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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological studies and clinical trials show that selenium supplementation results in reduction of prostate cancer incidence; however, the form of selenium and mechanisms underlying protection remain largely unknown. Toward this end, we compared the effects of naturally occurring selenomethionine (SM) and Se-methylselenocysteine (MSC) and synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) and p-xylylbis(methylselenide) p-XMS) organoselenium compounds in androgen responsive (AR) LNCaP and its androgen independent clone (AI) LNCaP C4-2 human prostate carcinoma cells on cell growth, secretion of prostate specific antigen (PSA), intracellular redox status and genomic profiles with emphasis on identifying redox sensitive genes. Both p-XSC and p-XMS reduced cell number and total protein concentration compared to control-treated AR and AI cells, while SM and MSC exhibited no effect on growth of AR and AI cells. SM, p-XSC and p-XMS but not MSC inhibited levels of secreted PSA in AR cells. SM, MSC and p-XMS increased glutathione (GSH) levels in AI LNCaP cells. By contrast, in both cell types, only p-XSC significantly decreased GSH concentrations to <50% of control suggesting either an increase in intracellular oxidative stress or a change in GSH/GSSG ratio. On the basis of RT-PCR analysis, SM and p-XSC increased p53 gene expression by 2-fold in AR cells but not in AI cells and only SM enhanced epidermal growth factor receptor in AR cells. Depending on the structure, organoselenium compounds exhibit differential effects on growth, PSA secretion, oxidative stress and selective gene responses in human prostate cancer cells and suggest the potential of developing novel organoselenium compounds as chemopreventive agents in models of human prostate cancer.
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PMID:Differential effects of naturally occurring and synthetic organoselenium compounds on biomarkers in androgen responsive and androgen independent human prostate carcinoma cells. 1720 24

The purpose of this study is to examine the differences in the induction of cytotoxic effects and poly(ADP-ribose) polymerase-1 activation in human MCF-7 breast cancer cells by quinonoid derivatives of naphthalene, including 1,2-naphthalenediol (NCAT), 1,4-naphthalenediol (NHQ), 1,2-naphthoquinone (1,2-NQ), and 1,4-naphthoquinone (1,4-NQ). Results from the cytotoxic response analyses in cells indicated that all naphthalene quinonoids induced cell death in MCF-7 cells at concentrations ranging from 0.1 to 100microM where NHQ and 1,4-NQ were more efficient than NCAT and 1,2-NQ in the induction of cell death. Results from Western blot analyses confirmed that treatment of cells with NCAT and NHQ resulted in up-regulation of p53 protein expression and a significant shift in bax/bcl2 ratio, suggesting the induction of p53-dependent apoptosis in MCF-7 cells. Additionally, we observed that all naphthalene quinonoids induced increases in reactive oxygen species (ROS) formation and glutathione (GSH) depletion in MCF-7 cells. The induction of ROS formation and GSH depletion in cells by naphthalene quinonoids decreases in the rank order 1,4-NQ>NHQ>1,2-NQ approximately equal to NCAT. Further investigation indicated that least-squares estimates of the overall rates of elimination (k(e)) of naphthalene quinonoids in MCF-7 cells decreased in the rank order 1,4-NQ>1,2-NQ>NHQ>NCAT. Values of k(e) were estimated to be between 0.280h(-1)(T(1/2)=151min) and 13.8h(-1)(T(1/2)=3.05min). These results provide evidence that the para-isomeric form of naphthalene quinonoids tend to induce acute production of ROS and alterations in intracellular redox status in cells, leading to the subsequent cell death. Further, all naphthalene quinonoids induced decreases in intracellular NAD(P)H and NAD(+) in MCF-7 cells at non-cytotoxic concentrations. The reduction of intracellular NAD(P)H in cells exposed to NCAT and 1,2-NQ was blocked by two types of poly(ADP-ribose) polymerase (PARP) inhibitors whereas PARP inhibitors did not prevent the reduction of NAD(P)H in cells exposed to NHQ and 1,4-NQ. Further investigation confirmed that increases in the number of DNA single-strand breaks were detected in MCF-7 cells exposed to NCAT and 1,2-NQ as measured by the single-cell gel electrophoresis (Comet) assay whereas NHQ and 1,4-NQ did not induce increases in the number of single-strand breaks in MCF-7 cells. Overall, results from our investigation suggest that while NHQ and 1,4-NQ are more efficient in the induction of cell death, NCAT and 1,2-NQ are prone to induce depletion of NAD(P)H and NAD(+) mediated by PARP-1 activation through formation of DNA single-strand breaks in human cultured cells.
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PMID:Disparity in the induction of glutathione depletion, ROS formation, poly(ADP-ribose) polymerase-1 activation, and apoptosis by quinonoid derivatives of naphthalene in human cultured cells. 1722 39

