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

Neutrophils are short-lived leukocytes that die by apoptosis. Whereas stress-induced apoptosis is mediated by the p38 mitogen-activated protein (MAP) kinase pathway (Frasch, S. C., Nick, J. A., Fadok, V. A., Bratton, D. L., Worthen, G. S., and Henson, P. M. (1998) J. Biol. Chem. 273, 8389-8397), signals regulating spontaneous neutrophil apoptosis have not been fully determined. In this study we found increased activation of protein kinase C (PKC)-beta and -delta in neutrophils undergoing spontaneous apoptosis, but we show that only activation of PKC-delta was directly involved in the induction of apoptosis. PKC-delta can be proteolytically activated by caspase 3. We detected the 40-kDa caspase-generated fragment of PKC-delta in apoptotic neutrophils and showed that the caspase 3 inhibitor Asp-Glu-Val-Asp-fluoromethylketone prevented generation of the 40-kDa PKC-delta fragment and delayed neutrophil apoptosis. In a cell-free system, removal of PKC-delta by immunoprecipitation reduced DNA fragmentation, whereas loss of PKC-alpha, -beta, or -zeta had no significant effect. Rottlerin and LY379196 inhibit PKC-delta and PKC-beta, respectively. Only Rottlerin was able to delay neutrophil apoptosis. Inhibitors of MAP-ERK kinase 1 (PD98059) or p38 MAP kinase (SB202190) had no effect on neutrophil apoptosis, and activation of p42/44 and p38 MAP kinase did not increase in apoptotic neutrophils. We conclude that spontaneous neutrophil apoptosis involves activation of PKC-delta but is MAP kinase-independent.
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PMID:Spontaneous neutrophil apoptosis involves caspase 3-mediated activation of protein kinase C-delta. 1060

Microtubule inhibitors are widely used in cancer chemotherapy, but the signaling mechanisms that link microtubule disarray to destructive or protective cellular responses are poorly understood. Because members of the mitogen-activated protein kinase (MAPK) family have been implicated in regulation of cell survival and cell death, we examined the extent and kinetics of activation of JNK, ERK, and p38 MAPKs in response to treatment of KB-3 carcinoma cells with several microtubule inhibitors. All four agents tested (vinblastine, vincristine, Taxol, and colchicine) caused significant (6- to 13-fold) activation of JNK, concomitant inactivation of ERK, and a reduction in basal p38 MAPK activity. JNK activation and ERK inactivation occurred prior to caspase 3 activation. The microtubule inhibitors also induced phosphorylation of Raf-1 kinase. SEK-1, upstream of JNK, was also activated and phosphorylated in response to the microtubule inhibitors, and sustained phosphorylation of three endogenous JNK substrates (c-Jun, ATF-2, and JunD) was observed. By comparison, the antitumor agent doxorubicin induced activation of JNK and p38 but had no effect on ERK activity or Raf-1. These data demonstrate that microtubule inhibitors elicit distinct and specific effects on MAPK-mediated signaling pathways and suggest in particular that coordinate and reciprocal alterations in JNK and ERK activities are important facets of the cellular response to microtubule disruption.
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PMID:Microtubule inhibitors elicit differential effects on MAP kinase (JNK, ERK, and p38) signaling pathways in human KB-3 carcinoma cells. 1062 71

The chelating and antioxidant effects of pyrrolidine dithiocarbamate (PDTC) have been investigated extensively for preventing cell death induced by different insults. However, the toxic effects of PDTC have been studied only recently and fewer studies on the toxic effects on astrocytes have been reported. In our study, we demonstrated that both PDTC and Cu(2+) alone were rated as only weakly toxic in inducing cell death in cortical astrocytes with IC(50) of 300 microM and 180 microM, respectively. However, PDTC and Cu(2+) in the complex form markedly potentiated with each other by about 1,000-fold with IC(50) of 0.3 microM PDTC plus 10 microM Cu(2+). Other metals at concentrations of 3-10 microM (VO(4)(5+), Cr(6+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+), Pb(2+), Bi(2+), Ba(2+), UO(2+), Cs(+), SeO(4)(2-), La(3+)) had no such potentiating effects on PDTC. Changes in morphology (nuclear condensation), apoptotic body formation, and hypodiploidity of DNA suggested that the PDTC-Cu(2+) complex induced cell death through an apoptotic process. Further studies showed that the PDTC-Cu(2+) complex decreased mitochondrial membrane potential, increased hydrogen peroxide production, and depleted GSH contents. After the increased oxidative stress, PDTC-Cu(2+) complex differentially activated JNKs, ERK, p38 and caspase 3, which caused PARP degradation in a time-dependent manner. All these effects were consistent with the increased cellular Cu contents. The nonpermeable copper-specific chelator bathocuproine disulfonate (BCPS), but not the permeable Cu(2+) chelator neocuproine, abolished all the observed effects. Antioxidants (N-acetylcysteine [NAC], vitamin C), catalase, and Cu(2+)-binding proteins (albumin, hemoglobin, and higher serum) reduced the cytotoxic effects of PDTC-Cu(2+) complex. We concluded that the death signaling pathway of PDTC-Cu(2+) complex was mediated by oxidative stress and subsequent JNK activation. These findings imply that PDTC, a widely used pesticide and medicine that is capable of penetrating the blood-brain barrier, may cause neurotoxicity through astrocyte dysfunction.
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PMID:Death signaling pathway induced by pyrrolidine dithiocarbamate-Cu(2+) complex in the cultured rat cortical astrocytes. 1094 Nov 51

