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1.
Gröbner S Adkins I Schulz S Richter K Borgmann S Wesselborg S Ruckdeschel K Micheau O Autenrieth IB 《Apoptosis : an international journal on programmed cell death》2007,12(10):1813-1825
Yersinia outer protein P (YopP) is injected by Y. enterocolitica into host cells thereby inducing apoptotic and necrosis-like cell death in dendritic cells (DC). Here we show the pathways
involved in DC death caused by the catalytic activity of YopP. Infection with Yersinia
enterocolitica, translocating catalytically active YopP into DC, triggered procaspase-8 cleavage and c-FLIPL degradation. YopP-dependent caspase-8 activation was, however, not mediated by tumor necrosis factor (TNF) receptor family
members since the expression of both CD95/Fas/APO-1 and TRAIL-R2 on DC was low, and DC were resistant to apoptosis induced
by agonistic anti-CD95 antibodies or TNF-related apoptosis-inducing ligand (TRAIL). Moreover, DC from TNF-Rp55−/− mice were not protected against YopP-induced cell death demonstrating that TNF-R1 is also not involved in this process. Activation
of caspase-8 was further investigated by coimmunoprecitation of FADD from Yersinia-infected DC. We found that both cleaved caspase-8 and receptor interacting protein 1 (RIP1) were associated with the Fas-associated
death domain (FADD) indicating the formation of an atypical death-inducing signaling complex (DISC). Furthermore, degradation
of RIP mediated by the Hsp90 inhibitor geldanamycin significantly impaired YopP-induced cell death. Altogether our findings
indicate that Yersinia-induced DC death is independent of death domain containing receptors, but mediated by RIP and caspase-8 at the level of DISC. 相似文献
2.
Furre IE Møller MT Shahzidi S Nesland JM Peng Q 《Apoptosis : an international journal on programmed cell death》2006,11(11):2031-2042
Photodynamic therapy (PDT) is a cancer treatment based on the interaction of a photosensitizer, light and oxygen. PDT with
the endogenous photosensitizer, protoporphyrin IX (PpIX) induced by 5-aminolevulinic acid (ALA) or its derivatives is a modification
of this treatment modality with successful application in dermatology. However, the mechanism of cell destruction by ALA-PDT
has not been elucidated. In this study a human T-cell lymphoma Jurkat cell line was treated with PDT using hexaminolevulinate
(HAL, hexylester of ALA). Four hours following treatment nearly 80% of the cells exhibited typical apoptotic features. Mitochondrial
pro-apoptotic proteins were evaluated by Western blots in subcellular fractionated samples. PDT caused cytosolic translocation
of cytochrome c and nuclear redistribution of apoptosis-inducing factor (AIF), but the release of mitochondrial Smac/DIABLO, Omi/HtrA2 and
EndoG was not observed. The release of cytochrome c was followed by the cleavage of caspase-9 and caspase-3 as well as its downstream substrates, together with oligonucleosomal
DNA fragmentation. The pan-caspases inhibitor, z-VAD.fmk, prevented oligonucleosomal DNA fragmentation, but failed to inhibit
PDT-mediated apoptosis. The apoptotic induction by AIF-mediated caspase-independent pathway was also found after HAL-PDT with
large-scale DNA fragmentation in the presence of z-VAD.fmk. These results demonstrate that cytochrome c-mediated caspase-dependent pathway and AIF-induced caspase-independent pathway are simultaneously involved in the apoptotic
induction by PDT. When the cytochrome c-induced caspase-dependent pathway is blocked, the cells go into apoptosis via AIF-mediated pathway, clearly demonstrating
that the cytochrome c-mediated caspase-dependent pathway is not required for such apoptotic induction. This finding may have an impact on improved
PDT effectiveness. 相似文献
3.
