Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53-mediated apoptosis may involve the induction of redox-controlling genes, resulting in the production of reactive oxygen species. Microarray expression analysis of doxorubicin exposed, related human lymphoblasts, p53 wild-type (WT) Tk6, and p53 mutant WTK1 identified the p53-dependent up-regulation of manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx). Consensus p53 binding sequences were identified in human MnSOD and GPx promoter regions. A 3-fold increase in the MnSOD promoter activity was observed after the induction of p53 in Li-Fraumeni syndrome (LFS) fibroblast, TR9-7, expressing p53 under the control of a tetracycline-regulated promoter. An increased protein expression of endogenous MnSOD and GPx also positively correlated with the level of p53 induction in TR9-7 cells. However, catalase (CAT) protein expression remained unaltered after p53 induction. We also examined the expression of MnSOD, GPx, and CAT in a panel of normal or LFS fibroblasts, containing either WT or mutant p53. We found increased MnSOD enzymatic activity, MnSOD mRNA expression, and MnSOD and GPx protein in LFS fibroblasts carrying a WT p53 allele when compared with homozygous mutant p53 isogenic cells. The CAT protein level was unchanged in these cells. We observed both the release of cytochrome C and Ca(2+) from the mitochondria into the cytoplasm and an increased frequency of apoptotic cells after p53 induction in the TR9-7 cells that coincided with an increased expression of MnSOD and GPx, and the level of reactive oxygen species. The increase in apoptosis was reduced by the antioxidant N-acetylcysteine. These results identify a novel mechanism of p53-dependent apoptosis in which p53-mediated up-regulation of MnSOD and GPx, but not CAT, produces an imbalance in antioxidant enzymes and oxidative stress.
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PMID:p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. 1505 85

Benzo(a)pyrene (BaP), a potent carcinogen, has been shown to induce apoptosis via activation of caspase-3. However, the upstream of caspase-3 and other apoptosis signaling remain to be elusive. Herein, we demonstrated that treatment of Hepa1c1c7 cells with BaP increased the transcriptional expression of aryl hydrocarbon nuclear transporter and cytochrome p450 1A1 in a time and dose-dependent manner but did not aromatic hydrocarbon receptor. Also, the catalytic activation of caspase-3 and caspase-9 was induced whereas that of caspase-3 and caspase-9 was not by the addition of BaP. BaP also induced the mitochondrial dysfunction, including transition of mitochondria membrane potential and cytosolic release of cytochrome c. Furthermore, a decrease in the expression of Bcl-2 to Bax ratio and phosphorylation of p53(Ser 15) were observed in BaP-treated cells. Taken together, these results demonstrated that BaP-induced apoptosis of Hepa1c1c7 cells via activation of intrinsic caspase pathway including caspase-3, caspase-9, with mitochondrial dysfunction and p53 activation.
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PMID:Benzo(a)pyrene-induced apoptotic death of mouse hepatoma Hepa1c1c7 cells via activation of intrinsic caspase cascade and mitochondrial dysfunction. 1512 97

Although suppression of apoptosis has been implicated as a mechanism for the hepatocarcinogenicity of peroxisome proliferators (PPs), they can also induce cell death in rat AH130 and human HepG2 hepatoma cells. To study how PPs induce cell death and to characterize the molecular events involved, we administered the hypolipidemic BR931, a peroxisome proliferator, to rat hepatoma FaO cells. Treatment with increasing concentrations of BR931 (0.015 to 0.6 mM) reduced cell viability in a dose- and time-dependent manner, associated with DNA fragmentation and morphological changes characteristic of apoptosis. BR931 also caused phosphorylation of p53 within 3 hours, translocation of the pro-apoptotic Bax protein to mitochondria, release of cytochrome-c into the cytosol, and activation of caspase-9 and -3. These results indicated that BR931 activated the intrinsic caspase cascade. Pretreatment with three different antioxidants, N-acetylcysteine, Vitamin C and Trolox, reduced apoptosis, suggesting that reactive oxygen species (ROS) plays a role in BR931-induced apoptosis. In support of this hypothesis, BR931 produced increased levels of 8-hydroxy-deoxy-guanosine, a marker of DNA oxidative damage. Antioxidants prevented the p53 phosphorylation, up-regulation of Bax and BR931-induced apoptosis. These results suggest that BR931 can increase generation of ROS, leading to DNA damage and p53 phosphorylation, which, in turn, induces the activation of Bax, release of cytochrome-c from mitochondria and activation of caspases, culminating in cell death.
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PMID:The peroxisome proliferator BR931 kills FaO cells by p53-dependent apoptosis. 1513 49

