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

The high mobility group (HMG) chromosomal proteins, which are common to all eukaryotes, bind DNA in a non-sequence-specific fashion to promote chromatin function and gene regulation. They interact directly with nucleosomes and are believed to be modulators of chromatin structure. They are also important in V(D)J recombination and in activating a number of regulators of gene expression, including p53, Hox transcription factors and steroid hormone receptors, by increasing their affinity for DNA. The X-ray crystal structure, at 2.2 A resolution, of the HMG domain of the Drosophila melanogaster protein, HMG-D, bound to DNA provides the first detailed view of a chromosomal HMG domain interacting with linear DNA and reveals the molecular basis of non-sequence-specific DNA recognition. Ser10 forms water-mediated hydrogen bonds to DNA bases, and Val32 with Thr33 partially intercalates the DNA. These two 'sequence-neutral' mechanisms of DNA binding substitute for base-specific hydrogen bonds made by equivalent residues of the sequence-specific HMG domain protein, lymphoid enhancer factor-1. The use of multiple intercalations and water-mediated DNA contacts may prove to be generally important mechanisms by which chromosomal proteins bind to DNA in the minor groove.
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PMID:The structure of a chromosomal high mobility group protein-DNA complex reveals sequence-neutral mechanisms important for non-sequence-specific DNA recognition. 1058 Dec 35

We established mouse lines containing either full-length wild-type p53 or nuclear localization signal-I (NLS-I) deleted p53 to study the role of NLS-I in p53 translocation and function. Induction of apoptosis in response to DNA damage, a primary function of p53, was tested in these cell lines. After exposure to gamma-ionizing radiation or hydrogen peroxide, DNA ladders and labeling of nucelosomal fragments were detected in cells with wild-type p53 gene, but not in p53 null cells or NLS-I deleted cells, suggesting that the NLS-I of p53 protein is necessary for apoptosis. Analysis of p53 protein from subcellular fractions indicated that NLS-I deprived p53 remained in the cytoplasmic fraction, which may explain why NLS-I deleted p53 failed to induce apoptosis.
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PMID:An intragenic deletion of nuclear localization signal-1 of p53 tumor suppressor gene results in loss of apoptosis in murine fibroblasts. 1066 95

The phosphoaminothiol WR1065, the active metabolite of the pro-drug amifostine (WR2721), protects cultured cells and tissues against cytotoxic exposure to radiation or chemotherapeutic agents. We show here that WR1065 and the pro-drug WR2721 activate the p53 tumor suppressor protein and induce the expression of the cyclin-dependent kinase inhibitor p21waf-1 in the breast cancer cell line MCF-7, and in the mouse fibroblast cell line balb/c 3T3. Using two MCF-7 derived cell lines, MN1 and MDD2, we show that induction of p21waf-1 is detectable in MN1 (expressing a functional p53) but not in MDD2 (p53 disabled). These effects are observed at concentrations of WR1065 (0.5 to 1 mM) identical to those required to protect against cytotoxicity by hydrogen peroxide. Induction of p53 is not prevented by addition of aminoguanidine, an inhibitor of Cu-dependent amine-oxidases which blocks the extra-cellular degradation of WR1065 into toxic metabolites. Moreover, spermidine, a natural polyamine structurally related to amifostine, does not activate p53. Induction of p53 by WR1065 results in a delay in the G1/S transition in MCF-7 and MN-1 cells, but not in the p53 disabled cells MDD2. These data indicate that WR1065, a polyamine analog with thiol anti-oxidant properties, activates a cell cycle check-point involving p53.
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PMID:The cytoprotective aminothiol WR1065 activates p21waf-1 and down regulates cell cycle progression through a p53-dependent pathway. 1071 9

The stress-activated protein kinase JNK plays an important role in the stability and activities of key regulatory proteins, including c-Jun, ATF2, and p53. To better understand mechanisms underlying the regulation of JNK activities, we studied the effect of expression of the amino-terminal JNK fragment (N-JNK; amino acids 1-206) on the stability and activities of JNK substrates under nonstressed growth conditions, as well as after exposure to hydrogen peroxide. Mouse fibroblasts that express N-JNK under tetracycline-off (tet-off) inducible promoter exhibited elevated expression of c-Jun, ATF2, and p53 upon tetracycline removal. This increased coincided with elevated transcriptional activities of p53, but not of c-Jun or ATF2, as reflected in luciferase activities of p21(Waf1/Cip1)-Luc, AP1-Luc, and Jun2-Luc, respectively. Expression of N-JNK in cells that were treated with H(2)O(2) impaired transcriptional output as reflected in a delayed and lower level of c-Jun-, limited ATF2-, and reduced p53-transcriptional activities. N-JNK elicited an increase in H(2)O(2)-induced cell death, which is p53-dependent, because it was not seen in p53 null cells yet could be observed upon coexpression of p53 and N-JNK. The ability to alter the activity of ATF2, c-Jun, and p53 and the degree of stress-induced cell death by a JNK-derived fragment identifies new means to elucidate the nature of JNK regulation and to alter the cellular response to stress.
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PMID:Amino-terminal-derived JNK fragment alters expression and activity of c-Jun, ATF2, and p53 and increases H2O2-induced cell death. 1074 85

