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)

We have previously characterized the cytotoxic action of diallyl disulfide (DADS) on neuroblastoma cells, and we have shown the crucial role of an early and massive reactive oxygen species production in the induction of c-Jun NH(2)-terminal kinase-mediated apoptotic pathway. In the present work, we report that DADS is ineffective in inducing apoptosis in a human adenocarcinoma gastric cell line (AGS). In particular, we show that AGS cells are able to recover from the p53/p21-mediated cell cycle arrest in the G(2)-M phase upon DADS treatment without committing cells to death. This event is most likely due to a peculiar surviving pathway of these cells involving: (a) the formation of mixed disulfides between reduced glutathione (GSH) and protein thiols, (b) a higher and inducible glutathione peroxidase activity, and/or (c) an efficient modulation of the phospho-active levels of the extracellular signal-regulated kinases 1 and 2 (ERK 1/2). Moreover, by increasing glutathione peroxidase expression or GSH concentrations, cell cycle arrest is fully abolished; the apoptotic death is induced by either decreasing the availability of intracellular GSH or inhibiting the reactivation of ERK 1/2. Altogether, our data show that ERK 1/2 participates in the active proliferation of AGS cells and that an efficient reactive oxygen species buffering system makes these cells resistant to DADS-mediated detrimental effects.
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PMID:Glutathione-related systems and modulation of extracellular signal-regulated kinases are involved in the resistance of AGS adenocarcinoma gastric cells to diallyl disulfide-induced apoptosis. 1635 86

Copper toxicity associated with Wilson's disease is known to cause neuronal damage and death in the basal ganglia and frontal cortex leading to Parkinson-like symptoms and cognitive deficits. Our previous work in cultured human NTERA-2-N neurons showed that copper-induced neuronal apoptosis is dependent on the induction and nuclear translocation of the tumor suppressor protein, p53. Because p53 acts as a DNA-binding transcription factor, this work used an oligonucleotide array to identify p53 target genes that are differentially regulated in copper-loaded neurons. Arrays representing 145 human genes expressed downstream of p53 were hybridized with labeled mRNA from control and copper-treated neurons. Differentially regulated mRNAs included those involved in the regulation of the cell cycle, cytoprotective mechanisms, and apoptotic mechanisms. Transfection of cells with a dominant-negative p53 construct enabled us to determine which molecular events were dependent on p53 expression. Copper treatment resulted in the upregulation of p21, reprimo, stathmin, and Tp53INP1, all known to participate in cell cycle arrest. Protective mechanisms included the upregulation of stat-3, and the heat-shock proteins, heat-shock protein (Hsp) 70 and Hsp 27. Both p53-dependent and -independent mechanisms leading to apoptosis were identified including insulin-like growth factor binding protein-6, glutathione peroxidase, bcl-2, RB-1, PUMA, and several members of the redox active PIG family of proteins. Thus it appears that following copper-mediated neuronal DNA damage, the regulation of a variety of pro- and antiapoptotic genes are responsible for determining neuronal fate.
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PMID:Expression profiling of p53-target genes in copper-mediated neuronal apoptosis. 1639 88

The p53 family consists of p53, p63, and p73, each of which has multiple isoforms due to transcription at two separate promoters and alternative splicing. Although p53 is a bona fide tumor suppressor, p63 appears to have a Janus-faced function as a tumor suppressor and an oncogene. To address the two opposing functions of p63, we analyzed its target genes. Here, we found that GPX2, which encodes a glutathione peroxidase, is up-regulated by p63 but not p53. Accordingly, a unique responsive element was found in the promoter of the GPX2 gene that can be activated and bound by p63 but not p53. We also found that upon overexpression, GPX2 alleviates the apoptotic response of MCF7 cells to oxidative stresses. Interestingly, the protective function of GPX2 is p53 dependent. Likewise, we showed that a deficiency in GPX2 renders MCF7 cells susceptible to oxidative stress-induced apoptosis. Given that the deltaN isoform of p63 is frequently overexpressed in tumor cells, the observations here provide an insight into the mechanism by which some isoforms of p63 serve as a pro-survival factor by up-regulating GPX2 to reduce the p53-dependent oxidative stress-induced apoptotic response.
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PMID:GPX2, a direct target of p63, inhibits oxidative stress-induced apoptosis in a p53-dependent manner. 1644 69

