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)

A growing body of evidence has suggested that oxidative stress causes cardiac injuries during ischemia/reperfusion. Extracellular signal-regulated kinases (ERKs) have been reported to play pivotal roles in many aspects of cell functions and to be activated by oxidative stress in some types of cells. In this study, we examined oxidative stress-evoked signal transduction pathways leading to activation of ERKs in cultured cardiomyocytes of neonatal rats, and determined their role in oxidative stress-induced cardiomyocyte injuries. ERKs were transiently and concentration-dependently activated by hydrogen peroxide (H2O2) in cardiac myocytes. A specific tyrosine kinase inhibitor, genistein, suppressed H2O2-induced ERK activation, while inhibitors of protein kinase A and C or Ca2+ chelators had no effects on the activation. When CSK, a negative regulator of Src family tyrosine kinases, or dominant-negative mutant of Ras or of Raf-1 kinase was overexpressed, activation of transfected ERK2 by H2O2 was abolished. The treatment with H2O2 increased the number of cells stained positive by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and induced formation of DNA ladder and activation of CPP32, suggesting that H2O2 induced apoptosis of cardiac myocytes. When H2O2-induced activation of ERKs was selectively inhibited by PD98059, the number of cardiac myocytes which showed apoptotic death was increased. These results suggest that Src family tyrosine kinases, Ras and Raf-1 are critical for ERK activation by hydroxyl radicals and that activation of ERKs may play an important role in protecting cardiac myocytes from apoptotic death following oxidative stress.
 ...
PMID:Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. 931 82

This study demonstrates that Ha-rasVal12 oncogene overexpression sensitizes NIH/3T3 fibroblasts to lovastatin (LOV) cytotoxicity. This sensitization is through apoptosis, which was characterized by increasing CPP32 (caspase-3) activity and DNA fragmentation. Bcl-2 overexpression increased the resistance of the Ha-ras transformants to LOV and rescued the cells from apoptosis, further confirming that the LOV-sensitive cells died of apoptosis. Further analysis showed that Ha-ras activity inversely correlated with WAF1 activity. LOV treatment suppressed Ha-ras activity but induced WAF1 activity and disrupted the cell population in G0/G1 and S phases. The Ha-ras transformants expressing either dominant negative RasAsn17 or Raf-1CB4 showed reverted susceptibility to LOV. These data confirm the involvement of Ras and demonstrate that Raf-1 signalling is required for LOV-induced cell death. Taken together, the possible action of LOV-induced apoptosis is through suppressing Ha-ras activity and increasing WAF1 activity, which alters cell cycle progression and finally activates suppressed apoptotic pathway in a Fas/Fas-L- and p53-independent fashion.
 ...
PMID:Ha-rasVal12 oncogene increases susceptibility of NIH/3T3 cells to lovastatin. 967 86

The bcl-2 protein plays an essential role in preventing cell death. Its activity is regulated through association with bcl-2 homologous and nonhomologous proteins and also by serine phosphorylation. We now report that bcl-2 can be proteolytically cleaved towards its N-terminus by a cysteine proteinase present in RL-7 lymphoma cell lysates, yielding a major product of apparent MW 20 kDa, different from the products of bcl-2 cleavage by HIV protease. Moreover, bcl-2 proteins mutated for Asp residues at positions 31 and 34 were efficiently cleaved by RL-7 cell lysates, indicating that this proteolytic activity is distinct from the caspase-3 that cleaves bcl-2 at Asp 34. This bcl-2 cleaving activity is inhibited by E-64 and is therefore distinct from the proteinases of the ICE/Ced-3 family (caspases), whereas reciprocally, ICE (caspase-1) is unable to cleave bcl-2. It is optimally active at pH 5, a feature distinguishing it from calpain, another non-ICE cysteine proteinase which has been associated with apoptosis. This novel bcl-2 cleaving protease, although constitutively present in RL-7 cells and resting peripheral blood lymphocytes (PBL) was upregulated following induction of apoptosis in RL-7 cells or mitogen activation in PBL. The N-terminus of bcl-2 which contains the BH4 domain that binds the kinase Raf-1 and the phosphatase calcineurin is essential for anti-apoptotic activity. Its cleavage might provide a novel post-translational mechanism for regulating bcl-2 function and could amplify ongoing programmed cell death.
 ...
PMID:N-terminus cleavage of bcl-2 by a novel cellular non-ICE cysteine proteinase. 973 98

