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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis occurs in the placenta throughout gestation, with a greater frequency near term in comparison to the first trimester. The Fas/FasL system represents one of the main apoptotic pathways controlling placental apoptosis. Although first trimester trophoblast cells express both Fas and FasL, they are resistant to Fas-induced apoptosis. Therefore, trophoblast resistance to Fas-mediated apoptosis may be due to the inhibition of the pathway downstream of Fas stimulation. Expression levels of X-linked inhibitor of apoptosis (XIAP) were recently shown to decrease in third trimester placentas, correlating with an increase in placental apoptosis. As a potent caspase inhibitor, XIAP prevents the activation of caspase-9 through its BIR3 domain and caspase-3 activation via the linker-BIR2 domain. In the present study, high levels of the active form of XIAP were detected in first trimester trophoblast cells, whereas term placental tissue samples predominantly expressed the inactive form of XIAP. Using a XIAP inhibitor, phenoxodiol, we demonstrate that XIAP inactivation sensitizes trophoblast cells to Fas stimulation, as evidenced by the anti-Fas mAb-induced decrease in trophoblast cell viability and increase in caspase-8, caspase-9 and caspase-3 activation. This suggests a functional role for XIAP in the regulation of the Fas apoptotic cascade in trophoblast cells during pregnancy.
Mol Hum Reprod 2004 Jan
PMID:X-linked inhibitor of apoptosis (XIAP) confers human trophoblast cell resistance to Fas-mediated apoptosis. 1466 4

Apoptosis plays an important role in atherosclerosis. The factors regulating this process are not well defined. We examined the relation of apoptotic cells with the terminal complement complex C5b-9 in human atherosclerotic lesions. The extent of apoptosis was determined using TdT dUTP nick-end labeling (TUNEL) and immunohistochemistry of apoptosis regulators caspase-3, caspase-9, Bax, and Bcl-2. C5b-9 was localized by immunohistochemistry and immunoelectron microscopy. The apoptotic index was higher in fibrous plaques when compared with intimal fatty streaks and intimal thickenings. Bax expression was present in TUNEL+ apoptotic cells, and Bcl-2 was rarely present in the atherosclerotic wall. Active caspase 9 and caspase 3 deposits were present in the same areas, suggesting an involvement of the mitochondrial pathway. C5b-9 deposits colocalized with TUNEL+ cells, and the percent of double-positive cells was 2% in fatty streaks, 12% in intimal thickenings, and 35% in fibrous plaques. Colocalization of apoptotic cells with C5b-9 was also confirmed by immunoelectron microscopy. In conclusion, some apoptotic cells carry C5b-9 deposits, suggesting that complement might be activated by apoptotic cells and involved in the promotion of apoptosis, contributing to the progression of atherosclerotic lesions.
Exp Mol Pathol 2004 Feb
PMID:C5b-9 terminal complement complex assembly on apoptotic cells in human arterial wall with atherosclerosis. 1473 64

Development of effective agents for treatment of hormone-refractory prostate cancer has become a national medical priority. We have reported recently that apigenin (4',5,7-trihydroxyflavone), found in many common fruits and vegetables, has shown remarkable effects in inhibiting cell growth and inducing apoptosis in many human prostate carcinoma cells. Here we demonstrate the molecular mechanism of inhibitory action of apigenin on androgen-refractory human prostate carcinoma DU145 cells that have mutations in the tumor suppressor gene p53 and pRb. Treatment of cells with apigenin resulted in a dose- and time-dependent inhibition of growth, colony formation, and G1 phase arrest of the cell cycle. This effect was associated with a marked decrease in the protein expression of cyclin D1, D2, and E and their activating partner, cyclin-dependent kinase (cdk)2, 4, and 6, with concomitant upregulation of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18. The induction of WAF1/p21 and its growth inhibitory effects by apigenin appears to be independent of p53 and pRb status of these cells. Apigenin treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1 (Apaf-1). This effect was found to result in a significant increase in cleaved fragments of caspase-9, -3, and poly(ADP-ribose) polymerase (PARP). Further, apigenin treatment resulted in downmodulation of the constitutive expression of nuclear factor-kappaB (NF-kappaB)/p65 and NF-kappaB/p50 in the nuclear fraction that correlated with an increase in the expression of IkappaB-alpha (IkappaBalpha) in the cytosol. Taken together, we concluded that molecular mechanisms during apigenin-mediated growth inhibition and induction of apoptosis in DU145 cells was due to (1) modulation in cell-cycle machinery, (2) disruption of mitochondrial function, and (3) NF-kappaB inhibition.
Mol Carcinog 2004 Feb
PMID:Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. 1475 Feb 16

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


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