Aubert M Pomeranz LE Blaho JA 《Apoptosis : an international journal on programmed cell death》2007,12(1):19-35
Expression of HSV-1 genes leads to the induction of apoptosis in human epithelial HEp-2 cells but the subsequent synthesis
of infected cell protein prevents the process from killing the cells. Thus, viruses unable to produce appropriate prevention
factors are apoptotic. We now report that the addition of either a pancaspase inhibitor or caspase-9-specific inhibitor prevented
cells infected with an apoptotic HSV-1 virus from undergoing cell death. This result indicated that HSV-1-dependent apoptosis
proceeds through the mitochondrial apoptotic pathway. However, the pancaspase inhibitor did not prevent the release of cytochrome
c from mitochondria, implying that caspase activation is not required for this induction of cytochrome c release by HSV-1. The release of cytochrome c was first detected at 9 hpi while caspase-9, caspase-3 and PARP processing were detected at 12 hpi. Finally, Bax accumulated
at mitochondria during apoptotic, but not wild type HSV-1 infection. Together, these findings indicate that HSV-1 blocks apoptosis
by precluding mitochondrial cytochrome c release in a caspase-independent manner and suggest Bax as a target in infected human epithelial cells. 相似文献
4.
Scheller C Knöferle J Ullrich A Prottengeier J Racek T Sopper S Jassoy C Rethwilm A Koutsilieri E 《Journal of cellular biochemistry》2006,97(6):1350-1361
CD95 (Fas/Apo-1) triggers apoptotic cell death via a caspase-dependent pathway. Inhibition of caspase activation blocks proapoptotic signaling and thus, prevents execution of apoptosis. Besides induction of apoptotic cell death, CD95 has been reported to trigger necrotic cell death in susceptible cells. In this study, we investigated the interplay between apoptotic and necrotic cell death signaling in T cells. Using the agonistic CD95 antibody, 7C11, we found that caspase inhibition mediated by the pancaspase inhibitor, zVAD-fmk, prevented CD95-triggered cell death in Jurkat T cells but not in A3.01 T cells, although typical hallmarks of apoptosis, such as DNA fragmentation or caspase activation were blocked. Moreover, the caspase-independent cell death in A3.01 cells exhibited typical signs of necrosis as detected by a rapid loss of cell membrane integrity and could be prevented by treatment with the radical scavenger butylated hydroxyanisole (BHA). Similar to CD95-induced cell death, apoptosis triggered by the DNA topoisomerase inhibitors, camptothecin or etoposide was shifted to necrosis when capsase activation was inhibited. In contrast to this, ZVAD was fully protective when apoptosis was triggered by the serpase inhibitor, Nalpha-tosyl-phenyl-chloromethyl ketone (TPCK). TPCK was not protective when administered to anti-CD95/ZVAD-treated A3.01 cells, indicating that TPCK does not possess anti-necrotic activity but fails to activate the necrotic death pathway. Our findings show (a) that caspase inhibition does not always protect apoptotic T cells from dying but merely activates a caspase-independent mode of cell death that results in necrosis and (b) that the caspase-inhibitor-induced shift from apoptotic to necrotic cell death is dependent on the cell type and the proapoptotic stimulus. 相似文献
5.
We investigated the ceramide-induced apoptosis and potential mechanism in A-431 cells. Ceramide treatment causes the round up and the death of A-431 cells that is associated with p38 activation and can be observed in 10 h. Short-time ceramide treatment-induced cell death is not associated with the typical apoptotic phenotypes, such as the translocation of phosphatidylserine (PS) from inner layer to outer layer of the plasma membrane, loss of mitochondrial membrane potential, DNA fragmentation, caspase activation, and PARP or PKC-delta degradation. SB202190, a specific inhibitor of p38 mitogen-activated protein (MAP) kinase, but not caspase inhibitor, blocks the cell death induced by short-time ceramide treatment (within 12 h). Whereas neither inhibition of p38 MAP kinase nor inhibition of caspases blocks cell death induced by prolonged ceramide treatment. Moreover, incubation of cells with ceramide for a long time (over 12 h) results in the reduction of proportion of S phase accompanied with typical apoptotic cell death phenotypes that are different from the cell death induced by short-time ceramide treatment. Our data demonstrated that ceramide-induced apoptotic cell death involves both caspase-dependent and caspase-independent signaling pathways. The caspase-independent cell death that occurred in relatively early stage of ceramide treatment is mediated via p38 MAP kinase, which can progress into a stage that is associated with changes of cell cycle events and involves both caspase-dependent and -independent mechanisms. 相似文献
6.
