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

The majority of breast carcinomas show reduced or no expression of the transcription factor, HOXA5. Recently, we have shown that HOXA5 is a potent transactivator of p53 in breast cells and thus may affect the response of breast cancer cells to DNA damage. To determine whether HOXA5 played a role in growth and homeostasis in breast cells, we studied its interaction with the progesterone receptor. The progesterone receptor (PR) belongs to the superfamily of nuclear receptors whose members co-ordinate morphogenesis of the mammary gland in response to binding to their cognate ligands. An increased expression of the endogenous PR gene was seen in MCF-7 cells following induced expression of an exogenously transfected HOXA5 gene. HOXA5, but not HOXB4, -B5, or -B7 activated the PR promoter in two breast cancer cell lines, MCF-7 and Hs578T. Deletion and mutation analysis of the promoter identified a single HOXA5-binding site required for transactivation of the PR gene by HOXA5. HOXA5 binds directly to this site in the PR promoter. Thus, HOXA5 may behave as a transcriptional regulator of multiple target genes, two among which are p53 and the progesterone receptor.
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PMID:HOXA5 regulates expression of the progesterone receptor. 1087 27

Proteins with expanded polyglutamine (polyQ) tracts have been linked to neurodegenerative diseases. One common characteristic of expanded-polyQ expression is the formation of intracellular aggregates (IAs). IAs purified from polyQ-expressing cells were dissociated and studied by protein blot assay and mass spectrometry to determine the identity, condition, and relative level of several proteins sequestered within aggregates. Most of the sequestered proteins comigrated with bands from control extracts, indicating that the sequestered proteins were intact and not irreversibly bound to the polyQ polymer. Among the proteins found sequestered at relatively high levels in purified IAs were ubiquitin, the cell cycle-regulating proteins p53 and mdm-2, HSP70, the global transcriptional regulator Tata-binding protein/TFIID, cytoskeleton proteins actin and 68-kD neurofilament, and proteins of the nuclear pore complex. These data reveal that IAs are highly complex structures with a multiplicity of contributing proteins.
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PMID:Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. 1130 10

p53 is a nuclear phosphoprotein that regulates cellular fate after genotoxic stress through its role as a transcriptional regulator of genes involved in cell cycle control and apoptosis. The C-terminal region of p53 is known to negatively regulate sequence specific DNA-binding of p53; modifications to the C-terminus relieve this inhibition. Two models have been proposed to explain this latency: (i) an allosteric model in which the C-terminal domain interacts with another domain of p53 or (ii) a competitive model in which the C-terminal and the core domains compete for DNA binding. We have characterized latent and active forms of dimeric p53 using gel mobility shift assays and NMR spectroscopy. We show on the basis of chemical shifts that dimeric p53 both containing and lacking the C-terminal domain are identical in conformation and that the C-terminus does not interact with other p53 domains. Similarly, NMR spectra of isolated core and tetramerization domains confirm a modular p53 architecture. The data presented here rule out an allosteric model for the regulation of p53.
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PMID:Latent and active p53 are identical in conformation. 1152 65

In transient expression assays for transcription, a vector carrying the experimental reporter is usually co-transfected with a second vector containing a distinct reporter gene as a control. The second reporter is linked to a constitutive promoter driving a low-level transcription that is unresponsive to the experimental trans-acting transcription factors used. The use of dual reporters enables the normalization of the experimental gene transcription with respect to the control reporter transcription. This method is expected to minimize the inherent variability in transfection data caused by changes in cell density and viability, cell lysis, and the recovery of samples at various stages of the experiment. Here, we report that one of the most widely used internal control reporters, the Renilla luciferase plasmid (pRL-TK), is unresponsive to human tumor suppressor protein p53, a potent transcriptional regulator; however, the reporter transcription is enhanced by another well-known transcriptional regulator, the adenoviral 125 EIA oncoprotein, thereby disqualifying pRL-TK as a universal internal control reporter for transcription assays. Our results reveal the necessity of stringent experiments to test the responsiveness of internal control plasmids to transcriptional regulators present in the assay to avoid the misinterpretation of transcriptional analysis data.
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PMID:Activation of pRL-TK by 12S E1A oncoprotein: drawbacks of using an internal reference reporter in transcription assays. 1157 Apr 96

