Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytosolic cytochrome c elevation has been associated with activation of caspase-3-like proteases. In this study, we demonstrate that treatment with the neurotoxin and potent calcium channel opener maitotoxin (MTX) induces cytochrome c release from the mitochondria that is not accompanied by caspase activation. Cytochrome c translocation in MTX-treated SH-SY5Y cells was readily apparent after 30 min and peaked at 2.5h. We assayed caspase activity by acetyl-Asp-Glu-Val-Asp-7-amido-4-methylcoumarin (Ac-DEVD-AMC) hydrolysis and by immunoblotting for caspase-3 processing and proteolysis of alphaII-spectrin and PARP. In contrast, treatment with pro-apoptosis agent staurosporine (STS) induced both cytochrome c release and caspase-3 activation after 2h. In addition, with MTX treatment, we found no evidence of caspase activation at any time point or MTX concentration used. Instead, we observed that caspase-9, Apaf-1 and caspase-3 were all partially truncated by calpain under these conditions. These combined effects likely contribute to the lack of caspase activation cascade in MTX-treated cells, despite the presence of cytochrome c in the cytosol.
...
PMID:Cytochrome c translocation does not lead to caspase activation in maitotoxin-treated SH-SY5Y neuroblastoma cells. 1254 51

Cisplatin (CDDP) is a potent DNA-damaging anticancer agent, and its cytotoxic action is exerted by the induction of apoptosis. However, activation of the transcription factor NF-kappaB results in protection against apoptosis. We examined the molecular mechanisms involved in the induction of apoptosis by CDDP as regards both suppression of NF-kappaB and activation of caspases. Human oral squamous carcinoma cells (B88) were employed in this study. We found that CDDP treatment affected neither NF-kappaB activity nor the expression levels of antiapoptotic proteins, including TRAF-1, TRAF-2, and cFLIP, in B88 cells. However, two apoptosome molecules, cytochrome c and Apaf-1, were significantly augmented in the cytoplasm by CDDP treatment. Further, the activation of caspase-9 and caspase-3, downstream molecules leading to mitochondria-mediated apoptosis, were detected after treatment with CDDP. Finally, apoptosis was also clearly observed, as evidenced by cleavage of PARP through the activation of caspase-3. These findings suggest that CDDP exerts its apoptotic action by the mitochondria-mediated activation of caspases but not by the activation of caspases due to the inhibition of NF-kappaB activity that follows the suppression of antiapoptotic proteins.
...
PMID:Cisplatin induces apoptosis in oral squamous carcinoma cells by the mitochondria-mediated but not the NF-kappaB-suppressed pathway. 1261 1

We studied the mechanism of the cytotoxic effects of 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT; induction with 1 mM ALA for 4 h followed by a blue light dose of 18 J/cm(2)) on the human promyelocytic leukemia cell line HL60 using biochemical and electron microscopy methods. The disruption of mitochondrial membrane potential, deltapsi(m), was paralleled by a decrease in ATP level, unmasking of the mitochondrial antigen 7A6, release of cytochrome c into the cytoplasm, activation of caspases 9 and 3 and cleavage of poly(ADP-ribose) polymerase (PARP). This was followed by DNA fragmentation. These data suggest that ALA-PDT activates the mitochondrial apoptotic pathway. The level of endoplasmic reticulum Ca(2+)-binding chaperones ERp57 and ERp72 and of anti-apoptotic proteins Bcl-2 and Bcl-x(L) was decreased whereas that of Ca(2+)-binding protein calmodulin and the stress protein HSP60 was elevated following ALA-PDT. Inhibition of the initiator caspase 9, execution caspase 3 and Ca(2+)-dependent protease m-calpain, did not prevent DNA fragmentation. We conclude that, in our in vitro model, ALA-based photodynamic treatment initiates several signaling processes in HL60 cells that lead to rapidly progressing apoptosis, which is followed by slow necrosis. Two apoptotic processes proceed in parallel, one representing the mitochondrial pathway, the other involving disruption of calcium homeostasis and activation of the endoplasmic reticulum stress-mediated pathway.
...
PMID:Mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by 5-aminolevulinic acid-based photodynamic therapy in HL60 leukemia cells. 1263 80