The stimulation of caspases is a critical event in apoptotic cell death. Several kinases critically involved in cell proliferation pathways have been shown to be cleaved by caspase-mediated mechanisms. Thus, the degradation of delta protein kinase C (PKC) and MEKK-1 by caspase-3 generates activated fragments corresponding to their catalytic domains, consistent with the observations that both enzymes are important for apoptosis. In contrast, other kinases reported to have anti-apoptotic properties, such as Raf-1 and Akt, are inactivated by proteolytic degradation by the caspase system. Since the atypical PKCs have been shown to play critical roles in cell survival, in the study reported here we have addressed the potential degradation of these PKCs by the caspase system in UV-irradiated HeLa cells. Herein we show that although zetaPKC and lambda/iotaPKC are both inhibited in UV-treated cells, only zetaPKC but not lambda/iotaPKC is cleaved by a caspase-mediated process. This cleavage generates a fragment that corresponds to its catalytic domain that is enzymatically inactive. The sequence where caspase-3 cleaves zetaPKC was mapped, and a mutant resistant to degradation was shown to protect cells from apoptosis more efficiently than the wild-type enzyme.
 ...
PMID:Cleavage of zetaPKC but not lambda/iotaPKC by caspase-3 during UV-induced apoptosis. 1019 49

Caveolae-like domains (CLDs) have been hypothesized to mediate apoptosis, since they contain sphingomyelin and initiate the conversion of sphingomyelin to ceramide. To address whether CLDs are directly involved in apoptosis, CLDs from U937 cells were isolated, taking advantage of their detergent insolubility and low density. The CLDs contained alkaline phosphatase as well as many signaling molecules, including Fyn, protein kinase Calpha, Raf-1, phospholipase Cgamma1, and tyrosine phosphoproteins. Immunoblotting and immunofluorescent data showed that TNF receptor 1 colocalized with CD36 in CLDs, suggesting that TNF-alpha-initiated apoptosis occurs in CLDs. When cells were incubated with lipoprotein-deficient medium, the cholesterol concentration was greatly decreased in CLDs but not in other fractions, implying that the CLDs were selectively disrupted. In the CLD-disrupted cells, the surface expression of TNF receptor 1 and CD36 was significantly reduced. Analysis of cellular morphology, percent DNA fragmentation, DNA laddering, and caspase-3 activity showed that TNF-alpha-mediated apoptosis was blocked in CLD-disrupted cells, whereas anti-Fas-mediated apoptosis was not. Since Fas was not found in CLDs of Jurkat cells, apoptosis by Fas ligation might not require CLDs. Taken together, these data strongly imply that TNF-alpha-mediated apoptosis is initiated in CLDs.
 ...
PMID:TNF-alpha-mediated apoptosis is initiated in caveolae-like domains. 1035 68

