EC:3.4.22.61 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.61 (caspase-8)
6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the effects of di(2-ethylhexyl) phthalate (DEHP) on gene expression in rat testis, 6-week-old male Sprague-Dawley rats were given a single oral dose of 20 or 2000 mg/kg and euthanized 3, 6, 24, or 72 h thereafter. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells were significantly increased in the testis at 24 and 72 h after the exposure to 2000 mg/kg of DEHP. On cDNA microarray analysis, in addition to apoptosis-related genes, genes associated with atrophy, APEX nuclease, MutS homologue (E. coli), testosterone-repressed-prostatic-message-2 (TRPM-2), connective tissue growth factor, collagen alpha 2 type V, and cell adhesion kinase were differentially expressed. To investigate the relationship between histopathological alteration and gene expression, we selected genes associated with apoptosis and analyzed their expression by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). With 20 mg/kg of DEHP treatment, bcl-2, key gene related to apoptosis, was increased. Up-regulation of bcl-2, inhibitor of Apaf-1/caspase-9/caspase-2 cascade of apoptosis, may be related to the fact that no morphological apoptotic change was induced after dosing of 20 mg/kg DEHP. With 2000 mg/kg of DEHP treatment, the apoptotic activator cascade, Fas/FasL, FADD/caspase-8/caspase-3 cascade, and Apaf-1/caspase-9/caspase-2 cascade were increased and bcl-2 was decreased. Thus, these gene regulations might lead the cells into apoptosis in the case of high exposure to DEHP. In contrast, FADD/caspase-10/caspase-6 cascade and caspase-11/caspase-3 cascade were not increased. These results indicate that the cascades of FADD/caspase-10/caspase-6 and caspase-11/caspase-3 are not related to apoptosis with DEHP treatment.
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PMID:Gene expression analysis of the rat testis after treatment with di(2-ethylhexyl) phthalate using cDNA microarray and real-time RT-PCR. 1547 63

The activated hepatic stellate cell (HSC) is an important fibrogenic cell type of the liver. Interferon-alpha (IFN-alpha) has recently been shown to elicit an antiapoptotic effect on activated HSC by a JAK-2-dependent inhibition of caspase-8 activation. As JAK-2 has so far been shown to be a member of the IFN-gamma signal transduction pathway we studied the effect of IFN-gamma on apoptosis as well as on its signaling in primary cultured rat HSC. IFN-gamma elicited a proapoptotic effect in activated HSC. The combination of both, IFN-gamma and IFN-alpha, however, completely cancelled each other's effect. No effect of the two cytokines on major members of apoptosis-regulating systems (CD95, CD95L, bcl-2, bax, bcl-xL, p53, p21WAF1, p27, NFkappaB) could be observed. Western Blot analysis revealed that gene expression of the chaperone HSP70 was found to be downregulated by IFN-gamma but upregulated by IFN-alpha. The effect could be abrogated by administration of both. After transfection of activated HSC with a pCMV-HSP70 M expression vector the proapoptotic effect of IFN-gamma was cancelled. Using HSP70 antisense, the antiapoptotic effect of IFN-alpha was cancelled as well. However IFN-gamma had no effect on upregulation of JAK-2 and pJAK-2 by IFN-alpha. Taken together IFN-gamma and IFN-alpha exert opposite effects on apoptosis in HSC. This effect is mediated by their counteracting effect on HSP70 expression which acts antiapoptotic at the level of caspase-8.
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PMID:Interferon-gamma acts proapoptotic on hepatic stellate cells (HSC) and abrogates the antiapoptotic effect of interferon-alpha by an HSP70-dependant pathway. 1554 Apr 63