The majority of human neoplasms have aberrations in the retinoblastoma pathway due to hyperactivation of cyclin-dependent kinases (CDK). Based on this observation, novel small molecules, such as flavopiridol and UCN-01, are being developed and are currently being tested in the clinic. Efforts to develop CDK modulators led us to the discovery of a novel class of CDK inhibitors, the paullones [Cancer Res 1999;59:2566]. Initial studies demonstrated that paullones inhibit CDKs in vitro, thereby blocking cell-cycle progression. However, the exact mechanism for the antiproliferative effects of paullones was never explored. In this report, we demonstrate for the first time that the most potent paullone, alsterpaullone (Alp), induced apoptosis and promoted loss in clonogenicity in the Jurkat cell line. Alp caused early activation of both caspase-8 and -9, leading to cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, apoptosis by Alp was not associated with loss in anti-apoptotic proteins such as XIAP or BCL-XL. Pre-incubation with cell-permeable inhibitors z-Asp(OMe)-Glu(OMe)-Val-Asp(Ome)-fluoromethylketone and benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (ZVAD) blocked Alp-induced apoptosis. Moreover, the general caspase inhibitor ZVAD blocked the cleavage and activation of most caspases tested except caspase-9. Studies of mitochondrial membrane potential also demonstrated that Alp is able to disrupt mitochondrial potential in the presence of ZVAD, suggesting that the activation of caspase-9 by Alp follows mitochondrial perturbation. Pre-incubation of Jurkat cells with ZVAD did not prevent the depletion of cyclin D3, loss of CDK, or cell-cycle arrest by Alp. In summary, these experiments suggest that Alp activates caspase-9 via mitochondrial perturbation. Active caspase-9 cleaves and activates caspase-8 and caspase-3, leading to apoptosis. In the presence of the general caspase inhibitor ZVAD, the cell-cycle effects of Alp are unaltered while apoptosis is blocked, suggesting that the CDK effects of Alp are not sufficient for Alp-induced apoptosis. Additional studies with paullones are warranted to further characterize their preclinical effects and to explore their potential use in the clinical setting.
...
PMID:Alsterpaullone, a novel cyclin-dependent kinase inhibitor, induces apoptosis by activation of caspase-9 due to perturbation in mitochondrial membrane potential. 1266 10

Focal ischemia by middle cerebral artery occlusion (MCAO) results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Recent studies have shown activation of the extrinsic and intrinsic pathways of caspase-mediated cell death, as well as activation of the caspase-independent signaling pathway of apoptosis in several paradigms of focal cerebral ischemia by transient MCAO to adult rats and mice. The extrinsic pathway (cell-death receptor pathway) is initiated by activation of the Fas receptor after binding to the Fas ligand (Fas-L); increased Fas and Fas-L expression has been shown following focal ischemia. Moreover, focal ischemia is greatly reduced in mice expressing mutated (nonfunctional) Fas. Increased expression of caspase-1, -3, -8, and -9, and of cleaved caspase-8, has been observed in the penumbra. Activation of the intrinsic (mitochondrial) pathway following focal ischemia is triggered by Bax translocation to and competition with Bcl-2 and other members of the Bcl-2 family in the mitochondria membrane that is followed by cytochrome c release to the cytosol. Bcl-2 over-expression reduces infarct size. Cytochrome c binds to Apaf-1 and dATP and recruits and cleaves pro-caspase-9 in the apoptosome. Both caspase-8 and caspase-9 activate caspase-3, among other caspases, which in turn cleave several crucial substrates, including the DNA-repairing enzyme poly(ADP-ribose) polymerase (PARP), into fragments of 89 and 28 kDa. Inhibition of caspase-3 reduces the infarct size, further supporting caspase-3 activation following transient MCAO. In addition, caspase-8 cleaves Bid, the truncated form of which has the capacity to translocate to the mitochondria and induce cytochrome c release. The volume of brain infarct is greatly reduced in Bid-deficient mice, thus indicating activation of the mitochondrial pathway by cell-death receptors following focal ischemia. Recent studies have shown the mitochondrial release of other factors; Smac/DIABLO (Smac: second mitochondrial activator of caspases: DIABLO: direct IAP binding protein with low pI) binds to and neutralizes the effects of the X-linked inhibitor of apoptosis (XIAP). Finally, apoptosis-inducing factor (AIF) translocates to the mitochondria and the nucleus following focal ischemia and produces peripheral chromatin condensation and large-scale DNA strands, thus leading to the caspase-independent cell death pathway of apoptosis. Delineation of the pro-apoptotic and pro-survival signals in the penumbra may not only increase understanding of the process but also help to rationalize strategies geared to reducing brain damage targeted at the periphery of the infarct core.
...
PMID:Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. 1272 25