To investigate low-dose/low-dose-rate effects of low-linear energy transfer (LET) ionizing radiation, we used gamma-irradiated cells adapted to grow in a three-dimensional architecture that mimics cell growth in vivo. We determined the cellular, molecular and biochemical changes in these cells. Quiescent normal human fibroblasts were irradiated with single acute or chronic doses (1-10 cGy) of (137)Cs gamma rays. Whereas exposure to an acute dose of 10 cGy increased micronucleus formation, protraction of the dose over 48 h reduced micronucleus frequency to a level similar to or lower than what occurs spontaneously. The protracted treatment also up-regulated the cellular content of the antioxidant glutathione. These changes correlated with modulation of phospho-TP53 (serine 15), a stress marker that was regulated by doses as low as 1 cGy. The DNA damage that occurred after exposure to an acute dose of 10 cGy was protected against in two ways: (1) up-regulation of cellular antioxidant enzyme activity by ectopic overexpression of MnSOD, catalase or glutathione peroxidase, and (2) inhibition of superoxide anion generation by flavin-containing oxidases. These results support a significant role for oxidative metabolism in mediating low-dose radiation effects and demonstrate that cell culture in three dimensions is ideal to investigate radiation-induced adaptive responses. Expression of connexin 43, a constitutive protein of gap junctions, and the G(1) checkpoint were more sensitive to regulation by gamma rays in cells maintained in a three-dimensional than in a two-dimensional configuration.
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PMID:Adaptive responses to low-dose/low-dose-rate gamma rays in normal human fibroblasts: the role of growth architecture and oxidative metabolism. 1714 77

Sporadic Parkinson's disease (PD) is characterized by progressive death of dopaminergic neurons within the substantia nigra. However, pathological cell death within this nucleus is not uniform. In PD, the lateral tier of the substantia nigra (SNl) degenerates earlier and more severely than the more medial nigral component (SNm). The cause of this brain regional vulnerability remains unknown. We have used DNA oligonucleotide microarrays to compare gene expression profiles from the SNl to those of the SNm in both PD and control cases. Genes expressed more highly in the PD SNl included the cell death gene, p53 effector related to PMP22, the tumour necrosis factor (TNF) receptor gene, TNF receptor superfamily, member 21, and the mitochondrial complex I gene, NADH dehydrogenase (ubiquinone) 1beta subcomplex, 3, 12 kDa (NDUFbeta3). Genes that were more highly expressed in PD SNm included the dopamine cell signalling gene, cyclic adenosine monophosphate-regulated phosphoprotein, 21 kDa, the activated macrophage gene, stabilin 1, and two glutathione peroxidase (GPX) genes, GPX1 and GPX3. Thus, there is increased expression of genes encoding pro-inflammatory cytokines and subunits of the mitochondrial electron transport chain, and there is a decreased expression of several glutathione-related genes in the SNl suggesting a molecular basis for pathoclisis. Importantly, some of the genes that are differentially regulated in the SNl are known to be expressed highly or predominantely in glial cells. These findings support the view that glial cells can be primarily affected in PD emphasizing the importance of using a whole tissue approach when investigating degenerative CNS disease.
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PMID:The medial and lateral substantia nigra in Parkinson's disease: mRNA profiles associated with higher brain tissue vulnerability. 1721 32

