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

The heme oxygenase (HO) isozymes catalyze oxidation of the heme molecule to biliverdin and carbon monoxide (CO) with the release of chelated iron. Presently, we have defined, for the first time, propensity for site of injury-directed induction of isozymes--the stress-inducible isozyme, HO-1, responds distal (below) and the glucocorticoid (GC)-inducible HO-2 responds proximal (above) to the site of injury. We have also shown that reactive iron (Fe3+) and cGMP staining spatially resemble that of HO-1; which, in turn, colocalizes in motor neurons with transcription factors: Fas-associated protein containing death domain (FADD), tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and p53. Spinal cord injury (SCI) was inflicted by clip compression for 30 min, and analyses were carried out after 4 h or 16 h. When compared with spinal cord segments proximal to the site of injury, northern blot analysis showed remarkably higher levels of HO-1 mRNA distal (below) to the site of injury at both time points. In contrast, HO-2 mRNA levels were elevated proximal (above) to the site of injury and more prominently at 16 h post SCI. Immunohistochemical analyses were carried out using 2 x 5 mm segments above and below the compression site. When compared with segments above the site of injury, the intensity of HO-1 immunostaining and the number of HO-1 positive neurons in the ventral horn motor neurons were prominently increased in segments below the injury. Western blot analysis confirmed the observations. HO-2 protein was mapped to the ventral horn motor neurons, oligodendrocytes, the Clarke's nucleus neurons and the ependymal cells. When compared with segments below the site of injury, neuronal HO-2 staining intensity was increased above the site of injury, and most notably at 16 h. These observations were also confirmed by western blotting and HO activity measurements. Tissue Fe3+ and cGMP staining were increased and prominently mapped below the site of injury, where cGMP colocalized with HO-1 in the nucleus of the motor neurons. Also, a site of injury-directed pattern of induction of FADD, TRAIL, and p53 immunoreactivity, and a widespread colocalization of the oncogenes with HO-1 protein, were found within motor neurons below the level of injury. We forward the hypothesis that HO-1 and HO-2 have different roles in the defense mechanisms of the injured nervous system. We hypothesize that HO-1 protects against further damage by contributing to controlled cell death through their intrinsic suicide program, while HO-2 is involved in suppression of inflammatory response by NO derived radicals.
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PMID:Site of injury-directed induction of heme oxygenase-1 and -2 in experimental spinal cord injury: differential functions in neuronal defense mechanisms? 1120 17

Previously, we showed that NO induces thymocyte apoptosis via a caspase-1-dependent mechanism [(1) ]. In the present study, we investigated the role of heme oxygenase, catalase, bax, and p53 in this process. The NO donor, S-nitroso-N-acetyl penicillamine (SNAP), induced DNA fragmentation in thymocytes in a time- and concentration-dependent way. SNAP (100 microM) induced 50--60% apoptosis; higher doses did not increase the rate of apoptosis significantly. SNAP decreased catalase and heme iron (Fe) levels without affecting superoxide dismutase, glutathione, or total Fe stores in thymocytes. SNAP significantly increased the expression of heme oxygenase 1 (HSP-32), p53, and bax but not bcl-2. Treatment with the heme oxygenase inhibitor, tin protoporphyrin IX inhibited SNAP-induced thymocyte apoptosis. Furthermore, thymocytes from p53 null mice were resistant to NO-induced apoptosis. Our data suggest that NO may induce its cytotoxic effects on thymocytes by modulating heme oxygenase and catalase activity as well as up-regulating pro-apoptotic proteins p53 and bax.
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PMID:Nitric oxide induces murine thymocyte apoptosis by oxidative injury and a p53-dependent mechanism. 1143 90