Induction of apoptosis contributes to the cytotoxic action of the intravenously applicable alkylphosphocholine erucylphosphocholine (ErPC). To define molecular requirements for ErPC-induced apoptosis, activation of caspases-8, -9 and -3 and cleavage of the caspase-3 substrates PARP and ICAD were tested in normal Jurkat T cells, Jurkat cells resistant to death receptor (CD95 or TNFalpha-related apoptosis inducing ligand (TRAIL)-induced apoptosis, Jurkat cells lacking caspase-8 or Fas-associated death domain (FADD) Jurkat cells expressing a dominant-negative caspase-9 or overexpressing Bcl-2 as well as BJAB B-lymphoma cells expressing a dominant-negative FADD (FADD-DN). ErPC induced a time- and dose-dependent apoptotic cell death in Jurkat and BJAB cells, which was characterized by breakdown of the phosphatidylserine asymmetry, depolarization of the mitochondrial membrane potential, release of cytochrome c, activation of caspases-9, -8 and -3, cleavage of PARP and ICAD, as well as chromatin condensation. ErPC-induced apoptosis was independent from CD95-receptor signaling and FADD since CD95- and TRAIL-resistant, caspase-8- and FADD-negative Jurkat cells, as well as BJAB cells expressing FADD-DN were sensitive to ErPC-induced apoptosis. In contrast, inhibition of caspase-9 and overexpression of Bcl-2 significantly reduced ErPC-induced caspase activation and apoptosis. Thus, ErPC triggers apoptosis via a Bcl-2-dependent mitochondrial but death receptor-independent pathway.
...
PMID:Intracellular mediators of erucylphosphocholine-induced apoptosis. 1273 Jun 76

Previous studies have identified RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) as a potential chemotherapeutic agent. VES induces human breast cancer cells to undergo apoptosis in a concentration- and time-dependent manner by restoring transforming growth factor beta (TGF-beta) and Fas (CD95) apoptotic signaling pathways, that contribute to the activation of c-Jun NH(2)-terminal kinase (JNK)-mediated apoptosis. The objective of these studies was to clarify biochemical events involved in VES-induced apoptosis. Data show that VES-induced apoptosis involves: (a) translocation of Bax from the cytosol to the mitochondria and cytochrome c release from the mitochondria to the cytosol as determined by Western immunoblot analyses of mitochondrial- and cytosolic-enriched cellular fractions; (b) increased permeabilization of mitochondrial membranes as determined by confocal and fluorescence-activated cell sorting analyses of loss of a mitochondrial selective fluorescent dye; (c) processing of caspase-9 and -3 but not caspase-8 to active forms and cleavage of poly(ADP-ribose) polymerase (PARP) as determined by Western immunoblot analyses using antibodies capable of detecting both proenzyme and processed enzyme forms or the intact or cleaved forms of PARP. Transient transfection of cells with antisense oligonucleotides to Bax or transient overexpression of Bcl-2 prevented VES-induced mitochondrial permeability transition and apoptosis. The use of cell-permeable caspase inhibitors indicated that caspase-9 and -3 but not caspase-8 are involved in VES-induced apoptosis. JNK inhibitor II blocked VES-induced Bax conformational change, indicating a role for JNK in Bax translocation to the mitochondria. Taken together, these data suggest that the activation of JNK, translocation of Bax to the mitochondria, increased mitochondrial membrane permeability with release of cytochrome c, and activation of caspase-9 and -3 are critical events in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
...
PMID:RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. 1275 Feb 70

