Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the processes of peripheral tissue remodeling and fibrinolysis through the regulation of plasminogen activation. We found that cultured human astrocytes efficiently released PAI-1, and that both mRNA expression and protein release of PAI-1 were suppressed by pretreatment of the cells with daunorubicin. To examine the role of PAI-1 in the nervous system, neuronally differentiated PC-12 cells (PC-12 neurons) were maintained in a PAI-1-deficient culture medium derived from daunorubicin-pretreated astrocytes. The deficiency of PAI-1 in the medium caused a significant reduction in Bcl-2 and Bcl-XL mRNAs and an increase in Bcl-XS and Bax mRNAs in PC-12 neurons at 3 h. The changes in balance between mRNA expressions of the anti- and pro-apoptotic Bcl-2 family proteins caused caspase-3 activation following the release of cytochrome c from mitochondria. Apoptotic morphological change and DNA fragmentation were also observed in the neuronal cells at 24 h. Addition of exogenous PAI-1 protein to the inhibitor-deficient medium blocked the apoptotic changes in PC-12 neurons. However, addition of PAI-1 antibodies to control medium caused similar apoptotic changes in PC-12 neurons. During the apoptotic processes, plasminogen activator (PA) activity in the PAI-1-deficient medium was as low as the control level. The present data suggest that PAI-1 has physiological functions other than its role as PA inhibitor for the survival of neurons.
 ...
PMID:Deficient release of plasminogen activator inhibitor-1 from astrocytes triggers apoptosis in neuronal cells. 1145 96

Pachymic acid (PA) is a natural triterpenoid known to inhibit the phospholipase A2 (PLA(2)) family of arachidonic acid (AA)-producing enzymes. PLA(2) is elevated in prostatic adenocarcinoma and conversion of AA to prostaglandins leads to AKT pro-survival activity. In this study, we investigated the effect of PA on the growth of human prostate cancer cells. PA significantly reduced cell proliferation and induced apoptosis in a dose- and time-dependent fashion, with androgen-insensitive DU145 prostate cancer cells showing greater growth inhibition relative to androgen-responsive LNCaP. Despite elevated protein expression of the cell cycle inhibitor, p21, apoptosis occurred in the absence of cell cycle arrest. PA-treatment decreased Bad phosphorylation, increased Bcl-2 phosphorylation, and activated caspases-9 and -3, suggesting that PA initiated apoptosis through mitochondria dysfunction. PA-treatment also decreased the expression and activation of proteins within the AKT signal pathway. We speculate that PA influenced apoptosis by reducing prostaglandin synthesis and AKT activity.
 ...
PMID:Induction of apoptosis in prostate cancer cells by pachymic acid from Poria cocos. 1591 45

Transforming growth factor-beta (TGF-beta) has been characterized as an injury-related factor, based on the observation that it is strongly up-regulated in many acute or chronic central nervous system disorders. TGF-beta is generally thought to be neuroprotective and several mechanisms have been proposed to explain this beneficial action. For instance, TGF-beta protects neurons against the potentiating effect of tissue-type plasminogen activator on NMDA receptor-mediated excitotoxicity, by up-regulating type-1 plasminogen activator inhibitor expression in astrocytes. TGF-beta has also anti-apoptotic properties, through a recruitment of a mitogen-activated protein kinase pathway and a concomitant activation of anti-apoptotic members of the Bcl-2 family. These multiple mechanisms might reflect the pleiotropic nature of TGF-beta, reinforcing the potential therapeutic value of this cytokine in several central nervous system disorders.
 ...
PMID:Transforming growth factor-beta signalling in brain disorders. 1627

