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)

p21waf1/cip1 mRNA and protein accumulate in intact cells exposed to oxidizing agents through a p53-independent, MAPK-dependent mechanism. Treatment with oxidizing agents also yields a second form of this protein (FM p21), characterized by a faster migration on SDS-PAGE. This phenomenon depends on the modification of intracellular redox conditions induced by diethylmaleate, a glutathione-depleting agent, being prevented by the pretreatment with the glutathione precursor N-acetylcysteine. The appearance of this FM p21 form is very early, being observed 5 min after exposure to diethylmaleate, long before the already observed accumulation of p21 induced by oxidative stress. Furthermore, experiments with dominant negative mutants of MEK demonstrate that, in contrast with that observed for the oxidative stress-induced accumulation of p21 mRNA and protein, the appearance of FM p21 form is not dependent from the activation of the MAPK pathway. It was previously observed (Tchou et al, 1996) that in some lung carcinoma cells long exposure to high doses of phorbol esters also induces the appearance of a faster-migrating p21 electrophoretic band and it was suggested that this could result from a different phosphorylation or from a proteolytic processing at the C-terminus of the protein. The latter is not the case for the diethylmaleate-induced FM p21 whose C-terminus is intact, as demonstrated by the expression of a C-terminus tagged p21 cDNA. On the contrary, the observed migration shift seems to be dependent on the hypophosphorylation of the protein; in fact, a pretreatment of cells with okadaic acid, an inhibitor of (serine/threonine) phosphatases, inhibits the oxidation-dependent appearance of the FM p21 and the block of protein synthesis, caused by cycloeximide, does not affect the appearance of FM p21, that thus could derive from the dephosphorylation of preexisting protein.
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PMID:A new p21waf1/cip1 isoform is an early event of cell response to oxidative stress. 984 80

Gemcitabine is a novel antimetabolite drug that acts by multiple mechanisms, including inhibition of ribonucleoside diphosphate reductase, of dCMP deaminase and of dCTP incorporation into DNA and RNA. Here, we report that gemcitabine induces cytotoxic and clonogenic death of 12 human malignant glioma cell lines at clinically relevant concentrations around 1 microM. Gemcitabine is thus approximately 100-fold more active than the congener drug, cytarabine. Gemcitabine cytotoxicity of glioma cells does not require wild-type p53 activity: (i) there was no difference in the susceptibility to gemcitabine between cell lines with wild-type p53 and cell lines with mutant or deleted p53; (ii) ectopic expression of a temperature-sensitive p53 protein either at wild-type (32.5 degrees C) or at mutant (38.5 degrees C) conformation had no significant influence on gemcitabine-induced cell death. Gemcitabine cytotoxicity was unaffected by the antioxidants, N-acetylcysteine and phenyl-N-tert-butyl-alpha-phenylnitrone. There was no correlation between the susceptibility to gemcitabine and the endogenous expression of the B cell lymphoma-2 (BCL-2)-family proteins BCL-2, BCL-XL, myeloid cell leukemia-1 (MCL-1), BCL-2-associated X protein (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-XS. Ectopic expression of BCL-2 moderately attenuated gemcitabine-induced cell death. Similarly, preexposure to the synthetic steroid, dexamethasone, which is commonly used to control cerebral edema in brain tumor patients, reduced gemcitabine cytotoxicity. We conclude that the clinical evaluation of gemcitabine for the adjuvant chemotherapy of malignant glioma is warranted.
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PMID:Gemcitabine cytotoxicity of human malignant glioma cells: modulation by antioxidants, BCL-2 and dexamethasone. 998 15