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.
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PMID:Akt-dependent antiapoptotic action of insulin is sensitive to farnesyltransferase inhibitor. 1102 30

Low oxygen and nutrient depletion play critical roles in tumorigenesis, but little is known about how they interact to produce tumor survival and tumor malignancy. In the present study, we investigated the mechanism underlying hypoxia-modulated apoptosis of serum-deprived HepG2 cells. Our results showed that hypoxia blocked the apoptosis, which was accompanied with decreased Bax/Bcl-2 ratio, inhibited cytochrome c release, and reduced caspase-3 activity. More importantly, increased expressions of VEGF and its receptor-2 (KDR) under hypoxic/serum-deprived condition suggest that VEGF may act as a survival factor in a self-promoting manner. Data were further supported by results that recombinant human VEGF (rhVEGF) suppressed the serum deprivation-induced apoptosis, and anti-VEGF neutralizing antibody block anti-apoptotic activity of hypoxia. In addition, inhibitors of receptor tyrosine kinase blocked antiapoptosis of hypoxia. Our study further showed that rhVEGF or hypoxia induced ERK phosphorylation in serum-deprived cells, and that a specific inhibitor of MAPK/ERK, PD98059 eliminated the anti-apoptotic activity of rhVEGF or hypoxia by increasing Bax/Bcl-2 ratio and caspase-3 activity. Our data led us to conclude that induction of ERK phosphorylation and decrease of Bax/Bcl-2 ratio by rhVEGF implies that hypoxia-induced VEGF prevents apoptosis of serum-deprived cells by activating the MAPK/ERK pathway. Taken together, we propose that hypoxia enhances survival of nutrient-depleted tumor cells by reducing susceptibility to apoptosis, which consequently leads to tumor malignancy.
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PMID:Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. 1103 Jan 51

When PC12 cells are deprived of trophic support they undergo apoptosis. We have previously shown that survival of trophic factor-deprived PC12M1 cells can be promoted by activation of the G protein-coupled muscarinic receptors. The mechanism whereby muscarinic receptors inhibit apoptosis is poorly understood. In the present study we investigated this mechanism by examining the effect of muscarinic receptor activation on the serum deprivation-induced activity of key players in apoptosis, the caspases, in PC12M1 cells. The results showed that m1 muscarinic activation inhibits caspase activity induced by serum deprivation. This effect appeared to be caused by the prevention of activation of caspases such as caspase-2 and caspase-3, and not by the inhibition of existing activity. Muscarinic receptor activation also stimulated the mitogen-activated protein kinase/extracellular signaling-regulated kinase (MAPK/ERK) and phosphoinositide (PI) 3-kinase signaling pathways. The PI 3-kinase pathway inhibitors wortmannin and LY294002, as well as the MAPK/ERK pathway PD98059 inhibitor, did not however suppress the inhibitory effect of the muscarinic receptors on caspase activity. The results therefore suggested that the muscarinic survival effect is mediated by a pathway that leads to caspase inhibition by MAPK/ERK- and PI 3-kinase-independent signaling cascades.
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PMID:M1 muscarinic receptors block caspase activation by phosphoinositide 3-kinase- and MAPK/ERK-independent pathways. 1104 77

In the present study, we investigated the effects of geranylgeraniol (GGO), a potent inducer of apoptosis in various lines of human tumor cells, on signal transduction cascades involved in apoptosis in human leukemia cells. GGO strongly induced the activation of c-Jun N-terminal kinase (JNK/SAPK) within 2 h in U937 and K562 cells, while neither ERK nor p38 was activated to any considerable extent during GGO-induced apoptosis. Transient expression of a constitutively active mutant form of mitogen-activated protein kinase kinase 1 (MEKK1), deltaMEKK1, or of deltaMEKK1-green fluorescent protein (GFP) in K562 cells activated JNK, but not a caspase-3-like protease, and was insufficient to induce cell death but rendered cells susceptible to GGO-induced cell death. Stable expressions of deltaMEKK1-GFP in U937 cells gave similar results. In contrast to VP-16-induced apoptosis, GGO-induced activation of JNK was almost completely inhibited by benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD) and by benzyloxycarbonyl-Asp-CH2OC[O]-2,6,-dichlorobenzene (Z-Asp), indicating that the JNK-activation step is located downstream of the caspase signaling pathway in GGO-induced apoptosis. Moreover, apoptosis induced by GGO was significantly inhibited in two lines of cells with a dominant-negative deletion mutation in c-Jun, indicating a requirement for JNK signaling. In addition, unlike the effects on other inducers of apoptosis, the activation of JNK and of the caspase-3-like protease by GGO was significantly delayed by 12-O-tetradecanoylphorbol-13-acetate (TPA), suggesting that the site of inhibition by TPA might be located upstream of the protease and JNK in the GGO-induced apoptotic signaling pathway.
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PMID:The mechanism of geranylgeraniol-induced apoptosis involves activation, by a caspase-3-like protease, of a c-jun N-terminal kinase signaling cascade and differs from mechanisms of apoptosis induced by conventional chemotherapeutic drugs. 1108 77

