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)

Trauma triggers diffuse apoptotic neurodegeneration in the developing rat brain. To explore the pathogenesis of this phenomenon we investigated the involvement of three possible mechanisms: death receptor activation, activation of the intrinsic apoptotic pathway by cytochrome c release into the cytoplasm, and changes in trophic support provided by endogenous neurotrophins. We detected a decrease in the expression of bcl-2 and bcl-x(L), two antiapoptotic proteins that decrease mitochondrial membrane permeability, an increase in cytochrome c immunoreactivity in the cytosolic fraction, and an activation of caspase-9 in brain regions which show apoptotic neurodegeneration following percussion brain trauma in 7-day-old rats. Increase in the expression of the death receptor Fas was revealed by RT-PCR analysis, Western blotting, and immunohistochemistry, as was activation of caspase-8 in cortex and thalamus. Apoptotic neurodegeneration was accompanied by an increase in the expression of BDNF and NT-3 in vulnerable brain regions. The pancaspase inhibitor z-VAD.FMK ameliorated apoptotic neurodegeneration with a therapeutic time window of up to 8 h after trauma. These findings suggest involvement of intrinsic and extrinsic apoptotic pathways in neurodegeneration following trauma to the developing rat brain. Upregulation of neurotrophin expression may represent an endogenous mechanism that limits this apoptotic process.
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PMID:Pathways leading to apoptotic neurodegeneration following trauma to the developing rat brain. 1250 17

We have investigated the hepatic response of female C57BL/6J wild-type and p53(+/-) hemizygous mice to genotoxic levels of diethylstilbestrol (DES) using cell cycle and apoptosis-focussed cDNA expression arrays. DES induced the expression of 12 genes (bad, bax, bcl-x, caspase-1, p53, cyclin D3, GADD45, p21, p15, p27, p57 and Skp1) and down-regulated the expression of eight genes (bcl-2, caspase-2, caspase-7, caspase-8, E124, iNOS, mdm2 and NFkappab1) at twofold or greater levels. Taken together, these changes were strongly reflective of the induction of apoptosis in the livers of DES-treated mice. Of those genes showing the greatest changes in response to DES, p53, p21 and p57 were expressed at 2.1, 1.7 and 1.6 times greater (respectively) in wild-type mice as compared with p53(+/-) hemizygous mice. Differences in p53, p21 and bax expression were confirmed by RT-PCR and we conclude that the compromised response of p53(+/-) mice is likely to play a central role in the earlier appearance of tumours in this model, following exposure to genotoxic carcinogens.
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PMID:A comparison of gene expression changes in response to diethylstilbestrol treatment in wild-type and p53+/- hemizygous knockout mice using focussed arrays. 1250 44

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 ecdysone-inducible mammalian expression system is frequently used for inducible transgene expression in vitro and in vivo. Here, we describe a strong antiapoptotic effect of ecdysone analogs in the human colon carcinoma cell line RKO, which is in contrast to published data that ecdysteroids do not influence mammalian cell physiology. Inhibition of Fas ligand- and TNF-related apoptosis-inducing ligand-induced apoptosis by muristerone A occurs at the level of caspase-8 activation and is neutralized by phosphatidylinositol-3-kinase/Akt, protein kinase C and mitogen-activated protein kinase inhibitors. Microarray, Northern and Western blot analysis revealed that incubation of RKO cells with muristerone A leads to changes in gene expression levels, including an upregulation of bcl-x(L) mRNA and protein levels. Our data imply that ecdysteroids and ecdysone mimics can induce and/or repress gene transcription in RKO and other mammalian cells, thereby influencing the apoptotic behavior. Therefore, the ecdysone-inducible mammalian expression system may not be suitable for the analysis of apoptosis-related genes.
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PMID:Agonists of an ecdysone-inducible mammalian expression system inhibit Fas Ligand- and TRAIL-induced apoptosis in the human colon carcinoma cell line RKO. 1608 89

It was shown recently that exposure of the developing rat brain during the peak of synaptogenesis to commonly used general anesthetics can trigger widespread apoptotic neurodegeneration in many regions of the developing rat brain and persistent learning/memory deficits later on in life. To understand the mechanism by which general anesthetics induce apoptotic neuronal death we studied two common apoptotic pathways--the intrinsic and the extrinsic pathway--at different time points during synaptogenesis. We found that the intrinsic pathway is activated early on during anesthesia exposure (within two hours), as measured by the down-regulation of bcl-x(L), up-regulation of cytochrome c and the activation of caspase-9 in 7-day-old rats (the peak of synaptogenesis), but remains inactivated in 14-day-old rats (the end of synaptogenesis). The extrinsic pathway is activated later on (within six hours of anesthesia exposure), as measured by the up-regulation of Fas protein and the activation of caspase-8 in 7-day-old rats, but remains inactivated in 14-day-old rats. Anesthesia-induced apoptotic neurodegeneration is age dependent with vulnerability closely correlating with the timing of synaptogenesis, i.e. the developing brain is most sensitive at the peak of synaptogenesis (7 days old) and least sensitive at the end of synaptogenesis (14 days old).
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PMID:Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. 1615 81

Small-cell lung carcinomas account for about 15-20% of lung cancer and are characterized by an intrinsic resistance to apoptosis. Increasing evidence suggests that alteration in apoptosis/antiapoptosis balance could lead to fundamental resistance of small-cell lung cancer to chemotherapy and radiation. These molecular alterations include alteration of mitochondrial pathways (BCL2 and BCLXL overexpression, activation of stress protein such as HSP 90 and HSP70, activation of PI3K/AKT/mTOR pathway). Others abnormalities could inhibit activation of extrinsic pathway such as caspase-8 and FAS underexpression as well as C-FLIP overexpression. New therapies targeting some of these abnormalities are under clinical evaluation and predictive factors of response are needed to personalize these therapies.
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PMID:[Anti-apoptotic mechanisms in small-cell lung carcinoma]. 2022 50