Histone deacetylase inhibitors modulate the transcription of target genes and represent a new class of anticancer agents. The histone deacetylase inhibitor FR901228 has been reported to show antiproliferative and apoptotic effects in various malignancies including small cell lung cancer (SCLC) in vitro; however, the underlying mechanism is not fully understood. BCL-2 and BCL-XL are antiapoptotic proteins, of which overexpression has been reported to confer resistance to anticancer agents. High levels of BCL-2 and BCL-XL are frequently expressed in SCLC tumors. The present study was designed to clarify the apoptotic pathway of FR901228 in SCLC cells in vitro. FR901228 induced apoptosis in three SCLC cell lines after 24 hours of treatment. FR901228 activated caspase-9 and caspase-3 but not caspase-8, and the caspase-3 inhibitor Z-DEVD-fmk blocked the cytotoxicity of FR901228. FR901228 down-regulated the expression of bcl-2 and bcl-xL mRNA through de novo protein synthesis and suppressed the expression of BCL-2 and BCL-XL proteins. In addition, the combination of bcl-2 antisense oligonucleotides with FR901228 enhanced FR901228-induced caspase-3 activity and cytotoxicity. These findings suggest that FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway. Considering the possible contributions of BCL-2 and BCL-XL to multidrug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary SCLC tumors.
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PMID:The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells. 1554 78

Studies with clastogenic carcinogen diethylstilbestrol (DES) resulted in a broad of spectrum of toxic and carcinogenic effects in humans and rodents, but the cellular and molecular mechanism(s) by which it induces cancer is not clear. To identify putative genetic targets for p53 in vivo, we applied the cDNA macroarray gene expression profiles associated with apoptosis by comparing p53+/- knockout mice and wild-type mice on the kidney and uterus of female mice. p53+/- knockout mice and wild-type mice were treated with DES (500 micromole kg(-1)) or vehicle i.p once daily for 4 days. Total RNAs were obtained from kidney and uterus of both control and DES-treated. The signal intensities of individual gene spots on the membrane were quantified and normalized to the expression level of the GAPDH gene as an internal control. Our results demonstrated that 16 genes; bad, bax, bcl-2, bcl-w, bcl-x, caspase-3, caspase-7, caspase-8, c-myc, E124, GADD45, mdm2, NKkappab1, p53, p21, Rb and trail were up-regulated and six genes; caspase-1, caspase-2, DR5, E2F1, FasL and iNOS did not changed in response to DES treatment in wild-type mice compared to p53+/- knockout mice. Most genes are involved in cell cycle regulation, signal transduction, apoptosis, or transcription. The greatest changes were seen in bad, bcl-x, mdm2, p53 and p21 gene expression in wild-type mice compared to p53+/- knockout mice. In comparing p53 and p21 gene expression in wild-type mice and p53+/- knockout mice, there was an 4.4-fold vs. 1.8-fold; 8-fold vs. 5.2-fold for kidney and 16-fold vs. 5.5-fold; 2.1-fold vs. 8.3-fold for uterus samples increase in induction (respectively). RT-PCR and densitometric analysis was used to confirm the biggest changes of p21, p53 and bax genes. Using this approach, we have identified apoptosis associated genes regulated in response to DES and have revealed putative differences between the isogenic parent strain and p53+/- knockout mice, which will contribute to a better understanding of toxicity/carcinogenicity mechanisms in this model.
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PMID:Gene expression profiling of p53(+/-) knockout and wild-type mice following diethylstilbestrol administration. 1554 18

The aromatase knockout (ArKO) mouse is unable to synthesize estrogens. Immunohistochemical studies on active caspase-3 and tyrosine hydroxylase (TH) revealed apoptosis of dopaminergic neurons in the medial preoptic area (MPO) and arcuate nucleus (Arc) of the hypothalamus of 1-year-old (1yo) male ArKO mice while no active caspase-3 was detected in wild type (WT). Furthermore, the number of TH-positive cells in the MPO and caudal Arc was significantly decreased in 1yo ArKO compared to WT. RNase protection assays support the presence of apoptosis in 1yo ArKO hypothalamus, revealing an up-regulation of pro-apoptotic genes: FASL, FADD, and caspase-8. Concomitantly, the ratio of bcl-2-related anti-apoptotic genes to pro-apoptotic genes in the hypothalamus of 1yo ArKO mice was significantly down-regulated. Previously, we have reported that no such changes were observed in the hypothalamus of female ArKO mice. Thus, we have provided direct evidence that estrogen is required to maintain the survival and functional integrity of dopaminergic neurons in the MPO and Arc of male, but not female mice.
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PMID:Estrogen deficiency leads to apoptosis in dopaminergic neurons in the medial preoptic area and arcuate nucleus of male mice. 1555 24