In the present study, we determined the impact of 5 and 10 days of muscle deconditioning induced by hindlimb suspension (HS) on the ubiquitin-proteasome system of protein degradation and caspase enzyme activities in rat soleus muscles. A second goal was to determine whether activities of matrix metalloproteinase-2/9 (MMP-2/9) and urokinase-type/tissue-type plasminogen activator (PAs) were responsive to HS. As expected, HS led to a pronounced atrophy of soleus muscle. Level of ubiquitinated proteins, chymotrypsin-like activity of 20S proteasome, and Bcl-2-associated gene product-1 protein level were all transitory increased in response to 5 days of HS. These changes may thus potentially account for the decrease in muscle mass observed in response to 5 days of HS. Caspase-3 activity was significantly increased throughout the experimental period, whereas activities of caspase-6, another effector caspase, and caspase-9, the mitochondrial-dependent activator of both caspase-3 and -6, were only increased in response to 10 days of HS. This suggests that caspase-3 may be regulated through mitochondrial-independent and mitochondrial-dependent mechanisms in response to HS. Finally, MMP-2/9 activities remained unchanged, whereas PAs activities were increased after 5 days of HS. Overall, these data suggest that time-dependent regulation of intracellular and extracellular proteinases are important in setting the new phenotype of rat soleus muscle in response to HS.
 ...
PMID:Regulation of ubiquitin-proteasome system, caspase enzyme activities, and extracellular proteinases in rat soleus muscle in response to unloading. 1733 80

Relative specific amino acid dependency is one of the metabolic abnormalities of melanoma cells and metabolic studies of this dependency are in their infancy. Herein, we review the current studies in this area and present new information that adds to the understanding of how tyrosine (Tyr) and phenylalanine (Phe) dependency as well as other amino acids regulate the cell behaviors of melanoma cells. Amino acid dependency of human melanoma cells is multifactorial and restricting Tyr and Phe to melanoma triggers a series of alterations in metabolic and signaling pathways in a time-ordered fashion to alter different cellular behaviors. For example, at early time points, the reduction of Tyr and Phe alters metabolic reactions quantitatively or qualitatively. The alterations include modulation of integrin/focal adhesion kinase (FAK)/G protein pathways and the plasminogen activator (PA)/PA inhibitor pathways to inhibit tumor cell invasion. At later time periods, a further drop in intracellular amino acids induces more metabolic alterations to impact the FAK/Ras/Raf and Bcl-2 pathways leading to apoptosis. The threshold effects and the targeting of multiple pathways by restriction of specific amino acids provide a connection between the metabolic alterations and signaling pathways that modulate the cellular behaviors of melanoma cells. Decoding the metabolic alterations that connect amino acid concentration to the crucial step(s) in signaling is important and an exciting area of cancer research.
 ...
PMID:Specific amino acid dependency regulates the cellular behavior of melanoma. 1751 32

We have previously reported that Fas-resistant A20 cells (FasR) have phospholipase D (PLD) activity upregulated by endogenous PLD2 overexpression. In the present study, we investigated how overexpressed PLD2 in FasR could generate survival signals by regulating the protein levels of anti-apoptotic Bcl-2 and Bcl-xL. To confirm the effect of PLD2 on Bcl-2 protein levels, we transfected PLD2 into wild-type murine B lymphoma A20 cells. The transfected cells showed markedly the increases in Bcl-2 and Bcl-xL protein levels, and became resistant to Fas-induced apoptosis, similar to FasR. Treatment of wild-type A20 cells with phosphatidic acid (PA), the metabolic end product of PLD2 derived from phosphatidylcholin, markedly increased levels of anti-apoptotic Bcl-2 and Bcl-xL proteins. Moreover, PA-induced expressions of Bcl-2 and Bcl-xL were enhanced by propranolol, an inhibitor of PA phospholydrolase (PAP), whereas completely blocked by mepacrine, an inhibitor of phospholipase A(2) (PLA(2)), suggesting that PLA(2) metabolite of PA is responsible for the increases in Bcl-2 and Bcl-xL protein levels. We further confirmed the involvement of arachidonic acid (AA) in PA-induced survival signals by showing that 1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA), PA without AA, was unable to increase Bcl-2 and Bcl-xL proteins. Moreover, PA notably increased cyclooxygenase (COX)-2 protein expression, and PA-induced expression of both Bcl-2 and Bcl-xL was inhibited by NS-398, a specific inhibitor of COX-2. Taken together, these findings demonstrate that PA generated by PLD2 plays an important role in cell survival during Fas-mediated apoptosis through the increased Bcl-2 and Bcl-xL protein levels which resulted from PLA(2) and AA-COX2 pathway.
 ...
PMID:Role of phospholipase D2 in anti-apoptotic signaling through increased expressions of Bcl-2 and Bcl-xL. 1754 81

Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine to generate phosphatidic acid (PA) and choline. There are at least two PLD isozymes, PLD1 and PLD2. Genetic and pharmacological approaches implicate both PLD isozymes in a diverse range of cellular processes, including receptor signaling, membrane transport control, and actin cytoskeleton reorganization. Several recent studies reported that PLD has a role in signaling pathways that oppose apoptosis and promote cell survival in cancer. In this study, we examined the role of PLD in taxotere-induced apoptosis in stomach cell lines; normal stomach (NSC) and stomach cancer cells (SNU 484). Taxotere treatment resulted in increase of PLD activity. To confirm the role of PLD in taxotere-induced apoptosis, PLDs were transfected into SNU 484 cells. Overexpression of PLD isozymes resulted in inhibition of taxotere-induced apoptotic cell death, evidenced by decreased degradation of chromosomal DNA, and increased cell viability. Concurrently, Bcl-2 expression was upregulated, and taxotere-induced activation of procaspase 3 was inhibited after PLD's transfection. However, when PLD was selectively inhibited by specific siRNA-PLD1 or -PLD2, taxotere-induced apoptosis was exacerbated in SNU 484 cells. On top of this, PA -- the product of PLDs, also resulted in upregulation of Bcl-2 in SNU 484. Although PA-induced Bcl-2 expression was blocked by mepacrine, an inhibitor of phospholipase A(2) (PLA(2)), increased Bcl-2 expression by PA was not abrogated by propranolol, an inhibitor of PA phospholyhydrolase (PAP). Taken together, PLD1 and PLD2 are closely related with Bcl-2 expression together with PLA(2), but not with PAP, during taxotere-induced apoptosis in SNU 484 cells.
 ...
PMID:Overexpression of phospholipase D suppresses taxotere-induced cell death in stomach cancer cells. 1819 Jul 95

The effect of bcl-2 expression on cell viability and recombinant protein synthesis was investigated in the Spodoptera frugiperda Sf-9 and Trichoplusia ni BTI-Tn-5B1-4 (High Fivetrade mark) insect cell lines. It was found that coinfection with a baculovirus expressing bcl-2 [Autographa californica nuclear polyhedrosis virus (AcNPV)-bcl2] extended the life span of High Fivetrade mark cells but not Sf-9 cells when compared to infection with recombinant baculoviruses expressing either human tissue plasminogen activator (AcNPV-tPA) or Escherichia coli beta-galactosidase (AcNPV-betagal). Similar results were obtained in coinfection experiments; i.e., AcNPV-bcl2 coinfection increased the life span of High Fivetrade mark cells over that of cells infected with either AcNPV-tPA or AcNPV-betagal alone, but they did not affect the life span of coinfected Sf-9 cells. Coinfection of Sf-9 cells with AcNPV-bcl2 and AcNPV-betagal resulted in a decrease in the maximum beta-gal expression levels of over 90% when compared to infection with AcNPV-betagal alone. A similar trend was found in the beta-gal mRNA levels. Coinfection also resulted in a reduced beta-gal expression level in High Fivetrade mark cells, but the reduction was consistent with what would be expected when two recombinant viruses compete for use of the cellular machinery. In contrast to the inhibitory effect of AcNPV-bcl2 coinfection on betagal expression, t-PA expression levels were either not affected (Sf-9 cells) or were increased 50% (High Fivetrade mark cells) over those obtained by infection with AcNPV-tPA alone. These results support the hypotheses that bcl-2 can inhibit transcription of genes under polyhedrin promoter control and that beta-gal expression levels, but not t-PA expression levels, are controlled at the transcriptional level. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 56: 380-390, 1997.
 ...
PMID:bcl-2 expression in Spodoptera Frugiperda Sf-9 and Trichoplusia Ni BTI-Tn-5B1-4 insect cells: effect on recombinant protein expression and cell viability. 1864 41