The heterodimeric hypoxia-inducible factor (HIF)-1 is a master transcriptional regulator of oxygen homeostasis and a possible target for gene therapy of ischemic disease. Although the role of oxygen concentration in HIF-1a protein stabilization is well established, it is less clear whether and how oxygen-regulated mechanisms contribute to HIF-1a protein modifications, nuclear translocation, heterodimerization with the b-subunit, recruitment of cofactors, and gene trans-activation. Because the HIF-1a protein is proteolytically degraded under normoxic conditions, we established two HeLa Tet-Off cell lines (HT42 and HT43), which inducibly overexpress high levels of HIF-1a under normoxic conditions, allowing to distinguish hypoxia-dependent from hypoxia-independent activation mechanisms. Using these cells, we found that normoxically induced HIF-1a is localized to the nucleus, binds DNA, and trans-activates reporter and endogenous target genes. The levels of p53 expression remained unaffected. The MAP kinase inhibitor PD98059 attenuated HIF-1a protein modifications and trans-activation ability but not protein stabilization and DNA-binding activity. Because overexpressed HIF-1a is fully localized to the nucleus but displays only partial DNA-binding and trans-activation activity, mitogen-activated protein kinase-dependent phosphorylation might be required for full HIF-1 activation. HIF-1a protein was also overexpressed in vivo, following the transplantation of HT42 cells into nude mice, demonstrating the feasibility of HIF-1a gene transfer.
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PMID:Dissecting hypoxia-dependent and hypoxia-independent steps in the HIF-1alpha activation cascade: implications for HIF-1alpha gene therapy. 1160 85

The adeno-associated virus type 2 (AAV-2) Rep proteins are essential for AAV DNA replication and regulation of AAV gene expression. We have identified a cellular protein interacting with Rep78 and Rep68 in yeast two-hybrid analysis and in GST pull-down assays. This protein has recently been described as both a p53 (p53BP3) and a topoisomerase I interacting protein (Topors). It contains an arginine/serine-rich domain, a RING finger domain and five PEST sequences. A minimal sequence sufficient for interaction with Rep was mapped to Topors amino acids 871 to 917. We show that the same region is also involved in the interaction with p53. Rep sequences involved in interaction with Topors were mapped to Rep amino acids 172 to 481. Overexpression of Topors stimulated AAV gene expression in the absence of helper virus, suggesting a function of Topors as a transcriptional regulator.
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PMID:Topors, a p53 and topoisomerase I binding protein, interacts with the adeno-associated virus (AAV-2) Rep78/68 proteins and enhances AAV-2 gene expression. 1184 45

Angiogenesis is an essential requirement for the development, progression and metastasis of malignant tumors. Vascular endothelial growth factor (VEGF) plays an essential role in the development of angiogenesis of numerous solid malignancies, including colon cancer. The tumor suppressor gene p53 is a potent transcriptional regulator of genes which are involved in many cellular activities, including cell-cycle arrest, apoptosis and angiogenesis. In order to better understand the relation among p53 status, VEGF expression and microvessels count (MVC) in colon cancer, we evaluated immunoreactivity for CD34 endothelium-associated antigen, VEGF and p53 proteins in 43 cases of colon adenocarcinoma. Our results demonstrated an association between VEGF expression, p53 status and angiogenesis, suggesting that mutant p53 plays a central role in promoting angiogenesis in colon cancer progression.
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PMID:Neoangiogenesis in colon cancer: correlation between vascular density, vascular endothelial growth factor (VEGF) and p53 protein expression. 1195 38