Mahlavu cells, poorly differentiated and p53 mutants of a human hepatoma subline, are known to be highly refractory to a number of chemotherapeutic agents and radiotherapy due to their high expressions of multidrug resistance gene-1 (MDR-1) and Bcl-2 proteins. Thus, it is desirable to search for an alternative strategy for effective eradication of this type of cancer cells. We present evidence here for the first time that 6-shogaol (6-SG), an alkanone isolated from the rhizomes of ginger, can effectively induce apoptotic cell death of Mahlavu cells via an oxidative stress-mediated caspase-dependent mechanism. The cascade of events in 6-SG-induced apoptosis of these cells involved an initial overproduction of reactive oxygen species (ROS) followed by a severe depletion of intracellular glutathione (GSH) contents. Both events consequently entailed a significant drop in mitochondrial transmembrane potential (DeltaPsim), which ultimately activated the activities of caspases 3/7 resulting in the DNA fragmentation. Interestingly, we also found that N-acetylcysteine (NAC), an antioxidant and a precursor of GSH biosynthesis, could offer a near complete protection of apoptotic cell death exerted by 6-SG. Similarly, exogenously added GSH could also provide protection with an equal efficacy. However, it was paradoxical that both Boc-Asp(OMe)-fmk (a broad caspases inhibitor) and cyclosporin A (an mitochondrial permeability transition opening inhibitor) could only partially protect these cells from 6-SG-induced apoptosis. Taking these data into consideration, it is obvious that GSH depletion is the major contributing factor in arbitrating 6-SG-induced apoptosis of Mahlavu cells. In conclusion, we provide here a novel modality that can help to eradicate a p53 mutant of human hepatoma cells by using a natural consistent isolated form of ginger. These data also provide evidence to reaffirm the notion that consumption of certain foodstuffs can be beneficial to health because some of the constituents contained in them may be anticarcinogenic.
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PMID:6-shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant Mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism. 1726 98

There is growing evidence to suggest that altered patterns of STC1 gene expression relate to the process of human cancer development. Our previous study has demonstrated the involvement of HIF-1 in the regulation of STC1 expression in human cancer cells. Recently, STC1 has been implicated as a putative pro-apoptotic factor in regulating the cell-death mechanism. Thus it would be of interest to know if STC1 is regulated by a tumor suppressor protein, p53. In this study, we provide evidence to demonstrate that the induction of STC1 expression in apoptotic human nasopharyngeal cancer cells (CNE2) is mediated by the activation of p53. Our study indicated that the activation of STC1 and heat-shock protein (hsp70) accompanied iodoacetamide (IDAM)-induced apoptosis in CNE-2. In addition, cellular events such as GSH depletion, mitochondrial membrane depolarization, reduction of pAkt and procaspase-3, and the induction of total p53 protein, acetylated p53, and annexin V positive cells were observed. The activation of STC1 was found to be at the transcriptional level and was independent of prior protein synthesis. Co-treatment of IDAM exposed cells with N-acetyl cysteine (NAC) prevented cell death by restoring mitochondrial membrane potential and cellular levels of GSH. NAC co-treatment also suppressed STC1 expression but had no effect on IDAM-induced hsp70 expression. RNA interference studies demonstrated that endogenous p53 was involved in activating STC1 gene expression. Collectively, the present findings provide the first evidence of p53 regulation of STC1 expression in human cancer cells.
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PMID:Induction of stanniocalcin-1 expression in apoptotic human nasopharyngeal cancer cells by p53. 1739 53

