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

Cystathionine gamma-lyase (CSE) is a key enzyme in the trans-sulfuration pathway, which uses L-cysteine to produce hydrogen sulfide (H2S). The CSE/H2S system has been shown to play an important role in regulating cellular functions in different systems. In the present study, we overexpressed CSE in human aorta smooth muscle cells (HASMCs) using a recombinant defective adenovirus containing CSE gene (Ad-CSE). Infection of HASMCs with Ad-CSE resulted in a significant increase in the expression of CSE protein and H2S production. Ad-CSE transfection inhibited cell growth and stimulated apoptosis, as evidenced by cell viability assay, Hoechst 33258 staining, TUNEL, and caspase 3 activation. CSE-mediated apoptosis was associated with an increased ERK and p38 MAPK activation, up-regulation of p21(Cip/WAK-1), and down-regulation of cyclin D1 expression. After inhibiting endogenous background CSE gene expression, direct administration of H2S at 100 microM induced apoptosis of HASMCs. The other two endproducts of CSE-catalyzed enzymatic reaction, ammonium and pyruvate, failed to do so. These results demonstrate that overexpression of CSE stimulates SMC apoptosis due to an increased endogenous production of H2S. Adenovirus-mediated transfer of CSE gene may provide a novel therapeutic approach in treating vascular diseases linked to abnormal cellular proliferation and vascular remodeling.
 ...
PMID:Pro-apoptotic effect of endogenous H2S on human aorta smooth muscle cells. 1650 67

The interaction between epithelial cells and micro-organisms is often a crucial initiating event in infectious diseases. Infection with Porphyromonas gingivalis, a Gram-negative anaerobe, is strongly associated with severe periodontal disease. This bacterium possesses an array of virulence factors, some of which can induce apoptosis. The tumour necrosis factor (TNF) receptor family is involved in the regulation of cellular homeostasis, cell surface molecules involved in phagocytosis, Fas ligand (L) expression and activation of the caspase cascade resulting in DNA fragmentation and cell blebbing. The current study examined the role of nuclear factor-kappaB (NFkappaB) in FasL-mediated apoptotic cell death in primary human gingival epithelial cells (HGEC) induced by heat-killed P. gingivalis, probably through TLR signalling pathways. A marked up-regulation of TLR2 and Fas-FasL was detected in HGEC stimulated with P. gingivalis. Activation of NFkappaB by P. gingivalis in HGEC was demonstrated by an NFkappaB promoter luciferase assay as well as by phosphorylation of p65 as detected by Western blotting. Activation of cleaved caspase-3 and caspase-8 resulted in apoptotic cell death of HGEC. The survival proteins c-IAP-1/c-IAP-2 were decreased in HGEC exposed to P. gingivalis. HGEC apoptosis induced by P. gingivalis was inhibited by an anti-human FasL monoclonal antibody. Blockade of NFkappaB by helenalin resulted in down-regulation of FasL whereas a caspase-8 inhibitor did not decrease FasL. Taken together, these studies show that P. gingivalis can induce epithelial cell apoptosis through Fas-FasL up-regulation and activation of caspase-3 and caspase-8.
 ...
PMID:Porphyromonas gingivalis enhances FasL expression via up-regulation of NFkappaB-mediated gene transcription and induces apoptotic cell death in human gingival epithelial cells. 1651 59

Infectious bursal disease virus (IBDV), the causative agent of a highly contagious disease in chickens, carries a small nonstructural protein (NS). This protein has been implicated to play a role in the induction of apoptosis. In this study, we investigate the kinetics of viral replication during a single round of viral replication and examine the mechanism of IBDV-induced apoptosis. Our results show that it is caspase dependent and activates caspases 3 and 9. Nuclear factor kappa B (NF-kappaB) is also activated and is required for IBDV-induced apoptosis. The NF-kappaB inhibitor MG132 completely inhibited IBDV-induced DNA fragmentation, caspase 3 activation, and NF-kappaB activation. To study the function of the NS protein in this context, we generated the recombinant rGLS virus and an NS knockout mutant, rGLSNSdelta virus, using reverse genetics. Comparisons of the replication kinetics and markers for virally induced apoptosis indicated that the NS knockout mutant virus induces earlier and increased DNA fragmentation, caspase activity, and NF-kappaB activation. These results suggest that the NS protein has an antiapoptotic function at the early stage of virus infection.
 ...
PMID:Nonstructural protein of infectious bursal disease virus inhibits apoptosis at the early stage of virus infection. 1653 4