The tumor suppressor p53 is a transcription factor that activates or represses its target genes after various genotoxic stresses. We have previously shown that sterol regulatory element-binding protein-1 (SREBP-1), a key transcriptional regulator of triglyceride synthesis, and the lipogenic enzymes under its control are markedly suppressed in adipocytes from genetically obese ob/ob mice. Here we demonstrate that p53 and its target genes are highly induced in adipocytes of ob/ob mice in a fed state, leading to the negative regulation of SREBP-1 and thereby lipogenic genes. In fact, disruption of p53 in ob/ob mice completely suppressed the p53-regulated genes to wild-type levels and partially restored expression of lipogenic enzymes. Consistently, reporter gene analysis showed that p53 overexpression suppressed the promoter activity of the SREBP-1c gene and its downstream genes. Thus, the activation of p53 might constitute a negative feedback loop against excess fat accumulation in adipocytes. In conclusion, we discovered a novel role of p53 in the pathophysiology of obesity.
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PMID:p53 Activation in adipocytes of obese mice. 1273 85

p53 is an important transcriptional regulator that is frequently mutated in cancer. Gene-profiling experiments of breast cancer cells infected with wt p53 revealed both MASPIN and desmocollin 3 (DSC3) to be p53-target genes, even though both genes are silenced in association with aberrant cytosine methylation of their promoters. Despite the transcriptional repression of these genes by aberrant DNA methylation, restoration of p53 resulted in the partial reactivation of both genes. This reactivation is a result of wt p53 binding to its consensus DNA-binding sites within the MASPIN and DSC3 promoters, stimulating histone acetylation, and enhancing chromatin accessibility of their promoters. Interestingly, wt p53 alone did not affect the methylation status of either promoter, suggesting that p53 itself can partially overcome the repressive barrier of DNA methylation. Pharmacologic inhibition of DNA methylation with 5-aza-2'-deoxycytidine in combination with restoration of wt p53 status resulted in a synergistic reactivation of these genes to near-normal levels. These results suggest that cancer treatments that target both genetic and epigenetic facets of gene regulation may be a useful strategy towards the therapeutic transcriptional reprogramming of cancer cells.
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PMID:Mutant p53 and aberrant cytosine methylation cooperate to silence gene expression. 1278 71

The tumor suppressor gene p53 is a potent transcriptional regulator for genes involved in many cellular activities including cell cycle arrest and apoptosis. In this study, we examined the role of p53 in neuronal death induced by the sodium channel modulator veratridine. We also analyzed the involvement of Ca2+, mitochondria and reactive oxygen species in p53 activation. Exposure of hippocampal neurons to veratridine (0.3-100 microM) resulted in a dose-dependent neuronal death, measured 24 h after treatment. p53-Like immunoreactivity, undetectable in neurons under control conditions, was observed in about 25% of neurons, 7 h after veratridine exposure. Treatments that modified the alkaloid-induced Ca2+ influx including tetrodotoxin or Ca2+ removal, prevented either veratridine-induced cell death or p53 immunoreactivity. Mitochondria were involved in veratridine-induced cell death, as the alkaloid collapsed inner transmembrane mitochondrial potential in a Ca2+ influx dependent manner. Treatments of neuronal cultures with the permeability transitory pore blockers cyclosporin A and bongkrekic acid prevented veratridine-induced p53 immunoreactivity and neuronal death, placing mitochondria upstream of veratridine-induced p53 immunoreactivity. Reactive oxygen species also participated in veratridine-induced neurotoxicity and p53 activation. Antisense knockdown of p53 resulted in a significant increase in neuronal survival after veratridine treatment. This protective effect was maintained on N-methyl-D-aspartate or ischemia-induced death but not on staurosporine cytotoxicity. These results together suggest that p53-expression is involved in veratridine-induced neuronal death and that p53 might be a link between toxic stimuli of different types and neuronal death.
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PMID:Role and regulation of p53 in depolarization-induced neuronal death. 1462 14


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