Although N-acetylcysteine is an antioxidant which has been expected to be a cancer chemopreventive agent, its safety and risk assessment have not been evaluated. N-acetylcysteine increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, whereas the amount of 8-oxodG in HP100, which is a hydrogen peroxide (H(2)O(2))-resistant cell line derived from HL-60, was not increased. To clarify the mechanism of cellular DNA damage, we investigated DNA damage and its site specificity induced by N-acetylcysteine, using (32)P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene. N-acetylcysteine induced extensive DNA damage in the presence of Cu(II). The DNA cleavage was enhanced by piperidine treatment, suggesting that N-acetylcysteine plus Cu(II) caused not only deoxyribose phosphate backbone breakage but also base modification. N-acetylcysteine plus Cu(II) frequently modified thymine and guanine residues. Bathocuproine, a specific Cu(I) chelator, and catalase inhibited the DNA damage, indicating the participation of Cu(I) and H(2)O(2) in the DNA damage. Typical hydroxyl radical scavengers did not inhibit N-acetylcysteine plus Cu(II)-induced DNA damage, whereas methional completely inhibited it. These results suggest that reactive species derived from the reaction of H(2)O(2) with Cu(I) participates in N-acetylcysteine plus Cu(II)-induced DNA damage. The content of 8-oxodG in calf thymus DNA was increased by N-acetylcysteine in the presence of Cu(II). The present study has demonstrated that N-acetylcysteine could induce metal-dependent H(2)O(2) generation and, subsequently, damage to cellular and isolated DNA. Therefore, it is reasonable to consider that N-acetylcysteine may have the dual function of carcinogenic and anti-carcinogenic potentials. This work requires further studies on safety and risk assessment of N-acetylcysteine.
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PMID:N-acetylcysteine, a cancer chemopreventive agent, causes oxidative damage to cellular and isolated DNA. 1042 96

Cyclin-dependent kinase (cdk) inhibitors, such as p16(INK4a) and p21(WAF1/CIP1), often inhibit G(1) cyclin kinases and result in G(1) arrest. It has been suggested that p21(WAF1/CIP1) may also play a role in other chemopreventive activities such as DNA repair, slowdown of DNA replication and induction of cellular differentiation. In this report we demonstrate that the antioxidant N-acetylcysteine (NAC), a well-known chemopreventive agent, induces p16(INK4a) and p21(WAF1/CIP1) gene expression and prolongs cell-cycle transition through G(1) phase. A portion of the G(1) arrest by NAC is governed by p16(INK4a); it is independent of p53. NAC's usual mechanism of increasing intracellular glutathione level is not required for the G(1) arrest. An antioxidant whose action is limited to scavenging radicals, Trolox, does not induce G(1) arrest. Taken together, these results suggest a potential novel molecular basis for chemoprevention by NAC.
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PMID:Induction of cyclin-dependent kinase inhibitors and G(1) prolongation by the chemopreventive agent N-acetylcysteine. 1046 36

We have shown that the loss of p53 function contributed to resistance of tumor cells to TNF-induced cytotoxicity. In the present study, we evaluated the effect of wild-type p53 (wt-p53) expression on TNF sensitivity, by introducing wt-p53 into MCF7/Adr cells in which p53 was deleted, via a recombinant adenovirus encoding p53 (Ad-p53). Our results indicate that infection with Ad-p53 (50-100 viral particles per cell) resulted in pronounced cytotoxicity, whereas infection with 10 viral particles per cell, which was weakly toxic for the MCF7/Adr cells, sensitized these cells to TNF-induced cell death. Moreover, expression of wt-p53 in MCF7/Adr cells induced the production of reactive oxygen intermediates (ROIs) and caused glutathione (GSH) depletion, indicating disturbances in the cellular redox state. Additional treatment of cells with the anti-oxidant and glutathione (GSH) precursor N-acetylcysteine (NAC) resulted in inhibition of p53-induced ROIs production and in partial restoration of intracellular GSH levels, which was associated with the ability of NAC to inhibit p53-modulated TNF-induced cytotoxicity. Interestingly, Ad-p53 was able to inhibit TNF-induced MnSOD mRNA expression in MCF7/Adr cells, which might contribute to the sensitization of cells to the cytotoxic action of TNF. Taken together, our data strongly suggest that wt-p53 expression sensitizes TNF-resistant MCF7 cells with p53 deletion to TNF-induced cell death by a pathway that is dependent on ROIs production.
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PMID:Adenovirus-mediated wild-type-p53-gene expression sensitizes TNF-resistant tumor cells to TNF-induced cytotoxicity by altering the cellular redox state. 1058 90