M Neuss R Monticone M S Lundberg A T Chesley E Fleck M T Crow 《The Journal of biological chemistry》2001,276(36):33915-33922
ARC is an apoptotic regulatory protein expressed almost exclusively in myogenic cells. It contains a caspase recruitment domain (CARD) through which it has been shown to block the activation of some initiator caspases. Because ARC also blocks caspase-independent events associated with apoptosis, such as hypoxia-induced cytochrome c release, we examined its role in cell death triggered by exposure to hydrogen peroxide (H(2)O(2)) in the myogenic cell line, H9c2. Cell death in this model was caspase-independent and characterized by dose-dependent reduction in ARC expression accompanied by disruption of the mitochondrial membrane potential (Delta psi(m)) and loss of plasma membrane integrity, typical of necrotic cell death. Ectopic expression of ARC prevented both H(2)O(2)-induced mitochondrial dysfunction and cell death without affecting the stress kinase response, suggesting that ARCs protective effects were downstream of early signaling events and not due to quenching of H(2)O(2). ARC was also effective in blocking H(2)O(2)-induced loss of membrane integrity and/or disruption of Delta psi(m) in two human cell lines in which it is not normally expressed. These results demonstrate that, in addition to its ability to block caspase-dependent and -independent events in apoptosis, ARC also prevents necrosis-like cell death via the preservation of mitochondrial function. 相似文献
7.
Aaron D. Dam Andrew S. Mitchell Joe Quadrilatero 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2013,1833(12):3426-3435
Apoptotic signaling plays an important role in skeletal muscle degradation, atrophy, and dysfunction. Mitochondria are central executers of apoptosis by directly participating in caspase-dependent and caspase-independent cell death signaling. Given the important apoptotic role of mitochondria, altering mitochondrial content could influence apoptosis. Therefore, we examined the direct effect of modest, but physiological increases in mitochondrial biogenesis and content on skeletal muscle apoptosis using a cell culture approach. Treatment of L6 myoblasts with SNAP or AICAR (5 h/day for 5 days) significantly increased PGC-1, AIF, cytochrome c, and MnSOD protein content as well as MitoTracker staining. Following induction of mitochondrial biogenesis, L6 myoblasts displayed decreased sensitivity to apoptotic cell death as well as reduced caspase-3 and caspase-9 activation following exposure to staurosporine (STS) and C2-ceramide. L6 myoblasts with higher mitochondrial content also exhibited reduced apoptosis and AIF release following exposure to hydrogen peroxide (H2O2). Analysis of several key apoptosis regulatory proteins (ARC, Bax, Bcl-2, XIAP), antioxidant proteins (catalase, MnSOD, CuZnSOD), and reactive oxygen species (ROS) measures (DCF and MitoSOX fluorescence) revealed that these mechanisms were not responsible for the observed cellular protection. However, myoblasts with higher mitochondrial content were less sensitive to Ca2 +-induced mitochondrial permeability transition pore formation (mPTP) and mitochondrial membrane depolarization. Collectively, these data demonstrate that increased mitochondrial content at physiological levels provides protection against apoptotic cell death by decreasing caspase-dependent and caspase-independent signaling through influencing mitochondrial Ca2 +-mediated apoptotic events. Therefore, increasing mitochondrial biogenesis/content may represent a potential therapeutic approach in skeletal muscle disorders displaying increased apoptosis. 相似文献
8.
