CML cells via activation of iNOS and caspase-3.
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PMID:Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells. 1271 96

Previous studies have shown that integrin activation and fluid shear stress can modulate the activity of sterol regulatory element binding proteins (SREBPs) in vascular endothelial cells. We investigated the role of small GTPase Rho-mediated signal transduction pathway in this mode of SREBP activation. Fluid shear stress activates the Rho downstream effectors ROCK, LIM kinase (LIMK), and cofilin. The various negative mutants of RhoA, ROCK, LIMK, and cofilin can block the shear stress activation of SREBPs. The shear stress-activated SREBP depends on S2P proteases but not caspase-3. Mechanistically, the endoplasmic reticulum-to-Golgi transport of SREBP cleavage-activating protein requires the actin-based cytoskeleton and is enhanced by the Rho-ROCK-LIMK-cofilin pathway. By enhancing the SREBP-mediated cholesterol metabolism, this unique mechanism may contribute to endothelial cell functions under flow.
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PMID:Rho-ROCK-LIMK-cofilin pathway regulates shear stress activation of sterol regulatory element binding proteins. 1277 80


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