Redox regulation of cell cycle progression during nitric oxide (NO) mediated cytostasis is not well-understood. In this study, we investigated the role of the intracellular antioxidant glutathione (GSH) in regulating specific signaling events that are associated with NO-mediated cell cycle arrest. Manipulation of intracellular GSH content through pharmacological inhibition of glutamate-cysteine ligase (GCL) indicated that GSH depletion potentiated nitrosative stress, DNA damage, phosphorylation of the tumor suppressor p53 (Ser-18) and upregulation of p21(cip1/waf1) upon NO stimulation. However, we found that neither overexpression of a dominant negative p53 nor pharmacological inhibition of p53 with cyclic pifithrin-alpha (cPFT-alpha) was sufficient to reverse NO-mediated cell cycle arrest or hypophosphorylation of retinoblastoma protein (Rb). We found that the decrease in cyclin D1 levels induced by NO was GSH-sensitive implying that the redox regulation of NO-mediated cytostasis was a multifaceted process and that both p53/p21(cip1/waf1) and p53 independent cyclin D1 pathways were involved. Together, our results demonstrate that GSH serves as an important component of cellular protective mechanisms against NO-derived nitrosative stress to regulate DNA damage checkpoint.
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PMID:Redox control of G(1)/S cell cycle regulators during nitric oxide-mediated cell cycle arrest. 1744 86

In order to examine the role of glutathione (GSH), a key cellular antioxidant, on spontaneous tumor development, we tested the effects of buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, and 1,2-oxothiazolidine-4-carboxylic acid (OTCA), a cysteine and GSH precursor, on tumor incidence and spectrum in p53 nullizygous (p53-/-) transgenic mice. Mice were randomly assigned to three groups: control (no treatment), BSO (20 mM in drinking water) or OTCA (6 g/kg in the diet) (n=30 per group). After 10 weeks, GSH levels were decreased 29-88% in all tissues except liver and brain in BSO-treated mice, while no changes were observed in most tissues from OTCA-treated animals. Mice in all groups showed similar survival patterns as well as incidence of the most commonly observed tumors: i.e., lymphomas (80%) and other tumors (38%). However, a 5-fold increase in incidence of colonic tumors (from 4-20%) was observed in the BSO-treated group, suggesting that GSH deficiency and loss of p53 function play contributory roles in colon carcinogenesis.
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PMID:Induction of colon tumorigenesis by glutathione depletion in p53-knock-out mice. 1748 76

Induction of cellular senescence is a common response of a normal cell to a DNA-damaging agent, which may contribute to cancer chemotherapy- and ionizing radiation-induced normal tissue injury. The induction has been largely attributed to the activation of p53. However, the results from the present study suggest that busulfan (BU), an alkylating agent that causes DNA damage by cross-linking DNAs and DNA and proteins, induces senescence in normal human diploid WI38 fibroblasts through the extracellular signal-regulated kinase (Erk) and p38 mitogen-activated protein kinase (p38 MAPK) cascade independent of the p53-DNA damage pathway. The induction of WI38 cell senescence is initiated by a transient depletion of intracellular glutathione (GSH) and followed by a continuous increase in reactive oxygen species (ROS) production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which leads to the activation of the Erk and p38 MAPK pathway. Incubation of WI38 cells with N-acetylcysteine (NAC) replenishes intracellular GSH, abrogates the increased production of ROS, ameliorates Erk and p38 MAPK activation, and attenuates senescence induction by BU. Thus, inhibition of senescence induction using a potent antioxidant or specific inhibitor of the Erk and p38 MAPK pathway has the potential to be developed as a mechanism-based strategy to ameliorate cancer therapy-induced normal tissue damage.
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PMID:Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway. 1751 65

There has been a relative paucity of effort at defining effector mechanisms of biliary damage in PBC. We hypothesize that biliary cells are destroyed secondary to the immunologic relationships of inflammation and biliary epithelial apoptosis and, in particular, that biliary damage is a result of reduced levels of glutathione-S-transferase (GST), the production of hypochlorous acid (HOCl) and its association with eosinophil peroxidase (EPO). To address this issue, we examined the expression of EPO and GST in PBC and control livers and demonstrated an increase of EPO within the portal areas of PBC. We also demonstrated that macrophages have evidence of phagocytosed EPO. Furthermore, we studied the influence of HOCl on apoptosis in cultured human biliary epithelial cells (BEC) as well as the associated activity of Bcl-2, Bax, p-JNK, JNK, p53, Fas and caspase-3. HOC1-induced apoptosis in BEC in a dose-dependent fashion increased the activity of caspase-3 and the expression of p53 and p-JNK. Pretreatment with l-buthionine-(S,R)-sulfoximine, a glutathione (GSH) inhibitor, potentiated the sensitivity of BEC to HOCl-induced apoptosis. We conclude that intracellular GSH reduction leads directly to BEC apoptosis. Modulation of these events will be critical to reduce immune-mediated destruction.
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PMID:Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis. 1754 21