Caspase-dependent and -independent cell death induced by 3-nitropropionic acid in rat cortical neurons 总被引:2,自引:0,他引:2
Mitochondria play a critical role in cell death by releasing apoptogenic factors, such as cytochrome c and apoptosis-inducing factor (AIF), from the intermembrane space into the cytoplasm. Because mitochondrial dysfunction has been shown to be involved in several neurodegenerative diseases, mitochondrial toxins are largely used to model these disorders. These include 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, which has been used to model Huntington's disease and was previously reported by us to induce apoptotic cell death through caspase activation. In the present study, we evaluated the involvement of caspase-independent neuronal cell death induced by 3-NP (1 mM) and the effect of z-VDVAD-fmk, an inhibitor of caspase-2, using cortical neurons in culture. Our results highly suggest that 3-NP induces both caspase-dependent and -independent cell death. We showed that z-VDVAD-fmk prevented both caspase-2 and -3-like activities evoked by 3-NP, but only partly prevented chromatin fragmentation/condensation. However, z-VDVAD-fmk did not avoid 3-NP-induced release of cytochrome c or AIF from mitochondria nor did it affect the levels of mitochondrial Bax. Furthermore, 3-NP-mediated decrease in plasma membrane integrity was not affected by z-VDVAD-fmk. Under these conditions, the inhibitor prevented the caspase-dependent cell death. 相似文献
9.
Choi JS Shin S Jin YH Yim H Koo KT Chun KH Oh YT Lee WH Lee SK 《Apoptosis : an international journal on programmed cell death》2007,12(7):1229-1241
Previous studies have suggested that upregulation of Cyclin A-dependent protein kinase 2 (Cdk2) activity is an essential event
in apoptotic progression and the mitochondrial permeability transition in human cancer cells. Here, we show that upregulated
Cyclin A/Cdk2 activity precedes the proteolytic cleavage of PARP and is correlated with the mitochondrial translocation of
Bax and the loss of mitochondrial transmembrane potential (Δψm) during etoposide-induced apoptosis in human cervical adenocarcinoma (HeLa) cells. Etoposide-induced apoptotic cell death
is efficiently prevented in cells that overexpress a dominant negative mutant of Cdk2 (Cdk2-dn) or p21WAF1/CIP1, a specific Cdk inhibitor. Conversely, apoptotic cell death is promoted in Cyclin A-expressing cells. Disruption of the mitochondrial
transmembrane potential in etoposide-induced cells is prevented in cells that overexpress Cdk2-dn or p21WAF1/CIP1, while this transition is prominently promoted in Cyclin A-expressing cells. We screened for mitochondrial Cdk2 targets in
the etoposide-induced cells and found that the mitochondrial level of Bax is elevated by more than three fold in etoposide-treated
cells and this elevation is effectively prevented in cells expressing Cdk2-dn under the same conditions. Thus, we suggest
that Cdk2 activity is involved in the mitochondrial translocation of Bax, which plays an important role in the mitochondrial
membrane permeability transition during apoptotic progression. 相似文献
10.
Induction of apoptosis may be a promising therapeutic approach in cancer therapy. Peroxisome proliferator-activated receptor-γ
(PPARγ) agonists induce apoptosis in various cancer cells. However, the molecular mechanism remains to be defined. The present
study was undertaken to determine the precise mechanism of cell death induced by ciglitazone, a synthetic PPARγ agonist, in
A172 human glioma cells. Ciglitazone resulted in a concentration- and time-dependent apoptotic cell death. Similar results
were obtained with troglitazone, another synthetic PPARγ agonist. Ciglitazone induced reactive oxygen species (ROS) generation
and ciglitazone-induced cell death was prevented by the antioxidant N-acetylcysteine, suggesting an important role of ROS generation in the ciglitazone-induced cell death. The cell death induced
by ciglitazone was inhibited by the PPARγ antagonist GW9662. Although ciglitazone treatment caused a transient activation
of extracellular signal-regulated kinase (ERK) and p38, the ciglitazone-induced cell death was not affected by inhibitors
of these kinses. Ciglitazone caused a loss of mitochondrial membrane potential and its effect was prevented by N-acetylcysteine and GW9662. The specific inhibitor of caspases-3 DEVD-CHO and the general caspase inhibitor z-DEVD-FMK did
not exert the protective effect against the ciglitazone-induced cell death and caspase-3 activity also was not altered by
ciglitazone. The ciglitazone-induced cell death was accompanied by down-regulation of XIAP and Survivin, but not by release
of apoptosis-inducing factor. Taken together, these findings suggest that down-regulation of XIAP and Survivin may play an
active role in mediating a caspase-independent and -PPARγ-dependent cell death induced by ciglitazone in A172 human glioma
cells. These data may provide a novel insight into potential therapeutic strategies for treatment of glioblastoma. 相似文献
11.
