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)

Asbestos causes pulmonary toxicity by mechanisms that in part involve reactive oxygen species (ROS). However, the precise source of ROS is unclear. We showed that asbestos induces alveolar epithelial cell (AEC) apoptosis by a mitochondrial-regulated death pathway. To determine whether mitochondrial-derived ROS are necessary for causing asbestos-induced AEC apoptosis, we utilized A549-rho(omicron) cells that lack mitochondrial DNA and a functional electron transport. As expected, antimycin, which induces an oxidative stress by blocking mitochondrial electron transport at complex III, increased dichlorofluoroscein (DCF) fluorescence in A549 cells but not in A549-rho(omicron) cells. Compared with A549 cells, rho(omicron) cells have less asbestos-induced ROS production, as assessed by DCF fluorescence, and reductions in total glutathione levels as well as less caspase-9 activation and apoptosis, as assessed by TdT-mediated dUTP nick end labeling staining and DNA fragmentation. A mitochondrial anion channel inhibitor that prevents ROS release from the mitochondria to the cytoplasm also blocked asbestos-induced A549 cell caspase-9 activation and apoptosis. Finally, a role for nonmitochondrial-derived ROS with exposure to high levels of asbestos (50 microg/cm(2)) was suggested by our findings that an iron chelator (phytic acid or deferoxamine) or a free radical scavenger (sodium benzoate) provided additional protection against asbestos-induced caspase-9 activation and DNA fragmentation in rho(omicron) cells. We conclude that asbestos fibers affect mitochondrial DNA and functional electron transport, resulting in mitochondrial-derived ROS production that in turn mediates AEC apoptosis. Nonmitochondrial-associated ROS may also contribute to AEC apoptosis, particularly with high levels of asbestos exposure.
Am J Physiol Lung Cell Mol Physiol 2004 Jun
PMID:Mitochondrial-derived free radicals mediate asbestos-induced alveolar epithelial cell apoptosis. 1476 69

Methylglyoxal (MG) is an endogenous metabolite that increases in the blood and tissues of diabetic patients and is believed to be linked to the development of chronic complications of diabetes. We showed previously that Jurkat cells treated with MG rapidly undergo apoptosis via c-Jun N-terminal kinase (JNK) activation. In this study, we examined whether phorbol 12-myristate 13-acetate (PMA) can prevent MG-induced apoptosis in Jurkat cells. The results showed the following: 1) PMA can prevent MG-induced apoptosis; 2) triggering of this antiapoptotic signal depends on the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathway; 3) PMA inhibits MG-induced activation of caspase-3 and caspase-9, release of cytochrome c, and decline of mitochondrial membrane potential, but it does not affect MG-induced JNK activation; 4) the ERK pathway modulates outer mitochondrial membrane permeability and regulates the mitochondrial death machinery; and 5) activated ERK prevents JNK-induced leakage of cytochrome c from isolated mitochondria. Taken together, these results suggest that PMA-induced ERK activation can protect Jurkat cells from methylglyoxal-induced apoptosis and that activated ERK exerts its antiapoptotic effects on mitochondria by inhibiting activated JNK-induced permeabilization of the outer mitochondrial membrane.
Mol Pharmacol 2004 Mar
PMID:Phorbol 12-myristate 13-acetate protects Jurkat cells from methylglyoxal-induced apoptosis by preventing c-Jun N-terminal kinase-mediated leakage of cytochrome c in an extracellular signal-regulated kinase-dependent manner. 1497 57

Ras activation is frequently observed in multiple myeloma either by mutation or through interleukin-6 receptor signaling. Recently, drugs designed to inhibit Ras have shown promise in preclinical myeloma models and in clinical trials. In this report, we characterize the pathways by which the clinically tested farnesyl transferase inhibitor (FTI) R115777 induces apoptosis in multiple myeloma cells. Contrary to the proposed mechanistic action of FTIs, we found that R115777 induces cell death despite Ras prenylation implying participation of Ras-independent mechanism(s). Apoptosis proceeded via an intrinsic cascade and was associated with an increase in the expression and activity of Bax. Bax activation correlated with a loss of mitochondrial membrane integrity and activation of the endoplasmic reticulum (ER) stress response. These pathways activate caspase-9 and consistent with this, cell death was prevented by caspase-9 blockade. Interestingly, cells overexpressing Bcl-X(L) remained partially sensitive to R115777 despite suppression of mitochondrial membrane dysfunction and ER-related stress. Taken together, these results indicate that R115777 induces apoptosis in a Ras-independent fashion via multiple intrinsic pathways.
Mol Cancer Ther 2004 Feb
PMID:R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways. 1498 58