Overexpression of the tumor suppressor gene, wild-type p53 (wtp53), using adenoviral vectors (Adp53) has been suggested to kill cancer cells by hydroperoxide-mediated oxidative stress [1,2] and nutrient distress induced by the glucose analog, 2-deoxyglucose (2DG), has been suggested to enhance tumor cell killing by agents that induce oxidative stress via disrupting hydroperoxide metabolism [3,4]. In the current study clonogenic cell killing of PC-3 and DU-145 human prostate cancer cells (lacking functional p53) mediated by 4 h exposure to 50 plaque forming units (pfus)/cell of Adp53 (that caused the enforced overexpression of wtp53) was significantly enhanced by treatment with 2DG. Accumulation of glutathione disulfide was found to be significantly greater in both cell lines treated with 2DG+Adp53 and both cell lines treated with 2DG+Adp53 showed a approximately 2-fold increases in dihydroethidine (DHE) and 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate (CDCFH(2)) oxidation, indicative of increased steady-state levels of O(2)(.-) and hydroperoxides, respectively. Finally, overexpression of catalase or glutathione peroxidase using adenoviral vectors partially, but significantly, protected DU-145 cells from the toxicity induced by 2DG+Adp53 treatment. These results show that treatment of human prostate cancer cells with the combination of 2DG (a nutrient stress) and overexpression of the tumor suppressor gene, wtp53, enhances clonogenic cell killing by a mechanism that involves oxidative stress as well as allowing for the speculation that inhibitors of glucose and hydroperoxide metabolism can be used in combination with Adp53 gene therapy to enhance therapeutic responses.
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PMID:2-Deoxyglucose combined with wild-type p53 overexpression enhances cytotoxicity in human prostate cancer cells via oxidative stress. 1815 76

Angiotensin II has been shown to be a cytokine especially acting as a growth factor. A local renin-angiotensin system has been identified in the prostate gland, and the physiologic function of angiotensin II seems to be similar in prostate cancer, as we previously reported. In the present study, we explored the biological role of angiotensin II in oxidative stress of prostate cancer cells. Activated Akt was determined, and the expression of oxidative stress-related proteins (p47phox, manganese superoxide dismutase 2, glutathione peroxidase) was examined by Western blotting in LNCaP cells, which were stimulated with angiotensin II and/or an angiotensin II receptor type 1 blocker, candesartan. To examine DNA damage induced by angiotensin II, 8-hydroxy-2'-deoxyguanosine was determined, and Western blots were analyzed to detect checkpoint proteins including p53, Chk2, and cdc2. Immunocytochemical studies of inducible nitric oxide synthase and superoxide anion radical (O(2)(-)) were done in LNCaP cells stimulated with angiotensin II. The phosphorylation of Akt was induced by angiotensin II treatment and inhibited by candesartan, as well as by LY294002, an inhibitor of phosphoinositide 3-kinase. Oxidative stress-related proteins were up-regulated by angiotensin II and inhibited by pretreatment with candesartan or catalase. The level of 8-hydroxy-2'-deoxyguanosine was increased by angiotensin II and conversely decreased by candesartan. Immunocytochemical studies showed that angiotensin II enhanced an inflammatory marker, inducible nitric oxide synthase, and the production of O(2)(-) radical. The hypothesis that angiotensin II has the potential to induce oxidative stress, which may be implicated in carcinogenesis of the prostate gland through long-term exposure to chronic inflammation is proposed.
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PMID:Angiotensin II induces oxidative stress in prostate cancer. 1831 86