Cell death by apoptosis is involved in the maintenance of T cell receptor diversity, self tolerance, and T-cell number homeostasis. Until recently, apoptosis was thought to require caspase activation. Evidence is now accumulating that a caspase-independent pathway exists, shown by in vitro experiments with broad-range caspase inhibitors. Mature T lymphocytes readily undergo caspase-independent apoptosis in vitro, and recent data suggest that this type of apoptosis may be involved in the negative selection of thymocytes. Mitochondria likely release death triggers specific for both caspase-dependent and caspase-independent apoptotic pathways (cytochrome c and AIF respectively) in response to apoptotic stimuli. A caspase-independent pathway is triggered first in activated T lymphocytes subjected to apoptotic stimuli that do not rely on receptors with death domains. In this pathway, the early commitment phase to apoptosis involves cell shrinkage, peripheral DNA condensation and the translocation of mitochondrial AIF to the cytosol and nucleus. This process is reversible until mitochondrial cytochrome c is released and m dissipated. Only at this stage are caspases activated. 相似文献
12.
Distinct roles of basal steady-state and induced H-ferritin in tumor necrosis factor-induced death in L929 cells 下载免费PDF全文
Xie C Zhang N Zhou H Li J Li Q Zarubin T Lin SC Han J 《Molecular and cellular biology》2005,25(15):6673-6681
Tumor necrosis factor (TNF) alpha is a cytokine capable of inducing caspase-dependent (apoptotic) cell death in some cells and caspase-independent (necrosis-like) cell death in others. Here, using a mutagenesis screen for genes critical in TNF-induced death in L929 cells, we have found that H-ferritin deficiency is responsible for TNF resistance in a mutant line and that, upon treatment with TNF, this line fails to elevate levels of labile iron pool (LIP), critical for TNF-induced reactive oxygen species (ROS) production and ROS-dependent cell death. Since we found that TNF-induced LIP in L929 cells is primarily furnished by intracellular storage iron, the lesser induction of LIP in H-ferritin-deficient cells results from a reduction of intracellular iron storage caused by less H-ferritin. Different from some other cell lines, the H-ferritin gene in L929 cells is not TNF inducible; however, when H-ferritin is expressed in L929 cells under a TNF-inducible system, the TNF-induced LIP and subsequent ROS production and cell death were all prevented. Thus, LIP is a common denominator of ferritin both in the enhancement of cell death by basal steady-state H-ferritin and in protection against cell death by induced H-ferritin, thereby acting as a key determinant of TNF-induced cell death. 相似文献
13.
RIP5 is a RIP-homologous inducer of cell death 总被引:2,自引:0,他引:2
Zha J Zhou Q Xu LG Chen D Li L Zhai Z Shu HB 《Biochemical and biophysical research communications》2004,319(2):298-303
Members of the RIP serine/threonine kinase family are involved in activation of NF-kappaB, JNK, and p38, and induction of apoptosis. Here we report the identification of a novel RIP-homologous protein designated as RIP5. The C-terminus of RIP5 contains a kinase domain, which is mostly homologous with the kinase domain of RIP. RIP5 also contains a large unconserved N-terminal domain. Overexpression of RIP5 induces cell death with characteristic apoptotic morphology. Overexpression of RIP5 also induces DNA fragmentation and this is blocked by the caspase inhibitor crmA. However, RIP5-induced apoptotic morphology is not blocked by crmA. These findings suggest that RIP5 may induce both caspase-dependent apoptosis and caspase-independent cell death. 相似文献
14.
