Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genotoxic stresses induce cellular responses that can be observed at the level of gene expression. We have studied changes in gene expression following BPDE exposure in HeLa cells by using a cDNA expression array of 597 human genes. After a 53-hr exposure to 0.4 microM BPDE, nine genes were upregulated. The protein products of these genes are: fos-related antigen 2, apoptotic cysteine protease MCH4, DB1 (zinc finger protein 91), transcription factor ETR103, integrin alpha, interleukin-4, interleukin-6, 23-kDa highly basic protein, and ribosomal protein S9. We observed the downregulation of gene expression of three genes: heat-shock protein 27, DNA-binding protein TAX, and NADH-ubiquinone oxidoreductase B18 subunit. These results suggest unknown functions or regulatory circuits for several of the responsive genes and demonstrate the complexity of cellular responses to genotoxic insults.
Environ Mol Mutagen 2000
PMID:Identification of genes responsive to BPDE treatment in HeLa cells using cDNA expression assays. 1104 1

Apoptotic cell death is induced in SH-SY5Y neuroblastoma cells following exposure to the protein kinase inhibitors staurosporine (100 nM) and 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine: H-7 (100 microM). This is associated with reduced levels of PARP 117 kDa and with the concomitant formation of PARP-cleaved products of 89 kDa that result from caspase-3 activation. The process is inhibited with DEVD-fmk, a potent caspase-3 (and caspase-8) inhibitor, thus indicating that staurosporine- and H-7-induced cell death in SH-SY5Y is mediated by caspase activation. Increased caspase-2- and caspase-3-like activities, but not caspase-9-like activity, were demonstrated by monitoring proteolysis of the corresponding colorimetric substrates. Caspase-2 activity peaked at 6 h, whereas caspase-3 peaked at 12 h in parallel with the maximal loss of cell viability. No modifications in the expression levels of Fas and Fas-L were observed by Western blotting. Furthermore, no activation of caspase-8 was elicited by colorimetric assays through the process of apoptosis of neuroblastoma cells. These findings indicate that the Fas/Fas-L-caspase-8 pathway of cell death signaling is not involved in staurosporine- and H-7-induced apoptosis in SH-SY5Y neuroblastoma cells.
Brain Res Mol Brain Res 2000 Dec 28
PMID:Staurosporine- and H-7-induced cell death in SH-SY5Y neuroblastoma cells is associated with caspase-2 and caspase-3 activation, but not with activation of the FAS/FAS-L-caspase-8 signaling pathway. 1114 7

Changes in epithelial cell shape can lead to cell death and detachment. Actin filaments are cleaved during apoptosis, but whether disruption in the actin cytoskeletal network, as one manifestation of cell shape change, can itself induce apoptosis is not known. We tested this hypothesis in the airway epithelial cell line 1HAEo(-) and in primary airway epithelial cells by preventing actin filament elongation with cytochalasin D or by aggregating actin filaments with jasplakinolide. Disruption of actin filament integrity promptly induced apoptosis in adherent epithelial cells within 5 h. Jasplakinolide-induced apoptosis did not disrupt focal adhesions, whereas cytochalasin D-induced apoptosis decreased focal adhesion protein expression and occurred despite ligation of the fibronectin receptor. Death induction was abrogated by the caspase inhibitors z-VAD-fmk and Ac-DEVD-cho but not by blocking the Fas (CD95) receptor. Whereas cytochalasin D--induced apoptosis was associated with cleavage of pro-caspase-8, jasplakinolide-induced apoptosis was not. Both agents induced formation of a death-inducing signaling complex. These data demonstrate that disruption of actin filament integrity with either cytochalasin D or jasplakinolide induces apoptosis in airway epithelial cells but by different mechanisms, and suggest that actin may be an early modulator of apoptotic commitment.
Am J Respir Cell Mol Biol 2001 Mar
PMID:Initiation of apoptosis by actin cytoskeletal derangement in human airway epithelial cells. 1124 27

beta-Lapachone, a novel anti-neoplastic drug, induces various cancer cells to undergo apoptosis. In a previous report, we showed that beta-lapachone-induced apoptosis of HL-60 cells is mediated by oxidative stress. However, in the present study, we found that beta-lapachone-induced apoptosis of human prostate cancer (HPC) cells may be independent of oxidative stress. In contrast to the 10-fold beta-lapachone-induced increase in H(2)O(2) production seen in HL-60 cells, only a 2- to 4-fold increase was observed in HPC cells. N-acetyl-L-cysteine (NAC), a thiol antioxidant, inhibited the apoptosis in DU145 cells after 12 h exposure to beta-lapachone. Nonetheless, NAC, along with other antioxidants, failed to exert similar effect in HPC cells subjected to beta-lapachone treatment for 24 h. Under this premise, we suggest that the oxidative stress may not play a crucial role in beta-lapachone-mediated HPC cell apoptosis. Here we demonstrate that damage to genomic DNA is the trigger for the apoptosis of HPC cells induced by beta-lapachone. According to our results, beta-lapachone stimulates DNA dependent kinase expression and poly(ADP-ribose) polymerase cleavage in advance of significant morphological changes. beta-Lapachone promotes the expression of cyclin-dependent kinase (cdk) inhibitors (p21(WAF1) and p27(Kip1)), induces bak expression, and subsequently stimulates the activation of caspase-7 but not of caspase-3 or caspase-8 during the apoptosis of HPC cells. Taken together, these results suggest that the signaling pathway involving the beta-lapachone-induced apoptosis of HPC cell may be by DNA damage, induction of cdk inhibitors (p21 and p27), and then subsequent stimulation of caspase-7 activation.
Mol Pharmacol 2001 Apr
PMID:Induction of CDK inhibitors (p21(WAF1) and p27(Kip1)) and Bak in the beta-lapachone-induced apoptosis of human prostate cancer cells. 1125 23

The oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a multifunctional molecule that induces monocytic differentiation of human myeloid leukemia cells and inhibits proliferation of diverse human tumor cell lines. The present studies on human osteosarcoma cells demonstrate that CDDO induces mitochondrial cytochrome c release, caspase-3 activation, and internucleosomal DNA fragmentation. Overexpression of the caspase-8 inhibitor CrmA blocked CDDO-induced cytochrome c release and apoptosis. By contrast, overexpression of the antiapoptotic Bcl-x(L) protein blocked CDDO-induced cytochrome c release, but only partly inhibited caspase-3 activation and apoptosis. In concert with these findings, we demonstrate that CDDO: 1) activates caspase-8 and thereby caspase-3 by a cytochrome c-independent mechanism and 2) induces cytochrome c release by caspase-8-dependent cleavage of Bid. The results also demonstrate that treatment of osteosarcoma cells with CDDO induces differentiation, as assessed by alkaline phosphatase activity and osteocalcin production, and that this response is abrogated in cells that overexpress CrmA. These findings demonstrate that CDDO induces both osteoblastic differentiation and apoptosis by caspase-8-dependent mechanisms.
Mol Pharmacol 2001 May
PMID:The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism. 1130 92

Proteins of the caspase family are involved in the signalling pathway that ultimately leads to programmed cell death (apoptosis), which has been reported to occur in some experimental models of stroke. In a previous paper we used quantitative reverse transcription and polymerase chain reaction (RT-PCR) to characterise changes in the mRNA expression of one member of this family, caspase-3, in a rat model of permanent focal ischemia. Here we have used this technique to study the expression of a further three caspases which are involved in different aspects of caspase signalling. Caspase-8, involved in Fas-mediated apoptosis, was upregulated in the cortex of ischemic rats. Caspase-11, which leads to the synthesis of the functional form of the cytokine interleukin-1 beta, also showed increased expression, but with a different temporal profile from caspase-8. In contrast, caspase-9, which forms part of the pathway signalling through the mitochondria, showed a decrease in expression. The expression of a further four caspases (1, 2, 6 and 7) has also been characterised in a simpler experiment. These caspases all showed distinctive patterns of expression following the induction of ischemia. These data lead us to conclude that caspase expression as a whole is under very strict transcriptional control in this model. Certain elements of caspase signalling, such as the Fas-induced pathway and the events upstream of IL-1 beta processing, are upregulated, while others are not. This may be due to some form of genetic program activated in response to ischemia in the brain and may highlight which biological pathways are modulated.
Brain Res Mol Brain Res 2001 Apr 18
PMID:Caspase mRNA expression in a rat model of focal cerebral ischemia. 1131 84

Cerebellar granule neurons (CGN) cultured in the presence of serum and depolarizing potassium concentrations undergo apoptosis when switched to serum-free medium containing physiological potassium concentrations. Here we show that processing of the key protease, caspase-3, depends on the activation of caspase-9, but not of caspase-8. Selective peptide inhibitors of caspase-9 block processing of caspase-3 and caspase-8 and inhibit apoptosis, whereas a selective inhibitor of caspase-8 blocks neither processing of caspase-3 nor cell death. The data obtained with peptide inhibitors were confirmed by adenovirally mediated ectopic expression of the cytokine response modifier A (crmA), the baculovirus protein p35, and the X chromosome-linked inhibitor of apoptosis (XIAP). Further, caspase-8-activating death receptors do not mediate apoptosis in CGN and potassium withdrawal-induced apoptosis evolves unaltered in gld or lpr mice, which harbor mutations in the CD95/CD95 ligand system. Thus, neuronal apoptosis triggered by potassium deprivation is death receptor-independent but involves the mitochondrial pathway of caspase activation.
Mol Cell Neurosci 2001 Apr
PMID:Cascade of caspase activation in potassium-deprived cerebellar granule neurons: targets for treatment with peptide and protein inhibitors of apoptosis. 1131 7