Aspirin-induced apoptosis is one of the important mechanisms for its antitumour effect against gastric cancer. We aimed at investigating the involvement of bcl-2 family members in the apoptotic pathway in gastric cancer. Gastric cancer cell line AGS and MKN-45 were observed as to cell growth inhibition and induction of apoptosis in response to treatment with aspirin. Cell proliferation was measured by MTT assay. Apoptosis was determined by 4'-6-diamidino-2-phenylindole staining. Protein expression was determined by western blotting. We showed that aspirin activated caspase-8, caspase-9 and capase-3, cleaved and translocated Bid, induced a conformational change in and translocation of Bax and cytochrome c release. In addition, suppression of caspase-8 with the specific inhibitor z-IETD-fmk, as well as the pan-caspase inhibitor z-VAD-fmk, prevented Bid cleavage and subsequent apoptosis. The caspase inhibitors failed to abolish the effects on Bax activation. In conclusion, our results identify a role of caspase-8/Bid and activation of Bax as a novel mechanism for aspirin-induced apoptosis in gastric cancer.
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PMID:Activation of the caspase-8/Bid and Bax pathways in aspirin-induced apoptosis in gastric cancer. 1557 84

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor specifically activated by hypoxia. Activation of proapoptotic caspase-9 and caspase-3 pathways, by binding with tumor suppressor p53, HIF-1alpha could lead to harmful actions such as apoptosis. We examined whether increasing oxygen levels by hyperbaric oxygen (HBO) offers neuroprotection, at least partially by suppression of HIF-1alpha and apoptotic genes. Male SD rats (n = 78) were randomly divided into 13 groups: 1 sham group, 6 groups of global ischemia-hypotension (GI), and 6 groups of HBO treatment after global ischemia-hypotension (GI + HBO). HBO (3 ATA for 2 h) was applied at 1 h after global ischemia-hypotension. Rats were sacrificed at 6, 12, 24, 48, and 96 h and 7 days. Global ischemia-hypotension (10 min ischemia, 30-35 mm Hg) produced a marked increase of HIF-1alpha expressions in the hippocampus and cortex at 6 h and peaked at 48-96 h. The expressions of p53, caspase-9, and caspase-3 were all increased in a similar time course. These molecular changes were accompanied by massive cell loss in the hippocampal regions and to a lesser degree in the cortex, with features of apoptosis. HBO treatment reduced expressions of HIF-1alpha, p53, caspase-9, and caspase-3 and decreased cell death. The protein levels of proapoptotic caspase-8 and antiapoptotic bcl-2 were increased after global ischemia-hypotension and HBO potentiated the expression of caspase-8 and decreased expression of bcl-2. These results indicate that HBO has multiple actions on apoptotic genes even though the overall effect of HBO was decreased HIF-1alpha expression and reduced apoptosis after global ischemia-hypotension.
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PMID:Multiple effects of hyperbaric oxygen on the expression of HIF-1 alpha and apoptotic genes in a global ischemia-hypotension rat model. 1558 27

The aim of the current study was to evaluate the protein expression involved in the progression from dysplasia to invasive esophageal squamous cell carcinomas and to analyze the prognostic value of markers. Immunohistochemistry was performed for cell cycle regulators [p53, p21, p27, p16, cyclin D1, Rb], apoptosis-related proteins [Fas, Fas-L, FADD, TRAIL, DR4, DR5, caspase-8, caspase-3, bcl-2, Bax], tumor suppressor proteins [beta-catenin, E-cadherin, FHIT, Smad 4, VHL, PTEN, KAI-1], and oncoproteins [c-myc, COX-2, EGFR]. Caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR revealed significant differences between dysplasia and their corresponding invasive cancer portion in 25 cases. In a total of 118 cases of invasive cancer, proteins with frequent (> or = 60% of the cases) alterations were p53 (overexpression in 64% of SCCs), p27 (loss in 91%), p16 (loss in 81%), and FHIT (loss in 75%). Early clinical stage and bcl-2 immunopositivity were related to the survival rate of patients. In conclusion, caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR may be involved in the progression from dysplasia to invasive esophageal SCCs. Clinical stage and bcl-2 are independent prognostic factors throughout the multivariate analysis.
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PMID:Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers. 1613 47

