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 shown that the protein phosphatase inhibitor okadaic acid (OA) induces caspase-3 activation and apoptosis in CHP-100 human neuroepithelioma cells. Herein we provide a more general picture of the effects brought about by OA in this system, also investigating whether caspase activation is necessary for apoptosis induction. We report that incubation for 24 h with 10 nM OA induced a large fraction of the cell population to undergo premature chromosome condensation (PCC) or mitotic arrest, but not apoptosis. The former two effects were also observed after cell treatment with 20 nM OA; however, at this concentration, typical apoptotic cells were also detected, characterized by pycnotic and fragmented nuclei. Occurrence of the above-mentioned apoptotic figures turned extensive at 100 nM OA. The pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD.fmk, 100 microM) fully prevented apoptosis induced by 20 nM OA, increasing PCC incidence. Conversely, 100 nM OA induced an apoptotic-like phenotype, even in the presence of Z-VAD.fmk: in this case, however, nuclei, albeit pycnotic, displayed morphological characteristics distinct from those of typical apoptotic cells; moreover, as assessed by flow cytometry, they were largely unfragmented. The reported OA effects occurred in a setting in which neither p53 nor p21(Cip1/Waf1) was upregulated, thus ruling out a role for these proteins in apoptosis induction. On the other hand, apoptotic doses of OA induced a shift of the retinoblastoma gene product to the hypophosphorylated state and its downregulation by a caspase-dependent mechanism.
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PMID:Caspase inhibition shifts neuroepithelioma cell response to okadaic acid from apoptosis to an apoptotic-like form of death. 1265 41

Proapoptotic gene transfer to promote death or to augment killing by DNA-damaging agents represents a promising strategy for cancer therapy. We have constructed an adenoviral Tet-Off trade mark vector with tightly controlled expression of Bid (Ad-Bid) (Clontech, Palo Alto, CA). Using the non-small cell lung cancer cell lines H460, H358, and A549, low dose Ad-Bid was shown to induce high levels of full-length Bid as well as caspase-3 and -9 activity. Although only a small fraction of Bid was processed to truncated Bid (a step inhibited by benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), Ad-Bid gene transfer resulted in mitochondrial changes consistent with apoptosis (mitochondrial depolarization, cytochrome c release), DNA fragmentation, and a dramatic loss of cell viability. The proapoptotic effects of Ad-Bid were independent of p53 status and were augmented markedly by caspase-8 activators such as the DNA-damaging agent cisplatin. When Ad-Bid and cisplatin were used together, chemosensitivity was restored in p53-null H358 cells, increasing death from 35% following treatment with cisplatin and Ad-LacZ to >90% death with Ad-Bid and cisplatin (Ad-Bid alone induced 50% cell death under these conditions). Ad-Bid can induce apoptosis in malignant cells and enhance chemosensitivity in the absence of p53, suggesting this approach as a potential cancer therapy.
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PMID:Adenoviral Bid overexpression induces caspase-dependent cleavage of truncated Bid and p53-independent apoptosis in human non-small cell lung cancers. 1269 Jan 7

Gliomatosis cerebri (GC) is a rare glial neoplasm with extensive diffuse brain infiltration but relative preservation of the underlying architecture. Previous molecular studies, mostly analyzing biopsy samples, have suggested an astrocytic origin of GC, but a larger collective of autopsy tissue has not been investigated so far. Furthermore, whether the widespread neoplastic infiltration is based on a monoclonal process is still a matter of debate. In the present study, we screened paraffin-embedded brain tissue from different areas of 18 cases (8 autopsy cases and 10 biopsies) for alterations in the TP53 and PTEN genes. Nuclear accumulation of p53 protein was detected in 9 cases (50%). Somatic TP53 mutations occurred in two autopsy cases (11% of all cases). In the first case, a C-->T transition in codon 273 (Arg-->Cys) was detected in all tumor samples. In the second case, in tumor samples from one hemisphere, nuclear accumulation of p53 was caused by a G-->A transition in codon 244 (Gly-->Asp). In the present series, no mutations within the coding region of PTEN were found. Pten expression was observed in two autopsy cases (25%) and seven biopsy samples (70%). These data suggest that TP53 is affected in some cases, but other yet-unidentified genetic alterations might contribute to tumorigenesis in GC. Furthermore, although GC might be a monoclonal process, the presence of different tumor clones cannot be ruled out.
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PMID:Analysis of TP53 and PTEN in gliomatosis cerebri. 1273 58