The metabolism of glutathione by membrane-bound &ggr;-glutamyl transpeptidase (GGT) has been recently recognized as a basal source of hydrogen peroxide in the extracellular space. Significant levels of GGT activity are expressed by malignant tumours, and in melanoma cell lines they were found to correlate with the malignant behaviour. As hydrogen peroxide and other oxidants can affect signal transduction pathways at several levels, the present study was aimed to verify: (i) the occurrence of GGT-dependent production of hydrogen peroxide in melanoma cells; (ii) the effects of GGT-dependent prooxidant reactions on known redox-sensitive cellular targets, i.e. protein thiols, the nuclear transcription factor NF-kappa B and p53. Two melanoma Me665/2 cell clones, exhibiting traces of (clone 2/21) or high (clone 2/60) GGT activity, were studied. The occurrence of GGT-dependent production of hydrogen peroxide was apparent in 2/60 cells, in which it was accompanied by lower levels of cell surface protein thiols. In 2/60 cells, GGT expression was also associated with higher levels of NF-kappa B activation, as compared to GGT-poor 2/21 cell clone. Indeed, stimulation or inhibition of GGT activity in 2/60 cells resulted in progressive activation or inactivation of NF-kappa B, respectively. An analysis of the p53 gene product indicated lack of protein expression in 2/60 cells, whereas a mutant protein was highly expressed in 2/21 cells. Taken together, these results indicate that the expression of GGT activity can provide melanoma cells with an additional source of hydrogen peroxide, and that such prooxidant reactions are capable to modify protein thiols at the cell surface level. In addition, GGT expression results in an up-regulation of the transcription factor NF-kappa B, which could explain the higher metastatic behaviour reported for GGT-rich melanoma cells as compared to their GGT-poor counterparts.
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PMID:Membrane gamma-glutamyl transpeptidase activity of melanoma cells: effects on cellular H(2)O(2) production, cell surface protein thiol oxidation and NF-kappa B activation status. 1089 82

Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. Direct exposure of human hepatoma cell line SMMC-7221 to hydrogen peroxide (H2O2) can induce apoptosis characterized by morphological evidence and fragmentation of DNA assayed by terminal deoxynucleotidyl transferase assay (TUNEL assay). Analysis of flow cytometry indicated that H2O2 can decrease the level of CD95(APO-1/Fas), and it is confirmed that H2O2 can also activate the differential expression of some specific gene such as p53 by means of RT-PCR technique. The results indicated that CD95 signal transduction system may be involved in the H2O2-induced apoptosis, and can regulate some specific genes associated with apoptosis in transcription and translation levels such as p53.
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PMID:Hydrogen peroxide-induced apoptosis in human hepatoma cells is mediated by CD95(APO-1/Fas) receptor/ligand system and may involve activation of wild-type p53. 1093 20

The present study investigates whether reactive oxygen species (ROS) are involved in p53 activation, and if they are, which species is responsible for the activation. Our hypothesis is that hydroxyl radical (.OH) functions as a messenger for the activation of this tumor suppressor protein. Human lung epithelial cells (A549) were used to test this hypothesis. Cr(VI) was employed as the source of ROS due to its ability to generate a whole spectrum of ROS inside the cell. Cr(VI) is able to activate p53 by increasing the protein levels and enhancing both the DNA binding activity and transactivation ability of the protein. Increased cellular levels of superoxide radicals (O(2)(-).), hydrogen peroxide (H(2)O(2)), and.OH radicals were detected on the addition of Cr(VI) to the cells. Superoxide dismutase, by enhancing the production of H(2)O(2) from O(2)(-). radicals, increased p53 activity. Catalase, an H(2)O(2) scavenger, eliminated.OH radical generation and inhibited p53 activation. Sodium formate and aspirin,.OH radical scavengers, also suppressed p53 activation. Deferoxamine, a metal chelator, inhibited p53 activation by chelating Cr(V) to make it incapable of generating radicals from H(2)O(2). NADPH, which accelerated the one-electron reduction of Cr(VI) to Cr(V) and increased.OH radical generation, dramatically enhanced p53 activation. Thus.OH radical generated from Cr(VI) reduction in A549 cells is responsible for Cr(VI)-induced p53 activation.
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PMID:The role of hydroxyl radical as a messenger in Cr(VI)-induced p53 activation. 1094 36