In view of the controversial role of catalytic activity on the cytotoxicity of phospholipase A(2) (PLA(2)), the present study is conducted to explore whether PLA(2) induces apoptotic process of human leukemia U937 cells through catalytic activity-independent pathway. Modification of His-48 (according to the sequence alignment with porcine pancreatic PLA(2)) with p-bromophenacyl bromide (BPB) caused over 99.9% drop in enzymatic activity Naja naja atra PLA(2). It was found that BPB-PLA(2)-induced apoptotic death of U937 cells was associated with mitochondrial depolarization, modulation of Bcl-2 family members, cytochrome c release and activation of caspases 9 and 3. Upon exposure to BPB-PLA(2), elevation of intracellular Ca(2+) levels and p38 MAPK activation were observed in U937 cells. Pretreatment with BAPTA-AM (Ca(2+) chelator) and nifedipine (L-type Ca(2+) channel blocker) abrogated Ca(2+) increase and p38 MAPK activation, and rescued viability of BPB-PLA(2)-treated U937 cells. BPB-PLA(2)-induced dissipation of mitochondrial membrane potential and down-regulation of Bcl-2 were suppressed by SB202190 (p38MAPK inhibitor). Although PLA(2) mutants in which His-48 and Asp-49 were substituted by Ala and Lys, respectively, did not display detectable PLA(2) activity, they induced death of U937 cells. The signaling pathway of PLA(2) mutants in inducing cell death was indistinguishable from that of BPB-PLA(2). Taken together, our data indicate that catalytic activity-independent pathway is involved in PLA(2)-induced apoptotic death of human leukemia U937 cells via mitochondria-mediated death pathway triggering by Ca(2+)-mediated p38 MAPK activation.
 ...
PMID:Catalytic activity-independent pathway is involved in phospholipase A(2)-induced apoptotic death of human leukemia U937 cells via Ca(2+)-mediated p38 MAPK activation and mitochondrial depolarization. 1911 7

Phospholipase A(2) (PLA(2)) from Naja naja atra venom induced apoptotic death of human leukemia K562 cells. Degradation of procaspases, production of tBid, loss of mitochondrial membrane potential, Bcl-2 degradation, mitochondrial translocation of Bax, and cytochrome c release were observed in PLA(2)-treated cells. Moreover, PLA(2) treatment increased Fas and FasL protein expression. Upon exposure to PLA(2), activation of p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun NH(2)-terminal kinase) was found in K562 cells. SB202190 (p38 MAPK inhibitor) pretreatment enhanced cytotoxic effect of PLA(2) and led to prolonged JNK activation, but failed to affect PLA(2)-induced upregulation of Fas and FasL protein expression. Sustained JNK activation aggravated caspase8/mitochondria-dependent death pathway, downregulated Bcl-2 expression and increased mitochondrial translocation of Bax. SP600125 (JNK inhibitor) abolished the cytotoxic effect of PLA(2) and PLA(2)-induced autocrine Fas death pathway. Transfection ASK1 siRNA and overexpression of dominant negative p38alpha MAPK proved that ASK1 pathway was responsible for PLA(2)-induced p38 MAPK and JNK activation and p38alpha MAPK activation suppressed dynamically persistent JNK activation. Downregulation of FADD abolished PLA(2)-induced procaspase-8 degradation and rescued viability of PLA(2)-treated cells. Taken together, our results indicate that JNK-mediated autocrine Fas/FasL apoptotic mechanism and modulation of Bcl-2 family proteins are involved in PLA(2)-induced death of K562 cells.
 ...
PMID:Taiwan cobra phospholipase A2-elicited JNK activation is responsible for autocrine fas-mediated cell death and modulating Bcl-2 and Bax protein expression in human leukemia K562 cells. 1993 32


1 2 Next >>