The p53 core DNA binding domain has been implied in Mdm2-mediated protein degradation. Here we show that the substitution of the serine residues 116 and 127 with alanine residues (S116/127A) has no effect on p53 DNA binding and protein stability. However, the substitution of the serine residues with the aspartic acid (S116/127D) abolished p53 DNA binding and led to protein stabilization. Importantly, we have shown that S116/127D exhibits a structural mutant conformation that results in a loss of p53-dependent transcription and Mdm2-mediated protein degradation.
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PMID:Identification of two serine residues important for p53 DNA binding and protein stability. 1275 97

Lung cancer, a disease related mostly to tobacco smoke exposure and a leading cause of cancer-related death in industrialized countries, is frequently associated with mutations in the p53 tumor suppressor gene. Genetic differences resulting in inter-individual variation in DNA repair capacity may in part account for susceptibility of a cell to genotoxic agents leading to somatic mutations, including p53 mutations, and eventual transformation of a normal cell into a malignant phenotype. The objective of this study is to investigate the relationship between the polymorphisms of two DNA repair genes, the nucleotide excision repair xeroderma pigmentosum group D (XPD) gene (codons 312 and 751) and the base excision repair X-ray repair cross-complementing group 1 (XRCC1) gene (codon 399), and p53 mutations among lung cancer patients. Lung tumors from 204 smokers with non-small cell lung cancer (NSCLC) were analyzed for mutations in exons 5-8 of the p53 gene and genotypes of XPD and XRCC1. p53 mutations were found in 20% (40/204) of the patients. Patients with the XPD codon 312 Asn allele were less likely to have p53 mutations (13.8%) than XPD 312 Asp/Asp (27.3%) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.20-0.89, P = 0.023]. No association was found between p53 mutations and either XPD Lys751Gln or XRCC1 Arg399Gln. However, the p53 mutation frequency increased with the increased number of the combined genotypes among XPD 312WT (Asp/Asp), XPD 751VT (Lys/Gln or Gln/Gln) or XRCC1 399VT (Arg/Gln or Gln/Gln) (P = 0.01, trend test). These results suggest that individuals who smoke and have the XPD codon 312 Asp/Asp genotype may be at a greater risk of p53 mutations, especially if combined with other polymorphisms that may result in deficient DNA repair.
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PMID:Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer. 1284 88

The first solid-phase synthesis of the chlorofusin peptide is described. The synthesis involved side-chain immobilization of N(alpha)-Fmoc-Asp-ODmab. Synthesis of the linear peptide, initially incorporating racemic Ade8 and unsubstituted ornithine in place of the chromophore-bearing residue, was followed by cyclization on resin and peptide release to give a mixture of diastereomers. Resynthesis identified (by HPLC) the second isomer as analogous to the natural product. Initial biological assays, using an immunofluorescence method, suggest that the compounds are not cytotoxic but do not inhibit the p53/mdm2 interaction. [structure: see text]
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PMID:Solid-phase synthesis of the cyclic peptide portion of chlorofusin, an inhibitor of p53-MDM2 interactions. 1468 62

Recently, it was discovered that herpesvirus-associated ubiquitin-specific protease (HAUSP) in human interacts with p53 protein, and removes the ubiquitin from ubiquitinated p53. Thus, human HAUSP stabilizes the status of p53, induces p53-dependent cell growth repression and apoptosis. In this study, we isolated and characterized a mouse orthologue of HAUSP, mHAUSP. The mHAUSP cDNA was cloned from mouse ES cells by RT-PCR. The open reading frame consists of 3,312 bp and encodes a predicted protein of 1,103 amino acids with a molecular weight of approximately 135 kDa. The N-terminal region contains the Cys, His, and Asp domains, which are highly conserved in all deubiquitinating enzymes. Northern blot analysis revealed that two transcripts were detected in various tissues, with strong expression in brain, lung, thymus, and testis. In vivo and in vitro deubiquitinating enzyme assays demonstrated that mHAUSP has deubiquitinating enzyme activity. The overexpression of mHAUSP reduces the amount of ubiquitinated p53, indicating that it functions as a deubiquitinating enzyme for p53.
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PMID:Identification and characterization of murine mHAUSP encoding a deubiquitinating enzyme that regulates the status of p53 ubiquitination. 1471 12