S100A2 is a calmodulin-like protein of unknown function, whose transcription is positively regulated in response to ErbB and p53 signaling. Expression of S100A2 is markedly increased in the context of ErbB-driven reactive epidermal hyperplasia, and decreased in the context of hypofunctional p53 mutations in carcinoma cell lines and tumors. This bimodal pattern of regulation suggests an important function for S100A2 in keratinocyte differentiation and carcinogenesis. Taking the biochemical approach to the determination of S100A2 function, we have characterized its physical state and subcellular localization in normal human keratinocytes. S100A2 in hypotonic lysates remained soluble after centrifugation at 100 000 x g, indicating that it is not associated with cell membranes. Permeabilization experiments confirmed the lack of membrane association and revealed a digitonin-insoluble nuclear fraction of S100A2, which was confirmed by immunofluorescence microscopy. Pulldown assays of epitope-tagged S100A2 and yeast two-hybrid screening revealed that S100A2 displays a strong propensity to homodimerize. Naturally expressed S100A2 dimers in normal human keratinocytes readily underwent intermolecular disulfide cross-linking unless a strong denaturant was present during cell lysis. Treatment of intact normal human keratinocytes with hydrogen peroxide strongly promoted S100A2 cross-linking. These results demonstrate that native S100A2 is a homodimer that does not depend on disulfide cross-linking for stability, but undergoes intermolecular cross-linking at cysteine residues in response to oxidative stress. Based on these findings, we propose that S100A2 may protect normal keratinocytes against carcinogens by participating in the cellular proof-reading response to oxidative stress.
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PMID:Biochemical characterization of S100A2 in human keratinocytes: subcellular localization, dimerization, and oxidative cross-linking. 1095 Dec 87

Clustering of apoptotic cells is a characteristic of many developing or renewing systems, suggesting that apoptotic cells kill bystanders. Bystander killing can be triggered experimentally by inducing apoptosis in single cells and may be based on the exchange of as yet unidentified chemical cell death signals between nearby cells without the need for cell-to-cell communication via gap junctions. Here we demonstrate that apoptotic cell clusters occurred spontaneously, after serum deprivation or p53 transfection in cell monolayers in vitro. Clustering was apparently induced through bystander killing by primary apoptotic cells. Catalase, a peroxide scavenger, suppressed bystander killing, suggesting that hydrogen peroxide generated by apoptotic cells is the death signal. Although p53 expression increased the number of apoptoses, clustering was found to be similar around apoptotic cells whether or not p53 was expressed, indicating that there is no specific p53 contribution to bystander killing. Bystander killing through peroxides emitted by apoptotic cells may propagate tissue injury in different pathological situations and be relevant in chemo-, gamma-ray, and gene therapy of cancer.
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PMID:Clustering of apoptotic cells via bystander killing by peroxides. 1097 25

Chromium and cadmium are widely used industrial chemicals. The toxicities associated with both metal ions are well known. However, less information is available concerning the mechanisms of toxicity. The results of in vitro and in vivo studies demonstrate that both cations induce an oxidative stress that results in oxidative deterioration of biological macromolecules. However, different mechanisms are involved in the production of the oxidative stress by chromium and cadmium. Chromium undergoes redox cycling, while cadmium depletes glutathione and protein-bound sulfhydryl groups, resulting in enhanced production of reactive oxygen species such as superoxide ion, hydroxyl radicals, and hydrogen peroxide. These reactive oxygen species result in increased lipid peroxidation, enhanced excretion of urinary lipid metabolites, modulation of intracellular oxidized states, DNA damage, membrane damage, altered gene expression, and apoptosis. Enhanced production of nuclear factor-kappaB and activation of protein kinase C occur. Furthermore, the p53 tumor suppressor gene is involved in the cascade of events associated with the toxicities of these cations. In summary, the results clearly indicate that although different mechanisms lead to the production of reactive oxygen species by chromium and cadmium, similar subsequent mechanisms and types of oxidative tissue damage are involved in the overall toxicities.
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PMID:Oxidative mechanisms in the toxicity of chromium and cadmium ions. 1098 87


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