Human epithelial cells infected with the parainfluenza virus simian virus 5 (SV5) show minimal activation of host cell interferon (IFN), cytokine, and cell death pathways. In contrast, a recombinant SV5 P/V gene mutant (rSV5-P/V-CPI-) overexpresses viral gene products and is a potent inducer of IFN, proinflammatory cytokines, and apoptosis in these cells. In this study, we have compared the outcomes of wild-type (WT) SV5 and rSV5-P/V-CPI- infections of primary human dendritic cells (DC), important antigen-presenting cells for initiating adaptive immune responses. We have tested the hypothesis that a P/V mutant which activates host antiviral responses will be a more potent inducer of DC maturation and function than WT rSV5, which suppresses host cell responses. Infection of peripheral blood mononuclear cell-derived immature DC with WT rSV5 resulted in high levels of viral protein and progeny virus but very little increase in cell surface costimulatory molecules or secretion of IFN and proinflammatory cytokines. In contrast, immature DC infected with the rSV5-P/V-CPI- mutant produced only low levels of viral protein and progeny virus, but these infected cells were induced to secrete IFN-alpha and other cytokines and showed elevated levels of maturation markers. Unexpectedly, DC infected with WT rSV5 showed extensive cytopathic effects and increased levels of active caspase-3, while infection of DC with the P/V mutant was largely noncytopathic. In mixed-culture assays, WT rSV5-infected DC were impaired in the ability to stimulate proliferation of autologous CD4+ T cells, whereas DC infected with the P/V mutant were very effective at activating T-cell proliferation. The addition of a pancaspase inhibitor to DC infected with WT rSV5 reduced cytopathic effects and resulted in higher surface expression levels of maturation markers. Our finding that the SV5 P/V mutant has both a reduced cytopathic effect in human DC compared to WT SV5 and an enhanced ability to induce DC function has implications for the rational design of novel recombinant paramyxovirus vectors based on engineered mutations in the viral P/V gene.
 ...
PMID:A simian virus 5 (SV5) P/V mutant is less cytopathic than wild-type SV5 in human dendritic cells and is a more effective activator of dendritic cell maturation and function. 1653 9

Transforming growth factor-beta superfamily has been implicated in tumorigenesis. We have recently shown that Nodal, a member of transforming growth factor-beta superfamily, and its receptor, activin receptor-like kinase 7 (ALK7), inhibit proliferation and induce apoptosis in human epithelial ovarian cancer cell lines. In this study, we further investigated the cellular mechanisms underlying the apoptotic action of ALK7 using an immortalized ovarian surface epithelial cell line, IOSE397, and an epithelial ovarian cancer cell line, OV2008. Infection of these cells with an adenoviral construct carrying constitutively active ALK7 (Ad-ALK7-ca) potently induced cell death; all cells died after 3 and 5 days of Ad-ALK7-ca infection in IOSE397 and OV2008 cells, respectively. ALK7-ca induced the expression of proapoptotic factor Bax but suppressed the expression of antiapoptotic factors Bcl-2, Bcl-XL, and Xiap. Silencing of Bax by small interfering RNA in IOSE397 cells significantly reduced ALK7-ca-induced apoptosis as measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay but partially blocked ALK7-ca-induced caspase-3 activation and did not affect the down-regulation of Xiap by ALK7-ca. Dominant-negative Smad2, Smad3, and Smad4 blocked ALK7-ca-regulated Xiap and Bax expression and caspase-3 activation. Thus, ALK7-induced apoptosis is at least in part through two Smad-dependent pathways, Bax/Bcl-2 and Xiap.
 ...
PMID:Activin receptor-like kinase 7 induces apoptosis through up-regulation of Bax and down-regulation of Xiap in normal and malignant ovarian epithelial cell lines. 1660 37