The p53 tumor suppressor gene is critically involved in cell cycle regulation, DNA repair, and programmed cell death. Several lines of evidence suggest that p53 death signals lead to caspase activation; however, the mechanism of caspase activation by p53 still is unclear. Expressing wild type p53 by means of an adenoviral expression vector, we were able to induce apoptotic cell death, as characterized by morphological changes, phosphatidylserine externalization, and internucleosomal DNA fragmentation, in p53(null) Saos-2 cells. This cell death was accompanied by caspase activation as well as by cleavage of caspase substrates and was preceded by mitochondrial cytochrome c release. The addition of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) directly after transduction almost completely prevented p53-induced apoptotic cell death but did not inhibit mitochondrial cytochrome c release. In contrast, N-acetylcysteine, even at high concentrations, could not prevent induction of programmed cell death by p53 expression. Cytosolic extracts from Saos-2 cells transduced with p53, but not from Saos-2 cells transduced with the empty adenoviral vector, contained a cytochrome c-releasing activity in vitro, which was still active in the presence of zVAD-fmk. When Bax was immunodepleted from the cytosolic extracts of p53-expressing cells before incubation with isolated mitochondria, the in vitro cytochrome c release was abolished. Thus, we could demonstrate in cells and in vitro that p53 activates the apoptotic machinery through induction of the release of cytochrome c from the mitochondrial intermembrane space. Furthermore, we provide in vitro evidence for the requirement of cytosolic Bax for this cytochrome c-releasing activity of p53 in Saos-2 cells.
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PMID:p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. 1070 5

The modification of intracellular redox conditions with diethylmaleate (DEM), a glutathione-depleting agent, induces a p53-independent growth arrest mediated by the accumulation of p21(waf1) mRNA and protein. The same treatment also induces the retinoblastoma protein (pRb) dephosphorylation. This dephosphorylation (i) is very fast, being observed already 5 min after the exposure of the cells to DEM, (ii) is dependent on the prooxidant effects of DEM, being prevented by the treatment with N-acetylcysteine and (iii) is completely reversible, since the rephosphorylation of pRb is promptly obtained upon the removal of the glutathione-depleting agent from the culture medium. The dephosphorylation of pRb is independent of the accumulation of p21(waf1) induced by DEM; in fact, p21(waf1) levels start to increase much later after DEM treatment and accordingly cyclin-dependent kinase activities are not yet induced when pRb is already dephosphorylated following DEM treatment. Finally, pRb dephosphorylation is catalyzed by phosphatases activated by DEM treatment.
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PMID:Retinoblastoma protein dephosphorylation is an early event of cellular response to prooxidant conditions. 1073 36

Epidemiological evidence has suggested an association between diets rich in antioxidants and diminished risks of various types of cancer. Proposed mechanisms for protective effects of antioxidants have involved inhibition of free radical-mediated DNA damage. Recent data suggest that antioxidants may prevent or eliminate cancerous cells through their ability to inhibit proliferation or to induce programmed cell death (PCD). To begin to identify cell cycle and cell death regulatory factors involved in antioxidant-induced growth arrest and PCD, we have studied colorectal carcinoma cells (CRCs) that differ in expression of the tumor suppressor protein p53, and of the cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1). The antioxidants, N-acetylcysteine (NAC) and vitamin E either inhibited proliferation in a p53-independent manner without affecting cell viability or induced cell death. Growth arrest was not associated with upregulation of the CDK inhibitors p21(Waf1/Cip1), p18(ink4c) or p16(ink4a), but was associated with a decrease in reactive oxygen species (ROS). In contrast to previous observations, the absence of p21(Waf1/Cip1) increased susceptibility of CRCs to antioxidant-induced PCD. NAC decreased levels of retinoblastoma protein (Rb) phosphorylation in all cells tested, but Rb was cleaved only in cells which underwent NAC-induced death. Although NAC decreased ROS in all cells studied, cell lines in which PCD occurred had higher baseline levels of ROS than cell lines in which proliferation was blocked. These observations suggest that expression of p21(Waf1/Cip1) and basal levels of ROS are important determinants of outcome after antioxidant treatment.
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PMID:p53-independent inhibition of proliferation and p21(WAF1/Cip1)-modulated induction of cell death by the antioxidants N-acetylcysteine and vitamin E. 1093 2