Apoptosis (programmed cell death) is a physiological process used to eliminate superfluous, damaged, infected, or aged cells in multicellular organisms. During apoptosis the cellular architecture is dismantled from within in a highly controlled fashion. Members of the caspase family of cysteine proteases are responsible for the destructive phase of apoptosis. One major pathway to caspase activation involves the formation of a multisubunit protease activation complex called the apoptosome. The apoptosome is assembled in response to signals that provoke mitochondrial outer membrane permeabilization and the release of cytochrome c into the cytosol. Recent studies indicate that the apoptosome is a wheel-like structure consisting of seven molecules of Apaf-1 and a similar number of caspase-9 dimers. Knowledge of the structure of the apoptosome will likely lead to the design of therapeutic modulators of apoptosis.
Mol Interv 2003 Feb
PMID:Portrait of a killer: the mitochondrial apoptosome emerges from the shadows. 1499 35

The oxysterol 7beta-hydroxycholesterol (7beta-OH) has been shown to induce apoptosis in a number of cell lines. Though not fully elucidated, the mechanism through which this oxysterol induces cell death is thought to involve the generation of an oxidative stress leading to perturbation of the mitochondrion and release of cytochrome c into the cytosol. Cytochrome c together with Apaf-1 causes activation of the initiator caspase, caspase-9, which in turn activates caspase-3 ultimately leading to the degradation of poly(ADP-ribose) polymerase (PARP). The objective of the present study was to investigate the signalling pathway in 7beta-OH-induced apoptosis in U937 cells, a human monocytic blood cell line known to undergo apoptosis upon treatment with 7beta-OH, over a time course of 48 h. Apoptosis was evident after 24 h incubation. Glutathione levels were decreased after 6 h and this was coupled with an increase in SOD activity. Through western blot analysis we examined expression of caspase-3, -8, and -9 and cleavage of the caspase-3 substrate PARP. The sequence proceeded with activation of caspase-9 after 9 h, caspase-3 at the 12 h timepoint, and cleavage of PARP after 24 h treatment with 7beta-OH. Caspase-8 did not appear to play a major role in this particular apoptotic pathway.
J Biochem Mol Toxicol 2004
PMID:Generation of an oxidative stress precedes caspase activation during 7beta-hydroxycholesterol-induced apoptosis in U937 cells. 1499 80

The expression of cyclooxygenase (COX)-2 is increased in human cancers including cholangiocarcinoma. This study was designed to evaluate the effect and mechanisms of the selective COX-2 inhibitor celecoxib in the growth control of human cholangiocarcinoma cells. Immunohistochemical analysis using human cholangiocarcinoma tissues showed increased levels of COX-2 as well as phospho-Akt (Thr (308)), a protein kinase activated by COX-2-mediated prostaglandins, in human cholangiocarcinoma cells. Treatment of cultured human cholangiocarcinoma cells (HuCCT1, SG231, and CCLP1) with celecoxib resulted in a dose- and time-dependent reduction of cell viability. Fluorescence microscopy, Western blot, and caspase activity assays demonstrated that celecoxib induced morphological features of apoptosis, activation of caspase-9 and caspase-3, and release of cytochrome c. The celecoxib-induced cell death was significantly blocked by N-benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone, a wide-spectrum caspase inhibitor. Furthermore, cholangiocarcinoma cells treated with celecoxib showed significant reduction of Akt phosphorylation, whereas the levels of Bcl-2 and Bax were not altered. Inhibition of Akt activation by LY294002 significantly decreased the viability of human cholangiocarcinoma cells. These findings suggest that celecoxib inhibits cholangiocarcinoma growth partly through induction of apoptosis and inhibition of Akt phosphorylation.
Mol Cancer Ther 2004 Mar
PMID:The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells. 1502 50