Amyloid beta-peptide (Abeta) contributes to the pathogenesis of Alzheimer's disease (AD), causing neuronal death through apoptosis. In this study, the neuroprotective role of small peptides, Gly-Pro-Glu (GPE), Gly-Glu (GE), Gly-Pro-Asp (GPD), and Gly-Pro-Arg (GPR) were examined against Abeta-induced toxicity in cultured rat hippocampal neurons. We report here that GPR (10-100 microM) prevented Abeta-mediated increase in lactate dehydrogenase (LDH) release and Abeta inhibition of MTT reduction, even in neurons that were pre-exposed to Abeta for 24 or 48 h. Since GPR prevented Abeta inhibition of MTT reduction, the anti-apoptotic effect of GPR was studied by examining activation of caspase-3 and expression of p53 protein. Caspase-3 was significantly activated by 20 microM Abeta25-35 and 5 microM Abeta1-40, but GPR effectively prevented the Abeta-mediated activation of caspase-3. Similarly, Abeta increased numbers of p53-positive cells, but GPR prevented this Abeta effect. Our findings suggest that GPR can rescue cultured rat hippocampal neurons from Abeta-induced neuronal death by inhibiting caspase-3/p53-dependent apoptosis.
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PMID:A three amino acid peptide, Gly-Pro-Arg, protects and rescues cell death induced by amyloid beta-peptide. 1476 84

Compared with other types of tumours, malignant melanomas are highly refractory to radio- or chemotherapy. To support the search for possible sensitizers, we explored the effects of the cellular oncoproteins c-Myc and N-Ras, which can decrease the clonogenic potential of irradiated p53-negative IGR39D melanoma cells. Using stable transfectants of this cell line, we showed that mutant N-Ras decreased the proliferation rate by inducing a prolonged cell cycle arrest. In contrast, c-Myc made these melanoma cells more prone to radiation-induced cell death. Membrane blebbing, the formation of apoptotic bodies and caspase activation, as measured by cleavage of Asp-Glu-Val-Asp (DEVD) substrate and poly(ADP-ribose) polymerase (PARP), indicate that these cells die by an apoptotic process. c-Myc also sensitized these p53-deficient melanoma cells to treatment with various cytotoxic drugs and heat shock. Similar results were obtained in inducible c-Myc models of IGR39D and in another melanoma cell line, 9007, which expresses functional p53. Together, these findings indicate that c-Myc is capable of sensitizing typically resistant tumour cells and that this occurs irrespective of the functional status of the p53 protein. Our results should facilitate the identification of factors that can be exploited for the treatment of aggressive cancers.
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PMID:c-Myc is able to sensitize human melanoma cells to diverse apoptotic triggers. 1509 Nov 88

The present study was designed to examine the roles of p53, reactive oxygen species (ROS), and ceramide, and to determine their mutual relationships during tumor necrosis factor (TNF)-alpha-induced apoptosis of human glioma cells. In cells possessing wild-type p53, TNF-alpha stimulated ceramide formation via the activation of both neutral and acid sphingomyelinases (SMases), accompanied by superoxide anion (O2-*) production, and induced mitochondrial depolarization and cytochrome c release, whereas p53-deficient cells were partially resistant to TNF-alpha and lacked O2-* generation and neutral SMase activation. Restoration of functional p53 sensitized glioma cells expressing mutant p53 to TNF-alpha by accumulation of O2-*. z-IETD-fmk (benzyloxycarbonyl-Ile-Glu-Thr-Asp fluoromethyl ketone), but not z-DEVD-fmk (benzyloxycarbonyl-Asp-Glu-Val-Asp fluoromethyl ketone), blocked TNF-alpha-induced ceramide formation through both SMases as well as O2-* generation. Caspase-8 was processed by TNF-alpha regardless of p53 status of cells or the presence of antioxidants. Two separate signaling cascades, p53-mediated ROS-dependent and -independent pathways, both of which are initiated by caspase-8 activation, thus contribute to ceramide formation in TNF-alpha-induced apoptosis of human glioma cells.
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PMID:Molecular mechanisms of TNF-alpha-induced ceramide formation in human glioma cells: P53-mediated oxidant stress-dependent and -independent pathways. 1513 91


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