Neonatal rat ventricular myocytes (NRVM) grown in normoxic environment are not susceptible to Fas-induced apoptosis. In the present work, we tested the hypothesis that free radical injury represented by transient exposure to H2O2 sensitizes NRVM to Fas-mediated apoptosis. NRVM were treated with H2O2 (0.5 mM) for 2-4 h and thereafter exposed for 7 h to recombinant Fas ligand (rFasL, 10 ng/ml) plus an enhancing antibody (1 microg/ml). Apoptotic cardiomyocytes were counted and apoptosis-related proteins were measured by Western blot. H2O2 alone induced apoptosis (9.4+/-1.0%) that was preceded by activation of caspases-8 and -3, and PARP degradation. Incubation of NRVM with H2O2, followed by exposure to rFasL, increased the apoptotic index to 13.8+/-2.0%, but did not change caspase-8 or PARP activation. To investigate the mechanism underlying the sensitizing affect of H2O2 towards Fas-induced apoptosis, we studied the effects of H2O2 on the expression of key apoptosis signaling proteins. Incubation with H2O2 for 2-4 h decreased Fas expression and the expression of the Fas-related antiapoptotic proteins FLIP(L) and ARC, and increased the expression of the antiapoptotic proteins bcl-2 and xIAP. FADD expression was unchanged. Next, we tested the effect of H2O2 on the apoptosis-inducing, Fas-dependent Daxx-ASK-1-JUN kinase pathway. H2O2 dramatically increased ASK-1 expression and JUN kinase activation, but did not effect Daxx expression. Based on these findings we concluded that H2O2 sensitizes NRVM to Fas-mediated apoptosis by activating the Daxx-ASK-1-JUN kinase pathway, and by shifting the balance between proapoptotic and antiapoptotic proteins towards the former.
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PMID:Hydrogen peroxide predisposes neonatal rat ventricular myocytes to Fas-mediated apoptosis. 1615 98

Chemotherapy has been used for treatment of breast cancer but with limited success. We characterized the effects of bcl-2 antisense and cisplatin combination therapy in two human isogenic breast carcinoma cells p53(+)MCF-7 and p53(-)MCF-7/E6. The transferrin-facilitated lipofection strategy we have developed yielded same transfection efficiency in both cells. Bcl-2 antisense delivered with this strategy significantly induced more cell death, apoptosis, and cytochrome c release in MCF-7/E6 than in MCF-7, but did not affect Fas level in both cells and activated caspase-8 equally. Cisplatin exerted same effects on cell viability and apoptosis in both cells, but released smaller amounts of cytochrome c while activated more caspase-8 in MCF-7/E6. The combination treatment yielded greater effects on cell viability, apoptosis, cytochrome c release, and caspase-8 activation than individual treatments in both cells although p53(-) cells were more sensitive. The potentiated activation of caspase-8 in the combination treatment suggested that caspase-8-mediated (but cytochrome c-independent) apoptotic pathway is the major contributor of the enhanced cell killing. Thus, bcl-2 antisense delivered with transferrin-facilitated lipofection can achieve the efficacy of killing breast cancer cells and sensitizing them to chemotherapy. Bcl-2 antisense and cisplatin combination treatment is a potentially useful therapeutic strategy for breast cancer irrespective of p53 status.
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PMID:BCL-2 antisense and cisplatin combination treatment of MCF-7 breast cancer cells with or without functional p53. 1622 92

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