A series of bisindolylmaleimide (Bis) compounds were designed as analogs of the natural compound staurosporine (STS), which is a potent inducer of apoptosis. Many of the Bis analogs appear to be highly selective inhibitors of the protein kinase C (PKC) family, including PKC-alpha, -beta, -gamma, -delta, -epsilon, and -zeta, unlike STS, which is an inhibitor of a broad spectrum of protein kinases. In this report we describe the effects of the Bis analogs, Bis-I, Bis-II, Bis-III and Ro-31-8220 on the survival and proliferation of HL-60 cells, which have been widely used as a model cell system for studying the biological roles of PKC. Treatment of HL-60 cells with Bis-I, Bis-II, Bis-III, or Ro-31-8220 blocked phosphorylation of the PKC target protein Raf-1 with equal potency but did not appear to affect the general phosphorylation of proteins by other kinases. However, the biological effects of the Bis compounds were different: Bis-I and Bis-II had no observable effects on either cell survival or proliferation; Bis-III inhibited cell proliferation but not survival, whereas Ro-31-8220 induced apoptosis. These results indicated that the members of the PKC family which could be inhibited by the Bis analogs were required neither for survival nor proliferation of HL-60 cells. Analyses of cells treated with Ro-31-8220 showed that the apoptotic effect of Ro-31-8220 on HL-60 cells was mediated by a well-characterized transduction process of apoptotic signals: i.e., mitochondrial cytochrome c efflux and the activation of caspase-3 in the cytosol. Moreover, the ability of Ro-31-8220 to induce apoptotic activation was completely inhibited by the over-expression of the apoptotic suppressor gene, Bcl-2, in the cells. Interestingly, proliferation of the Bcl-2-over-expressing cells was still sensitive to the presence of Ro-31-8220, suggesting that the inhibitory effects of Ro-31-8220 on viability and cell proliferation were mediated by different mechanisms. In particular, the apoptotic effect of Ro-31-8220 on cells was not altered by the presence of an excess amount of the other Bis analogs, suggesting that this effect is mediated by a factor(s) other than PKC or by a mechanism which was not saturable by the other Bis analogs. Finally, structure-function analyses of compounds related to Ro-31-8220 revealed that a thioamidine prosthetic group in Ro-311-8220 was largely responsible for its apoptotic activity.
 ...
PMID:The staurosporine analog, Ro-31-8220, induces apoptosis independently of its ability to inhibit protein kinase C. 1082 75

Enrichment of Neuro 2A cells with docosahexaenoic acid (22:6n-3) decreased apoptotic cell death induced by serum starvation as evidenced by the reduced DNA fragmentation and caspase-3 activity. The protective effect of 22:6n-3 became evident only after at least 24 h of enrichment before serum starvation and was potentiated as a function of the enrichment period. During enrichment 22:6n-3 incorporated into phosphatidylserine (PS) steadily, resulting in a significant increase in the total PS content. Similar treatment with oleic acid (18:1n-9) neither altered PS content nor resulted in protective effect. Hindering PS accumulation by enriching cells in a serine-free medium diminished the protective effect of 22:6n-3. Membrane translocation of Raf-1 was significantly enhanced by 22:6n-3 enrichment in Neuro 2A cells. Consistently, in vitro biomolecular interaction between PS/phosphatidylethanolamine /phosphatidylcholine liposomes, and Raf-1 increased in a PS concentration-dependent manner. Collectively, enrichment of neuronal cells with 22:6n-3 increases the PS content and Raf-1 translocation, down-regulates caspase-3 activity, and prevents apoptotic cell death. Both the antiapoptotic effect of 22:6n-3 and Raf-1 translocation are sensitive to 22:6n-3 enrichment-induced PS accumulation, strongly suggesting that the protective effect of 22:6n-3 may be mediated at least in part through the promoted accumulation of PS in neuronal membranes.
 ...
PMID:Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n-3). Role of phosphatidylserine in antiapoptotic effect. 1090 16