Hypertrophy is one mechanism of pancreatic beta-cell growth and is seen as an important compensatory response to insulin resistance. We hypothesized that the induction of protective genes contributes to the survival of enlarged (hypertrophied) beta-cells. Here, we evaluated changes in stress gene expression that accompany beta-cell hypertrophy in islets from hyperglycemic rats 4 weeks after partial pancreatectomy (Px). A variety of protective genes were upregulated, with markedly increased expression of the antioxidant genes heme oxygenase-1 and glutathione peroxidase and the antiapoptotic gene A20. Cu/Zn-superoxide dismutase (SOD) and Mn-SOD were modestly induced, and Bcl-2 was modestly reduced; however, several other stress genes (catalase, heat shock protein 70, and p53) were unaltered. The increases in mRNA levels corresponded to the degree of hyperglycemia and were reversed in Px rats by 2-week treatment with phlorizin (treatment that normalized hyperglycemia), strongly suggesting the specificity of hyperglycemia in eliciting the response. Hyperglycemia in Px rats also led to activation of nuclear factor-kappaB in islets. The profound change in beta-cell phenotype of hyperglycemic Px rats resulted in a reduced sensitivity to the beta-cell toxin streptozotocin. Sensitivity to the toxin was restored, along with the beta-cell phenotype, in islets from phlorizin-treated Px rats. Furthermore, beta-cells of Px rats were not vulnerable to apoptosis when further challenged in vivo with dexamethasone, which increases insulin resistance. In conclusion, beta-cell adaptation to chronic hyperglycemia and, hence, increased insulin demand is accompanied by the induction of protective stress genes that may contribute to the survival of hypertrophied beta-cells.
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PMID:Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survival during chronic hyperglycemia. 1181 49

Both heme oxygenase-1 (HO-1) and p21(WAF1/Cip1) (p21) are involved in the pathogenesis of human cancer and their functions are closely associated with apoptosis. However, how these two molecules regulate apoptosis in human gastric cancer is unknown. In this study, we studied how HO-1 and p21 were regulated in two gastric cancer cell lines, MKN-45 with wild p53 and MKN-28 with mutant p53. The cells were treated with hemin and cadmium to induce HO-1. The result showed that HO-1 protein was significantly induced by hemin and cadmium in both cells tested. Following the HO-1 expression, p21 level was also markedly induced. The cells with increased HO-1 and p21 showed obviously resistantance to apoptotic stimuli. The levels of HO-1 and p21 induced were significantly inhibited by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) and extracellular-regulated kinase (ERK) inhibitor (PD098059). Parallel to decreased HO-1 and p21 expression, the kinase inhibitors also significantly attenuated the resistance of the cells to apoptosis. The elevated HO-1 and p21 was further found to be associated with increase activity of the nuclear NF-kappaB and the inhibition of NF-kappaB led to the block of their induction. The elevated HO-1 and p21 were also demonstrated to be related to increased cellular inhibitor of caspase inbitory protein-2 (c-IAP2) and decreased caspapse-3 activity. It was noted that the above changes observed were not different between MKN-45 and MKN-28 cells, suggesting the functions of HO-1 and p21 were irrespective of the status of p53. In conclusion, we demonstrate that the resistance to apoptosis in gastric cancer cells with elevated HO-1 and p21 is independent of p53 status in a p38 MAPK- and ERK-mediated pathway with elevated c-IAP2 and decreased caspase-3 activity and that this pathway is sensitive to the inhibition of NF-kappaB.
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PMID:Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells. 1464 39

We have shown that mitochondrial DNA-depleted (rho(0)) SK-Hep1 hepatoma cells are resistant to apoptosis, contrary to previous papers reporting normal apoptotic susceptibility of rho(0) cells. We studied the changes of gene expression in SK-Hep1 rho(0) cells. DNA chip analysis showed that MnSOD expression was profoundly increased in rho(0) cells. O(2)(.) contents increased during rho(0) cell derivation but became normalized after establishment of rho(0) phenotypes, suggesting that MnSOD induction is an adaptive process to increased O(2)(.). rho(0) cells were resistant to menadione, paraquat, or doxorubicin, and O(2)(.) contents after treatment with them were lower in rho(0) cells compared with parental cells because of MnSOD overexpression. Expression levels and activity of glutathione peroxidases were also increased in rho(0) cells, rendering them resistant to exogenous H(2)O(2). rho(0) cells were resistant to p53, and intracellular ROS contents after p53 expression were lower compared with parental cells. Other types of rho(0) cells also showed increased MnSOD expression and resistance against ROS. Heme oxygenase-1 expression was increased in rho(0) cells, and a heme oxygenase-1 inhibitor decreased the induction of MnSOD in rho(0) cells and their resistance against ROS donors. These results indicate that rho(0) cells are resistant to cell death contrary to previous reports and suggest that an adaptive increase in the expression of antioxidant enzymes renders cancer cells or aged cells with frequent mitochondrial DNA mutations to resist against oxidative stress, host anti-cancer surveillance, or chemotherapeutic agents, conferring survival advantage on them.
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PMID:Resistance of mitochondrial DNA-depleted cells against cell death: role of mitochondrial superoxide dismutase. 1466 Jun 25