cAMP response-element binding (CREB) transcription factors transduce cell survival responses to peptide hormones and growth factors in normal tissues and mutant CREB proteins are implicated in tumorigenesis. Ovarian cancer most frequently arises from the ovarian surface epithelium (OSE), possibly due to repeat inflammation-associated injury-repair episodes that promote neoplasia. We asked if post-receptor signalling involving the CREB family of proteins plays a role in OSE cell survival. In an ovine ovulation model, abundant expression of phospho-CREB/activating transcription factor (ATF) protein was detected immunohistochemically, strongly localised to OSE cells in the proximity of pre-ovulatory follicles. Treatment of primary sheep OSE cell cultures with LH stimulated cAMP accumulation and reduced apoptosis (caspase 3/7 activity) in response to serum withdrawal. When OSE cells were infected with an adenovirus containing a CRE-luciferase construct, exposure to LH and FSH induced CRE-directed transcription. Finally, when a non-phosphorylatable mutant of CREB (Ad CREB(S133A)) was adenovirally expressed, apoptosis measured by activation of caspases was increased several fold relative to that caused by transfection with wild-type CREB (Ad CREB(WT)) or lacZ (Ad lacZ). To test the potential clinical relevance of these findings, we expressed mutant CREB protein in normal human OSE cells from four women and a series of cell lines derived from human ovarian cancers. Infection with Ad CREB(S133A) markedly increased apoptosis in normal human OSE but had no detectable effect on apoptosis in any of the cancer cell lines. We conclude that CREB/ATF signalling is important for the maintenance of OSE cell survival in vitro and is altered in human cell lines derived from ovarian cancers.
 ...
PMID:cAMP response element-binding (CREB) signalling and ovarian surface epithelial cell survival. 1706 10

Cultured cortical neurons exposed to the Human Immunodeficiency Virus gp120 coat protein undergo apoptosis involving activation of both caspase-8 and caspase-9. Additionally, gp120-mediated neuronal apoptosis requires the pro-apoptotic transcription factor p53. As caspase-8-induced apoptosis does not typically require p53, we examined the possibility of a novel role for p53 in caspase-8 activation initiated by gp120. We observed that gp120 treatment of cultured cortical neurons induced caspase-8 activity and Bid cleavage independently of p53, but induction of caspase-3 enzymatic activity required p53 expression. These findings suggested the possibility that p53 down-regulates a caspase-3 inhibitor. We observed high-level expression of the caspase-3/9 inhibitor X-linked inhibitor of apoptosis protein (XIAP) in cultured cortical neurons. Adenoviral expression of p53 or induction of endogenous p53 by camptothecin treatment reduced XIAP protein in neurons. Infection with a p53 expressing adenovirus increased expression of the mRNA for Omi/HtrA2, a protease that cleaves and inactivates XIAP. These findings suggest that p53 regulates neuronal apoptosis, in part, by suppressing the anti-apoptotic protein XIAP via transcriptional activation of Omi/HtrA2.
 ...
PMID:Activation of the extrinsic caspase pathway in cultured cortical neurons requires p53-mediated down-regulation of the X-linked inhibitor of apoptosis protein to induce apoptosis. 1748 72