CHO cells expressing the human insulin receptors (IR) were used to evaluate the effect of the potent farnesyltransferase inhibitor, manumycin, on insulin antiapoptotic function. Cell treatment with manumycin blocked insulin's ability to suppress pro-apoptotic caspase-3 activity which led to time-dependent proteolytic cleavage of two nuclear target proteins. The Raf-1/MEK/ERK cascade and the serine/threonine protein kinase Akt are two survival pathways that may be activated in response to insulin. We tested the hypothesis that inhibition of farnesylated Ras was causally related to manumycin-induced apoptosis and showed that the response to manumycin was found to be independent of K-Ras function because membrane association and activation of endogenous K-Ras proteins in terms of GTP loading and ERK activation were unabated following treatment with manumycin. Moreover, blocking p21Ras/Raf-1/MEK/ERK cascade by the expression of a transdominant inhibitory mSOS1 mutant in CHO-IR cells kept cells sensitive to the antiapoptotic action of insulin. Insulin-dependent activation of Akt was blocked by 4 h treatment with manumycin (P < 0.01), a kinetic too rapid to be explained by Ras inhibition. This study suggests that the depletion of short-lived farnesylated proteins by manumycin suppresses the antiapoptotic action of insulin at least in part by disrupting Akt activation but not that of the K-Ras/Raf-1/ERK-dependent cascade.
 ...
PMID:Akt-dependent antiapoptotic action of insulin is sensitive to farnesyltransferase inhibitor. 1102 30

HL-60/Bcr-Abl cells, with ectopic expression of p185 Bcr-Abl tyrosine kinase (TK), and K562 cells, with endogenous expression of p210 Bcr-Abl TK, display a high degree of resistance against antileukemic drug-induced apoptosis (G. Fang et al., Blood, 96: 2246-2256, 2000). Present studies demonstrate that treatment with ansamycin antibiotic geldanamycin (GA), or its less toxic analogue 17-allylamino-17-demethoxygeldanamycin (17-AAG), induces cytosolic accumulation of cytochrome c and cleavage and activities of caspase-9 and caspase-3, triggering apoptosis of HL-60/Bcr-Abl and K562 cells. GA or 17-AAG down-regulated intracellular Bcr-Abl and c-Raf protein levels, as well as reduced Akt kinase activity. Similar to Raf-1, v-Src, and Her-2-neu, Bcr-Abl TK has chaperone association with heat shock protein 90 (Hsp90). By binding and inhibiting Hsp90, GA or 17-AAG treatment shifted the binding of Bcr-Abl from Hsp90 to Hsp70 and induced the proteasomal degradation of Bcr-Abl, because cotreatment with proteasome inhibitor PSC341 reduced both GA (or 17-AAG)-mediated down-regulation of Bcr-Abl levels and inhibited apoptosis of HL-60/Bcr-Abl and K562 cells. These data establish the in vitro activity of GA and 17-AAG against Bcr-Abl-positive leukemic cells and support the in vivo investigation of 17-AAG against Bcr-Abl-positive leukemias.
 ...
PMID:Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. 1128 Jul 26

The involvement of MAPK pathways in differentiation, proliferation and survival was investigated by comparing Epo and GM-CSF signalling in human factor-dependent myeloerythroid TF-1 cells with abnormal Epo-R. GM-CSF withdrawal induced cell-cycle arrest and apoptosis accompanied by increased caspase-3 activity, DNA degradation and reduced expression of the antiapoptotic Bcl-2 and Bcl-xl proteins. Readministration of GM-CSF but not Epo reversed these processes and induced proliferation. The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. In contrast, Epo failed to activate the Raf-1/ERK1/2 MAPK pathway or to induce Egr-1 and/or c-Fos expression, while it induced erythroid differentiation in GM-CSF-deprived cells. In addition, the Epo-induced haemoglobin production was inhibited in the presence of GM-CSF. These results demonstrate that the activation of MAPK cascade is not necessary for Epo-induced haemoglobin production in TF-1 cells and suggest a negative cross-talk between the signalling of GM-CSF-stimulated cell proliferation and Epo-induced erythroid differentiation.
 ...
PMID:Activation of Raf/ERK1/2 MAP kinase pathway is involved in GM-CSF-induced proliferation and survival but not in erythropoietin-induced differentiation of TF-1 cells. 1160 85


1 2 3 4 5 Next >>