The development of head and neck squamous cell cancer (HNSCC) is known to be strongly associated with tobacco use. One of the main enzymes for bioactivation of tobacco-related substances is the cytochrome 450 (CYP)2E1, of which different genetic variants are described. Analyzing a correlation between certain neoplasia and alteration of the CYP2E1 gene, most studies focus on the polymorphisms -1053C>T and 7632T>A, but recently another polymorphism, named -71G>T, with enhanced transcriptional activity, has been identified. In the current case-control study we investigate the putative association of the mentioned CYP2E1 polymorphisms on the risk of HNSCC. Comparing 312 German individuals with HNSCC to 299 controls we found a significantly enhanced risk for the development of that neoplasia in smoking carriers of -71G>T heterozygosity, while in -1053C>T and 7632T>A polymorphisms a corresponding correlation was absent. Since a coincidence of an aberrant p53 gene and CYP2E1 mutations has been described, we choose a subgroup of 140 patients with HNSCC for analyzing an association of mutations in these two genes. However, no such association could be found in either of the mentioned polymorphisms. Further studies have to focus on the -71G>T polymorphism and its possible linkage to cancers, in which smoking is a known risk-factor, as well as its functional relevance concerning the bioactivation of tobacco-related substances.
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PMID:Association of cytochrome P450 2E1 polymorphisms and head and neck squamous cell cancer. 1517 63

It is now well established that a fraction of stress-induced wtp53 protein rapidly translocates to mitochondria in immortalized and transformed cells in culture. Mitochondrial p53 interacts with anti-apoptotic proteins of the Bcl 2 family at the outer mitochondrial membrane, resulting in membrane permeabilization, release of death effectors such as cytochrome C and subsequent rapid apoptosis. The significance and relevance of this direct mitochondrial p53 program to the overall p53-mediated stress response in vivo is underlined by a number of recent studies in animals and primary cells. They all support a role for this direct pathway in the physiologic and pathophysiologic response to genotoxic and hypoxic insults and occur precisely in those tissues where p53 plays a critical role in mediating apotpotis rather than cell cycle arrest.
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PMID:Stress-induced p53 runs a direct mitochondrial death program: its role in physiologic and pathophysiologic stress responses in vivo. 1561 31

The mechanism of action of the neurotoxin 6-hydroxydopamine (6-OHDA) is thought to involve the generation of free radicals and subsequent apoptotic processes. We have demonstrated in vitro that the neuroimmunophilin, FK506 (10-100 nM), dose dependently and significantly restored the ROS production to the control level, increased the Bcl-2 protein level, partly inhibited the cytochrome C release from mitochondria and reduced the caspase-3 activation in SH-SY5Y cells. On the other hand, there was no significant restoration of the ATP level by FK506 and the toxin activated proteins, p53 and Bax, were not normalized by FK506. In support of these latter results, daily administration of FK506 for 7 days to rats (0.5, 1 and 3 mg/kg i.p.) did not significantly prevent the apomorphine-induced contralateral circling, measured 2 weeks after unilateral nigral lesioning. Moreover, FK506 pretreatment did not significantly lower the toxin elevated lipid peroxidation levels, indicating that oxidative stress was present even after the FK506 treatment in the lesioned striatum. Taken together, our results with FK506 are inconsistent. We confirm the antioxidant nature of FK506, that is, it blocks ROS production in SH-SY5Y cells. However, there were no significant protective effects in any apoptotic analyses in SH-SY5Y cells and in animal studies, a 7-day FK506 pre-treatment was not able to reverse the toxic effect of 6-OHDA in a rat model of Parkinson's disease.
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PMID:Failure of FK506 (tacrolimus) to alleviate apomorphine-induced circling in rat Parkinson model in spite of some cytoprotective effects in SH-SY5Y dopaminergic cells. 1574 76

The cardiotoxicity of adriamycin limits its clinical use as a powerful drug for solid tumors and malignant hematological disease. Although the precise mechanism by which it causes cardiac damage is not yet known, it has been suggested that apoptosis is the principal process in adriamycin-induced cardiomyopathy, which involves DNA fragmentation, cytochrome C release, and caspase activation. However, there has been no direct evidence for the critical involvement of caspase-3 in adriamycin-induced apoptosis. To determine the requirements for the activation of caspase-3 in adriamycin-treated cardiac cells, the effect of a caspase inhibitor on the survival of and apoptotic changes in H9c2 cells was examined. Exposure of H9c2 cells to adriamycin resulted in a time- and dose-dependent cell death, and the cleavage of pro-caspase-3 and of the nuclear protein poly (ADP'ribose) polymerase (PARP). However, neither the reduction of cell viability nor the characteristic morphological changes induced by adriamycin were prevented by pretreatment with the general caspase inhibitor z-VAD.FMK. In contrast, caspase inhibition effectively blocked the apoptosis induced by H202 in H9c2 cells, as determined by an MTT assay or microscopy. We also observed that p53 expression was increased by adriamycin, and this increase was not affected by the inhibition of caspase activity, suggesting a role for p53 in adriamycin-induced caspase-independent apoptosis in cardiac toxicity.
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PMID:Induction of caspase-independent apoptosis in H9c2 cardiomyocytes by adriamycin treatment. 1579 49