Hexavalent chromium (Cr (VI)) is a highly toxic metal. Exposure to Cr (VI) compounds may affect reproductive functions. Due to the importance of anterior pituitary hormones on reproductive physiology we have studied the effects of Cr (VI) on anterior pituitary. We previously demonstrated that, after in vivo Cr (VI) administration, Cr accumulates in the pituitary gland and affects prolactin secretion. In vitro, Cr (VI) causes apoptosis in anterior pituitary cells due to oxidative stress generation. To better understand the mechanisms involved in Cr (VI)-induced apoptosis we studied: (a) whether Cr (VI) affects the intracellular antioxidant response and (b) which of the apoptotic factors participates in Cr (VI) effect. Our results show that Cr (VI) treatment induces a decrease in catalase and glutathione peroxidase (GPx) activity but does not modify glutathione reductase (GR) activity. Cr (VI) exposure causes an increase of GSH levels. p53 and Bax mRNA are also upregulated by the metal. Pifithrin alpha, a p53 transcriptional inhibitor, increases Cr (VI) cytotoxicity, suggesting a role of p53 as a survival molecule. The antioxidant N-acetyl-cysteine (NAC) could prevent Bax mRNA increase and caspase 3 activation, confirming that Cr (VI)-induced apoptosis involves oxidative stress generation.
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PMID:Mechanisms of chromium (VI)-induced apoptosis in anterior pituitary cells. 1854 7

The potential importance of stem cells in the adult central nervous system (CNS) that cannot only divide, but also participate in neurogenesis, is now widely appreciated. While we know that the trace element zinc is needed for brain development, the role of this essential nutrient in adult stem cell proliferation and neurogenesis has not been investigated. Adult male rats fed a zinc-restricted diet had approximately 50% fewer Ki67-positive stem cells in the subgranular zone (SGZ) and granular cell layer of the dentate gyrus compared to both zinc-adequate and pair-fed controls (p<0.05). Zinc-deficient rats also had a significant increase the number of TUNEL-labeled cells in the SGZ compared to pair-fed rats (p<0.05). To explore the mechanisms responsible for the effects of zinc deficiency, cultured human Ntera-2 (NT2) neuronal precursor cells were deprived of zinc using the chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). Consistent with the effects of deficiency in vivo, TPEN treatment resulted in a significant decrease in cellular proliferation, as measured by bromodeoxyuridine (BrdU) uptake, and an increase in caspase3/7-dependent apoptosis. These changes were accompanied by increases in nuclear p53. Oligonucleotide arrays, coupled with use of a dominant-negative p53 construct in NT2 cells, identified 14 differentially regulated p53 target genes. In the early phases zinc deficiency, p53 targets responsible for cell cycle arrest were induced. Continuation of deficiency resulted in the induction of a variety of pro-apoptotic genes such as transforming growth factor-beta (TGF-beta) and retinoblastoma-1 (Rb-1), as well as cellular protection genes such as glutathione peroxidase (GPx). These data suggest that zinc plays a role in neurogenesis by regulating p53-dependent molecular mechanisms that control neuronal precursor cell proliferation and survival.
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PMID:Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms. 1877 98

Pentachlorophenol (PCP) (C(6)HCl(5)O) is a synthetic toxic organochloride fungicide for humans which exhibit neurotoxic properties. In the present research, we describe the potential pathways implicated in PCP-induced apoptosis in an acute model of toxicity in rat cerebellar granule neurons (CGNs). In our experiments, acute exposure of CGNs to micromolar concentrations of PCP induced the transcriptional activity of genes related to the classical apoptosis pathway (caspase 3, caspase 8, Bad), oxidative stress and glutathione metabolism (glutathione peroxidase-1, catalase, glutathione-S-transferase-3 and superoxide dismutase-1), and mitogenic response (cyclin D1, cdk2, cdk4, cdkn2b). Results from Western blot also shown significative increases in the expression of cyclins D1, E and A and cdk4. The mitogenic response was also related to a significative increase in the phosphorylation of retinoblastoma protein (Rb). PCP would cause apoptosis up-regulating the transcriptional activity of p53 gene and also increasing their activation by phosphorylation, concomitant with a decrease in the sirtuin 1 content. In conclusion, acute exposure of CGNs to PCP induces the classical p53 apoptotic pathway, promotes the up-regulation of several genes related to oxidative stress and the over-expression of molecules involved in the cell cycle control.
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PMID:Evaluation of pathways involved in pentachlorophenol-induced apoptosis in rat neurons. 1944 31


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