Bronchial airway epithelial cells (BAEpC) are among the first cells to encounter M. tuberculosis following airborne infection. However, the response of BAEpC to M. tuberculosis infection has been little studied. This study investigates the response of a human BAEpC cell line (BEAS-2B) to infection with Mycobacterium bovis Bacille Calmette Guerin (BCG). Cultured human BEAS-2B cells were experimentally infected with BCG. Uninfected BEAS-2B cultures were included as controls. Following infection, BEAS-2B cells were evaluated by various methods at various time points up to 3 days. Cell proliferation was evaluated by cellular bioreduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Distribution of cells along the cell cycle was evaluated by FACS analysis of cellular DNA. Apoptotic cells were identified by cell death ELISA and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling method. Eighty-four apoptosis-relevant genes were screened by PCR gene microarray. Translation of Fas, Fas ligand (Fas-L), and Fas-associated death domain (FADD) were evaluated quantitatively by real-time PCR. Expression of Fas and FADD proteins was evaluated by immunofluorescence and Western blot. Activity of caspase-3 and caspase-8 was evaluated by colorimetric assay of their enzymatic activity. BCG infection of BEAS-2B cells inhibits proliferation, induces cell cycle arrest at the G(0)/G(1) phase, causes apoptosis, modulates transcription of multiple apoptosis-relevant genes, promotes translation of Fas, Fas-L, and FADD, upregulates expression of Fas and FADD proteins, and increases activity of caspase-3 and caspase-8. Infection with BCG does not cause any significant change in the secretion of TGF-beta. The roles of Fas and FADD as mediators of BCG-induced apoptosis in BEAS-2B cells were tested by partial blockade of Fas and FADD expression with silencing RNA. Partial blockade of Fas or FADD expression results in a decreased apoptotic response to BCG infection. In conclusion, BCG induces cell cycle arrest and apoptosis in BEAS-2B cells. BCG induced apoptosis of BEAS-2B cells via the Fas death receptor pathway.
 ...
PMID:Induction of cell cycle arrest and apoptosis by BCG infection in cultured human bronchial airway epithelial cells. 1752 97

Helicobacter pylori infection is associated with altered gastric epithelial cell turnover. To evaluate the role of oxidative stress in cell death, gastric epithelial cells were exposed to various strains of H. pylori, inflammatory cytokines, and hydrogen peroxide in the absence or presence of antioxidant agents. Increased intracellular reactive oxygen species (ROS) were detected using a redox-sensitive fluorescent dye, a cytochrome c reduction assay, and measurements of glutathione. Apoptosis was evaluated by detecting DNA fragmentation and caspase activation. Infection with H. pylori or exposure of epithelial cells to hydrogen peroxide resulted in apoptosis and a dose-dependent increase in ROS generation that was enhanced by pretreatment with inflammatory cytokines. Basal levels of ROS were greater in epithelial cells isolated from gastric mucosal biopsy specimens from H. pylori-infected subjects than in cells from uninfected individuals. H. pylori strains bearing the cag pathogenicity island (PAI) induced higher levels of intracellular oxygen metabolites than isogenic cag PAI-deficient mutants. H. pylori infection and hydrogen peroxide exposure resulted in similar patterns of caspase 3 and 8 activation. Antioxidants inhibited both ROS generation and DNA fragmentation by H. pylori. These results indicate that bacterial factors and the host inflammatory response confer oxidative stress to the gastric epithelium during H. pylori infection that may lead to apoptosis.
 ...
PMID:Helicobacter pylori infection induces oxidative stress and programmed cell death in human gastric epithelial cells. 1756 77

Cyclooxygenase-2 (COX-2) activity has been implicated in the pathogenesis of cerebral ischemia. To determine whether COX-2 activity within the neuron itself exacerbates hypoxic neuronal injury, neuron-enriched cultures were subjected to anoxia. Treatment with COX-2 selective antagonists decreased cell death. Neurons cultured from homozygous COX-2 gene disrupted mice were resistant to hypoxia compared to those of heterozygotes. Infection of primary neurons with AAV expressing COX-2 exacerbated cell death compared to neurons infected with enhanced green fluorescent protein (EGFP) control vector. Addition of PGE2, PGD2 or PGF2 alpha to the medium exacerbated injury, suggesting that the deleterious effects of COX-2 overexpression in hypoxia could be mediated by direct receptor mediated effects of prostaglandins. Overexpression of COX-2 did not increase expression of cyclin D1 or phosphoretinoblastoma protein (pRb), or cleavage of caspase 3 suggesting that this cell cycle mechanism does not mediate COX-2 toxicity in this model.
 ...
PMID:Neuronal cyclooxygenase-2 activity and prostaglandins PGE2, PGD2, and PGF2 alpha exacerbate hypoxic neuronal injury in neuron-enriched primary culture. 1776 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>