Deoxynivalenol (DON) and other ribotoxic trichothecenes cause immune stimulation and suppression in leukocytes by upregulating gene expression and apoptosis, respectively. The purpose of this study was to test the hypothesis that MAPKs mediate both apoptosis and survival in DON-exposed macrophages. At concentrations which partially inhibit translation, DON induced phosphorylation of p38 and ERK 1/2 mitogen activated protein kinases within 15 min in RAW 264.7 macrophages and these effects lasted up to 3 h. DON-exposed cells exhibited marked caspase 3-dependent DNA fragmentation after 6 h which was suppressed and attenuated by the p38 inhibitor SB203580 and ERK inhibitor PD98059, respectively. DON readily induced the phosphorylation and activity of p53 and this was inhibitable by SB203580. DON exposure evoked BAX translocation to mitochondria and corresponding cytochrome C release but did not alter mitochondrial membrane potential. The p53 inhibitor PFTalpha reduced both DON-induced phosphorylation of p53 and p53 binding activity. Moreover, both PFTalpha and p53 siRNA transfection suppressed DON-induced caspase-3 activity and subsequent DNA fragmentation. Concurrent with p53 activation, DON activated two anti-apoptotic survival pathways as evidenced by both ERK-dependent p90 Rsk and AKT activation. Taken together, the results indicate that DON initiates competing apoptotic (p38/p53/Bax/Mitochondria/Caspase-3) and survival (ERK/AKT/p90Rsk/Bad) pathways in the macrophage.
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PMID:Induction of competing apoptotic and survival signaling pathways in the macrophage by the ribotoxic trichothecene deoxynivalenol. 1597 93

Knocking out of Nurr1 gene, a member of nuclear receptor superfamily, causes selective agenesis of dopaminergic neurons in midbrain. Reduced expression of Nurr1 increases the vulnerability of mesencephalic dopamine neurons to dopaminergic toxins. We evaluated the role of nitric oxide as a possible mechanism for this increased susceptibility. Increased expression of neuronal nitric oxide synthase and increased 3-nitrotyrosine were observed in striatum of Nurr1 heterozygous (Nurr1 +/-) mice as compared with wild-type. Increased cytochrome C activation and consecutive release of Smac/DIABLO were also observed in Nurr1 +/- mice. An induction of active Caspase-3 and p53, cleavage of poly-ADP (RNase) polymerase and reduced expression of bcl-2 were observed in Nurr1 +/- mice. Methamphetamine significantly increased these markers in Nurr1 +/- mice as compared with wild-type. The present data therefore suggest that nitric oxide plays a role as a modulating factor for the increased susceptibility, but not the potentiation, of the dopaminergic terminals in Nurr1 +/- mice. We also report that this increased neuronal nitric oxide synthase expression and increased nitration in Nurr1 +/- mice led to the activation of apoptotic cascade via the differential alterations in the DNA binding activity of transcription factors responsible for the propagation of growth arrest as well as apoptosis.
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PMID:Nitric oxide mediates increased susceptibility to dopaminergic damage in Nurr1 heterozygous mice. 1612 11

In recent years, the understanding that regeneration progresses at the level of the myocardium has placed stem cell research at the center stage in cardiology. Despite an increasing interest in cell transplant research, relatively little is known about the biochemical regulation of the stem cell itself after transplantation into an ischemic heart. We demonstrated here, using rat mesenchymal stem cells (MSCs), that cells undergo caspase-dependent apoptosis in response to hypoxia and serum deprivation (SD), which are both components of ischemia in vivo. In particular, the treated cells exhibited mitochondrial dysfunction, including cytochrome C release, loss in DeltaPsim, and Bax accumulation, but in a p53-independent manner. Although the cells treated by hypoxia/SD possess the activity of caspase-8, zIEDT-fmk, a specific caspase-8 inhibitor, failed to inhibit cell apoptosis induced in our system. Taken together, our findings indicate that MSCs are sensitive to hypoxia/SD stimuli that involve changes in mitochondrial integrity and function but are potentially independent of caspase-8.
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PMID:Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. 1625 84


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