Cilenti L Soundarapandian MM Kyriazis GA Stratico V Singh S Gupta S Bonventre JV Alnemri ES Zervos AS 《The Journal of biological chemistry》2004,279(48):50295-50301
Omi/HtrA2 is a nuclear-encoded mitochondrial serine protease that has a pro-apoptotic function in mammalian cells. Upon induction of apoptosis, Omi translocates to the cytoplasm and participates in caspase-dependent apoptosis by binding and degrading inhibitor of apoptosis proteins. Omi can also initiate caspase-independent apoptosis in a process that relies entirely on its ability to function as an active protease. To investigate the mechanism of Omi-induced apoptosis, we set out to isolate novel substrates that are cleaved by this protease. We identified HS1-associated protein X-1 (HAX-1), a mitochondrial anti-apoptotic protein, as a specific Omi interactor that is cleaved by Omi both in vitro and in vivo. HAX-1 degradation follows Omi activation in cells treated with various apoptotic stimuli. Using a specific inhibitor of Omi, HAX-1 degradation is prevented and cell death is reduced. Cleavage of HAX-1 was not observed in a cell line derived from motor neuron degeneration 2 mice that carry a mutated form of Omi that affects its proteolytic activity. Degradation of HAX-1 is an early event in the apoptotic process and occurs while Omi is still confined in the mitochondria. Our results suggest that Omi has a unique pro-apoptotic function in mitochondria that involves removal of the HAX-1 anti-apoptotic protein. This function is distinct from its ability to activate caspase-dependent apoptosis in the cytoplasm by degrading inhibitor of apoptosis proteins. 相似文献
15.
Hypoxia-induced cell death of HepG2 cells involves a necrotic cell death mediated by calpain 总被引:2,自引:0,他引:2
Kim MJ Oh SJ Park SH Kang HJ Won MH Kang TC Hwang IK Park JB Kim JI Kim J Lee JY 《Apoptosis : an international journal on programmed cell death》2007,12(4):707-718
To elucidate mechanism of cell death in response to hypoxia, we attempted to compare hypoxia-induced cell death of HepG2 cells
with cisplatin-induced cell death, which has been well characterized as a typical apoptosis. Cell death induced by hypoxia
turned out to be different from cisplatin-mediated apoptosis in cell viability and cleavage patterns of caspases. Hypoxia-induced
cell death was not associated with the activation of p53 while cisplatin-induced apoptosis is p53 dependent. In order to explain
these differences, we tested involvement of μ-calpain and m-calpain in hypoxia-induced cell death. Calpains, especially μ-calpain,
were initially cleaved by hypoxia, but not by cisplatin. Interestingly, the treatment of a calpain inhibitor restored PARP
cleavage that was absent during hypoxia, indicating the recovery of activated caspase-3. The inhibition of calpains prevented
proteolysis induced by hypoxia. In addition, hypoxia resulted in a necrosis-like morphology while cisplatin induced an apoptotic
morphology. The calpain inhibitor prevented necrotic morphology induced by hypoxia and converted partially to apoptotic morphology
with nuclear segmentation. Our result suggests that calpains are involved in hypoxia-induced cell death that is likely to
be necrotic in nature and the inhibition of calpain switches hypoxia-induced cell death to apoptotic cell death without affecting
cell viability. 相似文献
16.