Avicins are proapoptotic and anti-inflammatory triterpene electrophiles isolated from an Australian desert tree, Acacia victoriae. The presence of two alpha,beta unsaturated carbonyl groups (Michael reaction sites) in the side chain of the avicin molecule prompted us to study its effects on NF-E2-related factor 2 (Nrf2), a redox-regulated transcription factor that controls the expression of a battery of detoxification and antioxidant proteins via its binding to antioxidant response element (ARE). Avicin D-treated Hep G2 cells showed translocation of Nrf2 into the nucleus and a time-dependent increase in ARE activity. These properties were sensitive to DTT, suggesting that avicins affect one or more critical cysteine residues, probably on the Keap1 molecule. Downstream of ARE, an activation of a battery of stress-induced proteins occurred. The implications of these findings were evaluated in vivo in mouse skin exposed to an ancient stressor, UV light. Avicins inhibited epidermal hyperplasia, reduced p53 mutation, enhanced apoptosis, decreased generation of 8-hydroxy-2'-deoxyguanosine, and enhanced expression of NADPH:quinone oxidoreductase 1 and heme oxygenase-1. These data, combined with our earlier published work, demonstrate that avicins represent a new class of plant stress metabolites capable of activating stress adaptation and suppressing proinflammatory components of the innate immune system in human cells by redox regulation. The relevance for treatment of clinical diseases in which stress responses are dysfunctional or deficient is discussed.
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PMID:Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery. 1470 10

A number of phenotypes persist in the progeny of irradiated cells for many generations including delayed reproductive death, cell transformation, genomic instability, and mutations. It appears likely that persistent phenotypes are inherited by an epigenetic mechanism, although very little is known about the nature of such a mechanism or how it is established. One hypothesis is that radiation causes a heritable increase in oxy-radical activity. In the present study, intracellular levels of reactive oxygen species (ROS) in human lymphoblast clones derived from individually X-irradiated cells were monitored for about 55 generations after exposure. A number of clones derived from irradiated cells had an increase in dichlorofluorescein (DCF) fluorescence at various times. Cells with abrogated TP53 expression had a decreased oxidant response. Flow cytometry analysis of clones with increased fluorescence did not detect increases in the sub-G(1) fraction or decreased cell viability compared to nonirradiated clones, indicating that increased levels of apoptosis and cell death were not present. The oxidative stress response protein heme oxygenase 1 (HO1) was induced in some cultures derived from X-irradiated cells but not in cultures derived from unirradiated cells. The expression of the dual specificity mitogen-activated protein (MAP) kinase phosphatase (MPK1/CL100), which is inducible by oxidative stress and has a role in modulating ERK signaling pathways, was also increased in the progeny of some irradiated cells. Finally, there was an increase in the phosphorylated tyrosine content of a prominent protein band of about 45 kDa. These results support the hypothesis that increased oxy-radical activity is a persistent effect in X-irradiated mammalian cells and further suggest that this may lead to changes in the expression of proteins involved in signal transduction.
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PMID:Increases in oxidative stress in the progeny of X-irradiated cells. 1544 41