Peripheral neuropathy following cisplatin treatment is a major limiting factor in cisplatin chemotherapy of cancer patients. We investigated the pathomechanism underlying cisplatin neuropathy using a mouse dorsal root ganglion neuron-neuroblastoma hybrid cell line (N18D3) developed in our laboratory. DNA fragmentation, a characteristic feature of apoptosis, was induced in hybrid neurons following treatment with cisplatin. Accumulation of p53, Fas, and Fas ligand (Fas-L) was also demonstrated in these neurons. Preincubation with N-acetylcysteine (NAC), a precursor of glutathione, blocked cisplatin-induced apoptosis completely, whereas Trolox, a vitamin E analogue, blocked it partially. Cisplatin-induced p53 accumulation was suppressed by NAC treatment, whereas p53 accumulation was retarded by Trolox treatment. In contrast, neither NAC nor Trolox showed any inhibitory effect on cisplatin-induced Fas/Fas-L accumulation. These results suggest that the neuroprotective effects of antioxidants against cisplatin-induced neurotoxicity in hybrid neurons are mediated mainly through the inhibition of p53 accumulation but not of Fas/Fas-L accumulation by these antioxidants.
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PMID:Cisplatin-induced apoptotic cell death in mouse hybrid neurons is blocked by antioxidants through suppression of cisplatin-mediated accumulation of p53 but not of Fas/Fas ligand. 1093 75

The transcription factor p53 can induce growth arrest or death in cells. Tumor cells that develop mutations in p53 demonstrate a diminished apoptotic potential, which may contribute to growth and tumor metastasis. Cellular levels of p53 are stabilized during hypoxia. The present study tested the hypothesis that reactive oxygen species (ROS) released from mitochondria regulate the cytosolic redox state and are required for the stabilization of p53 protein levels in response to hypoxia. Our results indicate that hypoxia (1.5% O2) increases mitochondrial ROS generation and increases p53 protein levels in human breast carcinoma MCF-7 cells and in normal human diploid fibroblast IMR-90 cells. MCF-7 cells depleted of their mitochondrial DNA (rho(o) cells) failed to stabilize p53 protein levels during hypoxia. The antioxidant N-acetylcysteine and the Cu/Zn superoxide dismutase inhibitor diethyldithiocarbamic acid abolished the hypoxia-induced increases in ROS and p53 levels. Rotenone, an inhibitor of mitochondrial complex I, and 4,4'-diisothiocyanato-stilbene-2,2'-disulfonate, a mitochondrial anion channel inhibitor, also abolished the increase in ROS signal and p53 levels during hypoxia. The p53-dependent gene p21WAF1/CIP1 was also induced by hypoxia in both MCF-7 and IMR-90 cells without affecting the growth rate of either cell line. In contrast, both cell lines exhibited increases in p21WAF1/CIP1 expression and growth arrest after gamma irradiation. Primary chick cardiac myocytes and murine embryonic fibroblasts also showed an increase in p53 protein levels in response to hypoxia without cell death or growth arrest. These results indicate that mitochondria regulate p53 protein levels during hypoxia through a redox-dependent mechanism involving ROS. Despite p53-induction, hypoxia alone does not cause either growth arrest or cell death.
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PMID:Redox regulation of p53 during hypoxia. 1095 77


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