p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release 总被引:16,自引:0,他引:16
Schuler M Bossy-Wetzel E Goldstein JC Fitzgerald P Green DR 《The Journal of biological chemistry》2000,275(10):7337-7342
The p53 tumor suppressor gene is critically involved in cell cycle regulation, DNA repair, and programmed cell death. Several lines of evidence suggest that p53 death signals lead to caspase activation; however, the mechanism of caspase activation by p53 still is unclear. Expressing wild type p53 by means of an adenoviral expression vector, we were able to induce apoptotic cell death, as characterized by morphological changes, phosphatidylserine externalization, and internucleosomal DNA fragmentation, in p53(null) Saos-2 cells. This cell death was accompanied by caspase activation as well as by cleavage of caspase substrates and was preceded by mitochondrial cytochrome c release. The addition of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) directly after transduction almost completely prevented p53-induced apoptotic cell death but did not inhibit mitochondrial cytochrome c release. In contrast, N-acetylcysteine, even at high concentrations, could not prevent induction of programmed cell death by p53 expression. Cytosolic extracts from Saos-2 cells transduced with p53, but not from Saos-2 cells transduced with the empty adenoviral vector, contained a cytochrome c-releasing activity in vitro, which was still active in the presence of zVAD-fmk. When Bax was immunodepleted from the cytosolic extracts of p53-expressing cells before incubation with isolated mitochondria, the in vitro cytochrome c release was abolished. Thus, we could demonstrate in cells and in vitro that p53 activates the apoptotic machinery through induction of the release of cytochrome c from the mitochondrial intermembrane space. Furthermore, we provide in vitro evidence for the requirement of cytosolic Bax for this cytochrome c-releasing activity of p53 in Saos-2 cells. 相似文献
17.
Asiatic acid (AA), a triterpene, is known to be cytotoxic to several tumor cell lines. AA induces dose- and time-dependent
cell death in U-87 MG human glioblastoma. This cell death occurs via both apoptosis and necrosis. The effect of AA may be
cell type-specific as AA-induced cell death was mainly apoptotic in colon cancer RKO cells. AA-induced glioblastoma cell death
is associated with decreased mitochondrial membrane potential, activation of caspase-9 and -3, and increased intracellular
free Ca2+. Although treatment of glioblastoma cells with the caspase inhibitor zVAD-fmk completely abolished AA-induced caspase activation,
it did not significantly block AA-induced cell death. AA-induced cell death was significantly prevented by an intracellular
Ca2+ inhibitor, BAPTA/AM. Taken together, these results indicate that AA induces cell death by both apoptosis and necrosis, with
Ca2+-mediated necrotic cell death predominating. 相似文献
18.
In mitochondria, oxidative phosphorylation and enzymatic oxidation of biogenic amines by monoamine oxidase produce reactive
oxygen and nitrogen species, which are proposed to cause neuronal cell death in neurodegenerative disorders, including Parkinson’s
and Alzheimer’s disease. In these disorders, mitochondrial dysfunction, increased oxidative stress, and accumulation of oxidation-modified
proteins are involved in cell death in definite neurons. The interactions among these factors were studied by use of a peroxynitrite-generating
agent, N-morpholino sydnonimine (SIN-1) and an inhibitor of complex I, rotenone, in human dopaminergic SH-SY5Y cells. In control cells,
peroxynitrite nitrated proteins, especially the subunits of mitochondrial complex I, as 3-nitrotyrosine, suggesting that neurons
are exposed to constant oxidative stress even under physiological conditions. SIN-1 and an inhibitor of proteasome, carbobenzoxy-l-isoleucyl-γ-t-butyl-l-analyl-l-leucinal (PSI), increased markedly the levels of nitrated proteins with concomitant induction of apoptosis in the cells.
Rotenone induced mitochondrial dysfunction and accumulation and aggregation of proteins modified with acrolein, an aldehyde
product of lipid peroxidation in the cells. At the same time, the activity of the 20S β-subunit of proteasome was reduced
significantly, which degrades oxidative-modified protein. The mechanism was proved to be the result of the modification of
the 20S β-subunit with acrolein and to the binding of other acrolein-modified proteins to the 20S β-subunit.