Apoptotic response of keratinocytes to UVB irradiation has physiological significance on photocarcinogenesis. Here, we show that the sustained release of Smac/DIABLO from mitochondria is an important event for the onset of apoptosis in keratinocytes exposed to UVB irradiation. In human keratinocyte HaCaT cells, UVB irradiation at 500 J/m(2), but not at 150 J/m(2), induces apoptosis. Significant activations of caspases-9 and -3, and slight activation of caspase-7 were observed only in 500 J/m(2) UVB irradiated HaCaT cells. Correspondingly, the cleavage of PARP, a substrate of caspases-3 and -7, was detected in cells irradiated at 500 J/m(2) UVB, but not at 150 J/m(2). However, with both 150 and 500 J/m(2) UVB irradiation, cytochrome c, an activator of caspase-9 via the formation of apoptosome, was released from mitochondria to the cytosol at the same extent. In contrast, significant amounts of Smac/DIABLO are released from mitochondria to the cytosol only with 500 J/m(2) UVB irradiation, and that the level of XIAP is decreased. These results suggest that the extent of Smac/DIABLO efflux from mitochondria is a determinant whether a cell will undergo apoptosis or survival.
...
PMID:Sustained release of Smac/DIABLO from mitochondria commits to undergo UVB-induced apoptosis. 1276 89

LIGHT is a new member of the tumor necrosis factor superfamily, which binds to lymphotoxin beta receptor, herpes virus entry mediator, or TR6. This work was carried out to elucidate the molecular mechanism of LIGHT-sensitized, interferon gamma (IFNgamma)-mediated apoptosis of MDA-MB-231 cells. It was revealed that LIGHT treatment resulted in down-regulation of anti-apoptosis Bcl-2 family member: Bcl-2, Bcl-X(L), Bag-1, and Mcl-1; up-regulation of pro-apoptosis Bcl-2 family member: Bak and Ser (112)-phosphor-Bad; down-regulation of pro-apoptosis Bcl-2 member Bax; the other pro-apoptosis member Bid remains unaltered. LIGHT treatment also resulted in activation of caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, DFF45, and PARP. However, caspase activation and caspase activity, especially caspase-3 activity, is not required for LIGHT-induced apoptosis of MDA-MB-231 cells, since caspase-3 inhibitor, benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, and a broad range caspase inhibitor, benzyloxycarbonyl-val-ala-asp-fluoromethylketone failed to block the apoptosis induced by LIGHT and IFNgamma in MDA-MB-231 cells. In summary, LIGHT-sensitized IFNgamma-mediated apoptosis of MDA-MB-231 cells is probably through down-regulation of anti-apoptosis Bcl-2 family members; it could be caspase (especially caspase-3)-independent, even though extensive caspase activation was observed.
...
PMID:LIGHT sensitizes IFNgamma-mediated apoptosis of MDA-MB-231 breast cancer cells leading to down-regulation of anti-apoptosis Bcl-2 family members. 1276 29

We have previously shown that Smac/DIABLO release from mitochondria appears to be the principal pathway by which TRAIL induces apoptosis of human melanoma. We report that TRAIL-induced release of Smac/DIABLO appears to be downregulated by concomitant signaling through the MEK Erk1/2 kinase pathway and that this inhibits TRAIL-induced apoptosis. Inhibition of Erk1/2 signaling by either the MEK inhibitor U0126 or a dominant-negative mutant of MKK1 markedly sensitized melanoma cells to TRAIL-induced apoptosis. The site in the apoptotic pathway acted on by U0126 appeared to be downstream of caspase-8 and Bid but upstream of caspase-3 in that the levels of proteolytic cleavage of caspase-8 and Bid by TRAIL were similar in cells with or without exposure to U0126. Caspase-3 activation and cleavage of its substrates, PARP, ICAD and XIAP, were however increased by cotreatment with U0126. This was associated with a rapid reduction in mitochondrial transmembrane potential (MMP) and increased release of Smac/DIABLO into the cytosol. Exploration of events leading to the changes in MMP revealed an increased translocation of Bax from the cytosol to mitochondria in the presence of U0126. There was also a delayed decrease in the levels of expression of Mcl-1. Bcl-2 and Bcl-X(L). Over expression of Bcl-2 blocked TRAIL-induced apoptosis in the presence of U0126. Cytochrome c appeared not to play a major role in sensitization of melanoma to TRAIL in that caspase-9 activation was not detected in most of the cell lines. These results suggest that Erk1/2 signaling may protect melanoma cells against TRAIL-induced apoptosis by inhibiting the relocation of Bax from the cytosol to mitochondria and that this may reduce TRAIL-mediated release of Smac/DIABLO and induction of apoptosis.
...
PMID:Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. 1277 38


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

---