Sodium nitroprusside (SNP), a widely used nitric oxide donor, has recently been shown to mediate chondrocyte apoptosis by generating reactive oxygen species, whereas more potent nitric oxide donors do not induce chondrocyte apoptosis. The present study was performed to investigate the protective effect of a low concentration of SNP upon the cytotoxicity of chondrocytes to higher concentrations of SNP, and to elucidate the underlying mechanism. Human osteoarthritis chondrocytes were cultured as monolayers, and first-passage cells were used for the experiments. Chondrocyte death induced by 1 mM SNP was completely inhibited by pretreating with 0.1 mM SNP. This protective effect of SNP was replicated by the guanosine-3',5'kappa-cyclic monophosphate analog, DBcGMP. Protection from chondrocyte death conferred by 0.1 mM SNP was mediated by heme oxygenase 1 (HO-1), as was revealed by the increased expression of HO-1 in 0.1 mM SNP pretreated chondrocytes and by the reversal of this protective effect by the HO-1 inhibitor, zinc protoporphyrin. SNP-mediated chondrocyte protection correlated with the downregulation of both extracellular signal-regulated protein kinase 1/2 and p38 kinase activation. SNP at 0.1 mM induced significant NF-kappaB activation as revealed by electrophoretic mobility shift assays, and the inhibition of NF-kappaB by MG132 or Bay 11-7082 nullified 0.1 mM SNP-mediated chondrocyte protection. The upregulation of p53 and the downregulation of Bcl-XL and Mcl-1 by 1 mM SNP were reversed by 0.1 mM SNP pretreatment at the protein level by western blotting. Our study shows that priming with 0.1 mM SNP confers complete protection against cell death induced by 1 mM SNP in human articular chondrocytes. This protective effect was found to be correlated with the upregulation of both HO-1 and NF-kappaB and with the concomitant downregulation of both extracellular signal-regulated protein kinase 1/2 and p38 activation.
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PMID:The mechanism of low-concentration sodium nitroprusside-mediated protection of chondrocyte death. 1589 39

We have recently shown that the natural bile pigment bilirubin has antiproliferative effects on vascular smooth muscle cells (VSMCs). Bilirubin is the end product of heme catabolism mediated by heme oxygenases and has for decades been considered a toxic waste product of our bodies. However, 14 separate studies and a meta-analysis have documented an inverse correlation between atherosclerosis and the levels of bilirubin in normal individuals. Having high normal or supranormal levels of bilirubin is associated with less atherosclerotic-type disease as compared with that in individuals with low normal levels of bilirubin. This combined with experimental data showing anti-atherosclerotic properties of the enzyme heme oxygenase-1 encouraged us to hypothesize that bilirubin and its precursor biliverdin, would act to ameliorate components of atherosclerosis, in a manner similar to what has been shown with HO-1. Both did so in an animal model of restenosis in which vascular smooth muscle cell proliferation leads to intimal proliferation and causes narrowing of the vessels. We also analyzed the antiproliferative effects of the bile pigments in an in vitro system where bilirubin/biliverdin caused p53 dependent cell cycle arrest by hypophosphorylation of the retinoblastoma tumor suppressor protein in growth factor stimulated VSMCs.
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PMID:Bilirubin and biliverdin treatment of atherosclerotic diseases. 1724 20

The preferential retention of the arginine allele at the p53 codon 72 locus is commonly observed in tumours from arginine/proline heterozygotes. Considering that cancer cells are harboured in a hypoxic environment in vivo, we here tested the hypothesis that the p53 codon 72 proline allele confers a survival disadvantage in presence of hypoxia. Here, we show that the transient transfection of the proline allele in p53 null cancer cells exposed to low oxygen tension or to the hypoxia-mimetic drug Desferoxamine induces a higher amount of cell death than the arginine allele. Accordingly, proline allele transiently transfected cell lines express lower levels of hypoxia pro-survival genes (HIF-1alpha, carbonic anhydrase IX, vascular endothelial growth factor, heme oxygenase-I, hepatocyte growth factor receptor, vascular endothelial growth factor receptor 2), compared to those transiently transfected with the arginine allele. Further, we report that the exposure of the arginine/proline heterozygote MCF-7 breast cancer cell line to cytotoxic concentration of Desferoxamine for several weeks, gives raise to hypoxia-resistant clones, carrying the arginine, but not the proline allele. These data indicate that the p53 codon 72 proline allele is less permissive for the growth of cancer cells in a hypoxic environment, and suggest that the preferential retention of the arginine allele in the tumour tissues of arginine/proline heterozygous patients may depend upon its lowered capacity to induce cell death in a hypoxic tumour environment.
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PMID:The p53 codon 72 proline allele is endowed with enhanced cell-death inducing potential in cancer cells exposed to hypoxia. 1740 54


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