Tumor necrosis factor (TNF)-alpha is released in acute inflammatory lung syndromes linked to the extensive vascular dysfunction associated with increased permeability and endothelial cell apoptosis. TNF-alpha induced significant decreases in transcellular electrical resistance across pulmonary endothelial cell monolayers, reflecting vascular barrier dysfunction (beginning at 4 h and persisting for 48 h). TNF-alpha also triggered endothelial cell apoptosis beginning at 4 h, which was attenuated by the caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone. Exploring the involvement of the actomyosin cytoskeleton in these important endothelial cell responses, we determined that TNF-alpha significantly increased myosin light chain (MLC) phosphorylation, with prominent stress fiber and paracellular gap formation, which paralleled the onset of decreases in transcellular electrical resistance and enhanced apoptosis. Reductions in MLC phosphorylation by the inhibition of either MLC kinase (ML-7, cholera toxin) or Rho kinase (Y-27632) dramatically attenuated TNF-alpha-induced stress fiber formation, indexes of apoptosis, and caspase-8 activity but not TNF-alpha-induced barrier dysfunction. These studies indicate a central role for the endothelial cell cytoskeleton in TNF-alpha-mediated apoptosis, whereas TNF-alpha-induced vascular permeability appears to evolve independently of contractile tension generation.
Am J Physiol Lung Cell Mol Physiol 2001 Jun
PMID:Differential effect of MLC kinase in TNF-alpha-induced endothelial cell apoptosis and barrier dysfunction. 1135 Jul 95

The potential efficacy of prodrug activation of a transduced suicide gene in a cancer cell may be impaired or enhanced by oncoproteins produced by that cell. In the context of a gene therapy protocol for chronic myeloid leukemia (CML) we examined whether the Bcr-Abl fusion protein would have either of these effects. Thus, the mechanism of cell killing by transfer of herpes simplex virus thymidine kinase (HSV-tk) and subsequent ganciclovir (GCV) treatment was examined in pre-B (TonB210.1) cells and myeloid cells (32D) and in their BCR-ABL-expressing counterparts. HSV-tk-transduced cell lines, either in the presence or in the absence of BCR-ABL expression, became susceptible to GCV at concentrations which were nontoxic to the nontransduced cells. This susceptibility was represented by apoptotic cell death in all cases. Apoptosis was observed after 24 h of treatment with GCV in the tk-transduced parental cells and in the BCR-ABL-expressing TonB210.1 cells but only after a delay of more than 24 h in the 32Dp210 cells compared to 32D. Cell death in the BCR-ABL-expressing clones was preceded by S- and G2/M-phase cell cycle arrest. Activation of FAS/APO-1 and caspase-8 was observed in all the tk-transduced cell lines after GCV treatment. However, the caspase-8 inhibitor Z-IETD-FMK only partially abrogated tk/GCV-induced apoptosis. A possible role for inhibition of Bcl-2 or Bcl-x(L) expression in the apoptosis induced by GCV was observed in the tk-transduced TonB210.1 cells but not in the 32D or 32Dp210 cells. The data demonstrate that expression of the Bcr-Abl oncoprotein does not block the apoptosis induced by the HSV-tk/GCV system, suggesting that this suicide gene therapy strategy could be considered for the treatment of CML in blast crisis.
Mol Ther 2001 May
PMID:BCR-ABL-expressing cells transduced with the HSV-tk gene die by apoptosis upon treatment with ganciclovir. 1135 68

This study was designed to detect apoptosis in the human amnion and to elucidate the signalling pathway involved in its regulation. Samples of human amnion were obtained from 34 women (weeks 11-42 of gestation) and studied using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) method with light microscopy (LM) and transmission electron microscopy (TEM). Apoptotic regulators in the samples were studied by immunohistochemistry and caspase activity assay. The TUNEL method with LM demonstrated that the percentage of TUNEL-positive cells in the amniotic epithelium was the highest in weeks 40-41 of gestation (P < 0.05) independent of the onset of labour, and the cells were often detached from the epithelium into the amniotic cavity at term. The TUNEL method with TEM clearly showed the characteristic features of apoptosis such as the nuclear condensed chromatin with abundant free 3'-OH DNA ends, cell shrinkage and a decrease in the number of desmosomes, except for the presence of apoptotic bodies. Fas and Fas ligand (FasL) were constantly expressed on apical membranes of amniotic epithelial cells from weeks 16-27 through to 40-41 of gestation, while no Bcl-2 expression was observed throughout the gestational periods. Activities of caspase-3 and caspase-8, but not of caspase-9, were higher in weeks 40-41 than those from weeks 16-27 of gestation (P < 0.01). We conclude that apoptosis in term amniotic epithelium is independent of Bcl-2 regulation and onset of labour, and may play an important role in the fragility and rupture of human fetal membranes at term.
Mol Hum Reprod 2001 Jul
PMID:Apoptosis in the normal human amnion at term, independent of Bcl-2 regulation and onset of labour. 1142 Mar 92


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