Increased oxidative stress caused by SIN-1 treatment induced a decline in the mitochondrial membrane potential, ΔΨm, and activated
mitochondrial apoptotic signaling and induced cell death in SH-SY5Y cells. As another pathway, p38 mitogen-activated protein
(MAP) kinase and exracellular signal-regulated kinase (ERK) mediated apoptosis induced by SIN-1. On the other hand, a series
of neuroprotective propargylamine derivatives, including rasagiline [N-propargyl-1(R)aminoindan]and (−)deprenyl, intervened in the activation of apoptotic cascade by reactive oxygen species-reactive nitrogen
species in mitochondria through stabilization of the membrane potential, ΔΨm. In addition, rasagiline induced antiapoptotic
Bcl-2 and glial cell line-derived neurotrophic factor (GDNF) in SH-SY5Y cells, which was mediated by the ERK-nuclear factor
(NF)-κB pathway. These results are discussed in relation to the interaction of oxidative stress and mitochondria in the regulation
of neuronal death and survival in neurodegenerative diseases. 相似文献
19.
Apoptosis inducing factor mediates caspase-independent 1-methyl-4-phenylpyridinium toxicity in dopaminergic cells 总被引:10,自引:0,他引:10
Parkinson's disease is a debilitating neurodegenerative disease characterized by loss of midbrain dopaminergic neurons. These neurons are particularly sensitive to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes parkinsonian syndromes in humans, monkeys and rodents. Although apoptotic cell death has been implicated in MPTP/MPP+ toxicity, several recent studies have challenged the role of caspase-dependent apoptosis in dopaminergic neurons. Using the midbrain-derived MN9D dopaminergic cell line, we found that MPP+ treatment resulted in an active form of cell death that could not be prevented by caspase inhibitors or over-expression of a dominant negative inhibitor of apoptotic protease activating factor 1/caspase-9. Apoptosis inducing factor (AIF) is a mitochondrial protein that may mediate caspase-independent forms of regulated cell death following its translocation to the nucleus. We found that MPP+ treatment elicited nuclear translocation of AIF accompanied by large-scale DNA fragmentation. To establish the role of AIF in MPP+ toxicity, we constructed a DNA vector encoding a short hairpin sequence targeted against AIF. Reduction of AIF expression by RNA interference inhibited large-scale DNA fragmentation and conferred significant protection against MPP+ toxicity. Studies of primary mouse midbrain cultures further supported a role for AIF in caspase-independent cell death in MPP+-treated dopaminergic neurons. 相似文献
20.
Yoshiya Ohno Masanori Nakamura Yoshiyuki Hashimoto 《Biochemical and biophysical research communications》2008,367(4):775-781
Programmed cell death (PCD) is categorized as apoptotic, autophagic, or necrosis-like. Although the possibility that plural (two or three) death signals could be induced by a given stimulus has been reported, the precise mechanisms regulating PCD are not well understood. Recently, we have obtained two anti-chicken transferrin receptor (TfR) monoclonal antibodies (mAbs; D18 and D19) inducing a unique cell death. Although the cell death had several features of apoptosis, autophagic and necrosis-like morphological alterations were simultaneously observed in electron microphotographs. In addition to cells with condensed chromatin and an intact plasma membrane (apoptotic cells), cells having many vacuoles in the cytoplasm (autophagic cells), and enlarged cells with ruptured plasma membranes (necrosis-like cells) were observed in DT40 cells treated with the mAbs, however, the latter two types of dead cells were not detected upon treatment with staurosporine, a typical apoptosis inducer. In autophagic cells, numerous membrane-bound vesicles occupying most of the cytoplasmic space, which frequently contained electron-dense materials from cytoplasmic fragments and organelles, were observed. The simultaneous induction of multiple death signals from a stimulus via the TfR is of great interest to those researching cell death. In addition, activation of caspases was observed in DT40 cells treated with D19, however, the cell death was not inhibited with z-VAD-fmk, a pan-caspase inhibitor, suggesting that at least in part, a caspase-independent pathway is involved in the TfR-mediated cell death. 相似文献