Overexpression of the anti-apoptotic protein Bcl-2 has been associated with several malignancies, including small cell lung cancer (SCLC). In the present study, we have investigated if Bcl-2 contributes to the emergence of cisplatin resistance in SCLC H69 cells. The ability of cisplatin to induce apoptosis was decreased in H69 cells that acquired resistance to cisplatin (H69/CP). The level of Bcl-2 was, however, substantially reduced in H69/CP cells compared to parental H69 cells. There was little change in Bcl-2 content in H69 cells that were resistant to etoposide (VP-16) or Taxol. Bcl-2 was constitutively phosphorylated at serine 70 in H69 cells but not in H69/CP cells and cisplatin had little effect on Bcl-2 phosphorylation. The level of procaspase-3 was elevated in H69/CP cells but the ability of cisplatin to induce mitochondrial depolarization, caspase-9 activation, and poly(ADP-ribose) polymerase (PARP) cleavage was compromised in H69/CP cells. The level of the anti-apoptotic protein Bcl-x(L) and the pro-apoptotic protein Bax was slightly reduced in H69/CP cells but the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family proteins was not sufficient to explain cellular resistance to cisplatin. These results suggest that the acquisition of cisplatin resistance by H69 cells was not due to an increase in the level/phosphorylation status of the anti-apoptotic protein Bcl-2.
Mol Cancer Ther 2004 Mar
PMID:Down-regulation of Bcl-2 is associated with cisplatin resistance in human small cell lung cancer H69 cells. 1502 53

The cellular mechanisms underlying the neurodegenerative process in Parkinson's disease are not well understood. Using RNA interference (RNAi), we demonstrate that caspase-3-dependent proteolytic activation of protein kinase Cdelta (PKCdelta) contributes to the degenerative process in dopaminergic neurons. The Parkinsonian toxin MPP(+) activated caspase-3 and proteolytically cleaved PKCdelta into catalytic and regulatory subunits, resulting in persistent kinase activation in mesencephalic dopaminergic neuronal cells. The caspase-3 inhibitor Z-DEVD-FMK and the caspase-9 inhibitor Z-LEHD-FMK effectively blocked MPP(+)-induced PKCdelta proteolytic activation. To characterize the functional role of PKCdelta activation in MPP(+)-induced dopaminergic cell death, RNAi-mediated gene knockdown was performed. Among four siRNAs designed against PKCdelta, two specifically suppressed PKCdelta expression. The application of siRNA abolished the MPP(+)-induced PKCdelta activation, DNA fragmentation, and tyrosine hydroxylase (TH)-positive neuronal loss. Together, these results suggest that proteolytic activation of PKCdelta may be a critical downstream event in the degenerative process of Parkinson's disease.
Mol Cell Neurosci 2004 Mar
PMID:Suppression of caspase-3-dependent proteolytic activation of protein kinase C delta by small interfering RNA prevents MPP+-induced dopaminergic degeneration. 1503 69

Evidence suggests N-methyl-D-aspartate receptor (NMDAR) activation is involved in the degeneration of striatal medium-sized spiny neurons (MSNs) in Huntington's disease (HD). We tested the hypothesis that enhanced NMDAR-mediated excitotoxicity is mediated by the mitochondrial-associated apoptotic pathway in cultured MSNs from YAC transgenic mice expressing full-length huntingtin (htt) with a polyglutamine (polyQ) expansion of 46 or 72 (YAC46 or YAC72). NMDAR-mediated Ca(2+) transients and mitochondrial membrane depolarization were significantly increased in YAC compared to wild-type mice MSNs. Inhibitors of the mitochondrial permeability transition (mPT), cyclosporin A and bongkrekic acid, and coenzyme Q10 (an anti-oxidant involved in bioenergetic metabolism) dramatically diminished NMDA-induced cell death and eliminated genotypic differences. In YAC46 MSNs, NMDA stimulated significantly higher activation of caspase-3 and caspase-9 but not caspase-8, and NMDA-induced caspase-3 and -9 activation was markedly attenuated by cyclosporin A. Agents that improve mitochondrial function or inhibit the permeability transition may eliminate increased caspase activation and cell death associated with enhanced NMDAR activity in HD.
Mol Cell Neurosci 2004 Mar
PMID:Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington's disease. 1503 75

Age-related changes and regional differences in caspase expression were determined in the primate brain. Using immunoblot analysis, the levels of endogenous caspase-3, caspase-9 and cytochrome c-triggered activated caspase-3 were examined in brain homogenates from the prefrontal, motor and visual cortices, cerebellum, hippocampus and amygdala of 4-year-old and 20-year-old rhesus macaques. Procaspase-3 was detected in similar quantities in all brain regions of both young and aging macaques. Being found in all brain regions, caspase-9 was significantly elevated in old macaques as compared to young ones. After incubation with cytochrome c, active forms of caspase-3 were detected in all brain regions of young and old macaques. In almost all brain regions of old monkeys, the levels of cytochrome c-dependent caspase-3 activation were higher than those of young macaques. These results suggest that the aging rhesus macaque brain has a lower threshold to apoptotic stimuli.
Brain Res Mol Brain Res 2004 Apr 07
PMID:Age-related alterations in cytochrome c-mediated caspase activation in rhesus macaque monkey (Macaca mulatta) brains. 1504 72


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