The cellular mechanisms that modulate the redox state of p53 tumor suppressor remain unclear, although its DNA binding function is known to be strongly inhibited by oxidative and nitrosative stresses. We show that human p53 is subjected to a new and reversible posttranslational modification, namely, S-glutathionylation in stressed states, including DNA damage. First, a rapid and direct incorporation of biotinylated GSH or GSSG into the purified recombinant p53 protein was observed. The modified p53 had a significantly weakened ability to bind its consensus DNA sequence. Reciprocal immunoprecipitations and a GST overlay assay showed that p53 in tumor cells was marginally glutathionylated; however, the level of modification increased greatly after oxidant and DNA-damaging treatments. GSH modification coexisted with the serine phophorylations in activated p53, and the thiol-conjugated protein was present in nuclei. When tumor cells treated with camptothecin or cisplatin were subsequently exposed to glutathione-enhancing agents, p53 underwent dethiolation accompanied by detectable increases in the level of p21waf1 expression, relative to the DNA-damaging drugs alone. Mass spectrometry of GSH-modified p53 protein identified cysteines 124, 141, and 182, all present in the proximal DNA-binding domain, as the sites of glutathionylation. Biotinylated maleimide also reacted rapidly with Cys141, implying that this is the most reactive cysteine on the p53 surface. The glutathionylatable cysteines were found to exist in a negatively charged microenvironment in cellular p53. Molecular modeling studies located Cys124 and -141 at the dimer interface of p53 and showed glutathionylation of either residue would inhibit p53-DNA association and also interfere with protein dimerization. These results show for the first time that shielding of reactive cysteines contributes to a negative regulation for human p53 and imply that such an inactivation of the transcription factor may represent an acute defensive response with significant consequences for oncogenesis.
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PMID:Human p53 is inhibited by glutathionylation of cysteines present in the proximal DNA-binding domain during oxidative stress. 1755 31

Ionizing radiation induces the production of reactive oxygen species, which play an important causative role in apoptotic cell death. Therefore, compounds that scavenge reactive oxygen species may confer regulatory effects on apoptosis. Recently, it has been shown that the decomposition product of the spin-trapping agent alpha-phenyl-N-t-butylnitrone, N-t-butyl hydroxylamine (NtBHA), mimics alpha-phenyl-N-t-butylnitrone and is much more potent in delaying reactive oxygen species-associated senescence. We investigated the effects of NtBHA on ionizing radiation-induced apoptosis. Upon exposure to 2Gy of gamma-irradiation, there was a distinct difference between the control cells and the cells pre-treated with 0.1mM NtBHA for 2h in regard to apoptotic parameters, cellular redox status, mitochondria function, and oxidative damage to cells. NtBHA effectively suppressed morphological evidence of apoptosis and DNA fragmentation in U937 cells exposed to ionizing radiation. The generation of intracellular reactive oxygen species was higher and the GSH level was lower in control cells compared to NtBHA-treated cells. The ionizing radiation-induced mitochondrial damage reflected by the altered mitochondrial permeability transition, the increase in the accumulation of reactive oxygen species, and the reduction of ATP production were significantly higher in control cells compared to NtBHA-treated cells. NtBHA pre-treated cells showed significant inhibition of apoptotic features such as activation of caspase-3, up-regulation of Bax and p53, and down-regulation of Bcl-2 compared to control cells upon exposure to ionizing radiation. This study indicates that NtBHA may play an important role in regulating the apoptosis induced by ionizing radiation presumably through scavenging of reactive oxygen species.
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PMID:N-t-Butyl hydroxylamine regulates ionizing radiation-induced apoptosis in U937 cells. 1776 3


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