Caspase-3 knockout mice exhibit thickening of the internal granule cell layer of the cerebellum. Concurrently, it has been shown that intracerebral injection of pituitary adenylate cyclase-activating polypeptide (PACAP) induces a transient increase of the thickness of the cerebellar cortex. In the present study, we have investigated the possible effect of PACAP on caspase activity in cultured cerebellar granule cells from 8-day-old rat. Incubation of granule neurons with PACAP for 24 h promoted cell survival and prevented DNA fragmentation. Exposure of cerebellar granule cells to the specific caspase-3 inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp fluoromethylketone (Z-DEVD-FMK) for 24 h markedly enhanced cell survival and inhibited apoptotic cell death. Time-course studies revealed that PACAP causes a prolonged inhibition of caspase-3 activity without affecting caspase-1. Administration of graded concentrations of PACAP for 3 h induced a dose-dependent inhibition of caspase-3 activity. Incubation of granule cells with both dibutyryl-cAMP (dbcAMP) and phorbol 12-myristate 13-acetate (PMA) mimicked the inhibitory effect of PACAP on caspase-3. Cotreatment of cultured neurons with the protein kinase A inhibitor H89 and the protein kinase C inhibitor chelerythrine abrogated the effect of PACAP on caspase-3 activity. In contrast, the ERK kinase inhibitor U0126 did not affect the action of PACAP on caspase-3 activity. These data demonstrate that PACAP prevents cerebellar granule neurons from apoptotic cell death through a protein kinase A- and protein kinase C-dependent inhibition of caspase-3 activity.
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PMID:The neuroprotective effect of pituitary adenylate cyclase-activating polypeptide on cerebellar granule cells is mediated through inhibition of the CED3-related cysteine protease caspase-3/CPP32. 1108 78

Adipocyte number, a determinant of adipose tissue mass, reflects the balance between the rates of proliferation/differentiation vs. apoptosis of preadipocytes. The percentage of 3T3-L1 preadipocytes undergoing cell death following serum deprivation was reduced by 10 nM insulin-like growth factor (IGF)-1 (from 50.0 +/- 0.7% for control starved cells to 27.5 +/- 3.1%). TUNEL staining confirmed the apoptotic nature of the cell death. The protective effect of IGF-1 was blocked by phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin, and LY294002, but was unaffected by rapamycin, PD98059, or SB203580, which inhibit mammalian target of rapamycin (mTOR), ERK kinase (MEK1), and p38 MAPK respectively. Exogenous PI(3,4,5)P3 (10 microM), the principal product of IGF-1-stimulated PI3K in 3T3-L1 preadipocytes, had a modest survival effect on its own, reducing cell death from 47.9 +/- 3.4% to 35.6 +/- 3.5%. When added to the combination of IGF-1 and LY294002, PI(3,4,5)P3 reversed most of the inhibitory effect of LY294002 on IGF-1-dependent cell survival, protein kinase B/Akt phosphorylation, and caspase-3 activity. Taken together, these results implicate PI(3,4,5)P3 as a necessary signal for the anti-apoptotic action of IGF-1 on 3T3-L1 preadipocytes.
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PMID:Phosphatidylinositol-3,4,5-trisphosphate is required for insulin-like growth factor 1-mediated survival of 3T3-L1 preadipocytes. 1114 83

Proteasome inhibition leads to accumulation of transcription factors, heat shock proteins, cyclins, and other proteasome substrate proteins by blocking their proteolytic degradation. An increase in gene transcription upon proteasome inhibition was found for a group of proteins, including p21(WAF1/CIP1), ubiquitin, and transcription factors. In this study, we have demonstrated selective up-regulation of extracellular signal-regulated kinase 3 (ERK3) mRNA and protein expression upon treatment with peptide-based proteasome inhibitors or lactacystin. ERK3 is a family member of the mitogen-activated protein kinases (also called ERK) that are key mediators of signal transduction from the cell surface to the nucleus. ERK3 up-regulation is independent of the p53, Bcl2, and caspase 3 status of cells. p38 pathway kinase inhibitors prevent proteasome-dependent ERK3 induction and enhance the antiproliferative effect of proteasome inhibitors. MCF-7 cells expressing ERK3 ectopically show increased resistance toward proteasome inhibition. The results indicate that ERK3 expression is a consequence of p38 pathway activation and most probably represents an intracellular defense or rescue mechanism against cell stress and damage induced by proteasome inhibition.
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PMID:Proteasome- and p38-dependent regulation of ERK3 expression. 1114 4


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