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

Single-stranded DNA has been speculated to be the initial signal in the DNA damage signaling pathway. We showed that introduction of single-stranded DNA with diverse sequences into mammalian cells induced DNA damage as well as apoptosis signals. Like DNA damaging agents, single-stranded DNA up-regulated p53 and activated the nuclear kinase ataxia telangiectasia mutant (ATM) as evidenced by phosphorylation of histone 2AX, an endogenous ATM substrate. Single-stranded DNA also triggered apoptosis as evidenced by the formation of caspase-dependent chromosomal DNA strand breaks, cytochrome c release, and increase in reactive oxygen species production. Moreover, single-stranded DNA-induced apoptosis was reduced significantly in p53 null cells and in cells treated with ATM small interfering RNA. These results suggest that single-stranded DNA may act upstream of ATM/p53 in DNA damage signaling.
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PMID:Single-stranded DNA induces ataxia telangiectasia mutant (ATM)/p53-dependent DNA damage and apoptotic signals. 1254 Aug 48

Efficient gene delivery of a baculovirus-derived vector (BV-p53-lacZ) to a human osteogenic sarcoma cell line, Saos-2, was serendipitously found while evaluating the vector for gene delivery to human p53-null tumour cells in a previous study. Therefore, we investigated other human, rat and mouse osteogenic sarcoma and other types of tumour cell lines for transduction efficiency via baculovirus vectors containing a lacZ reporter gene under the control of either a cytomegalovirus or Rous sarcoma virus promoter. The expression of beta-galactosidase protein, assessed by X-Gal staining and beta-galactosidase ELISA, demonstrated an extremely high level of transduction efficiency in some osteogenic sarcoma cell lines, such as U-2OS, Saos-2 and Saos-LM2. These human osteogenic sarcoma cell lines showed levels of beta-galactosidase expression 5-40 times greater than HepG2 cells, which were previously thought to be the mammalian cells most susceptible to baculovirus-mediated gene delivery. The level of acetylated histone proteins in these tumour lines did not correlate well with the high level of reporter gene expression. These results strongly suggest that some osteogenic sarcoma cells are highly susceptible to baculovirus-mediated gene delivery and that a baculovirus-derived vector is an efficient gene delivery vehicle into human osteogenic sarcoma cells.
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PMID:Effective transduction of osteogenic sarcoma cells by a baculovirus vector. 1260 22

Ionizing radiation induces genomic instability, which is transmitted through many generations after irradiation in the progeny of surviving cells. To detect delayed activation of p53, we constructed a reporter plasmid containing the p53-responsible promoter and the bacterial beta-galactosidase (beta-gal) gene and introduced it into human fibrosarcoma (HT1080) cells, which retain wild-type p53 function. The resultant clones induce beta-gal protein after X-irradiation, and the induction kinetics were similar to those of p21(WAF1/CIP1) protein. More than 90% of the cells were stained blue when the cells were incubated with X-gal 4 h after 6 Gy of X-rays, whereas very few control cells were beta-gal positive. The primary colonies formed after 6 Gy of X-rays were collected, and they were subjected to secondary colony formation. We observed that a significant number of surviving colonies contained beta-gal-positive cells, suggesting that delayed activation of p53 occurred in the progeny of irradiated cells. We also found higher frequency of phosphorylation of p53, NBS1, and CHK2/Cds1 in the progeny of surviving cells. Furthermore, foci formation of phosphorylated histone H2AX was detected in the progeny of surviving cells. These findings provide the possibility that the observed instability results from these DNA breaks, i.e., the breaks lead to delayed chromosome rearrangements, delayed cell death, and so forth, many generations after irradiation and that activation of p53 function may eliminate cells that have potentially accumulated genomic alterations.
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PMID:Delayed reactivation of p53 in the progeny of cells surviving ionizing radiation. 1261 6

The inhibitor-of-growth (ING) family of proteins was founded by human ING1, a tumor suppressor interacting with p53 in vivo and required for its function in transcription/apoptosis. There are five different ING genes in humans, three of which have been linked to p53 function. In this study, we analyzed the three ING family members present in yeast. We demonstrate that each one is purified as a key component of a specific histone-modifying complex. Pho23 is part of Rpd3/Sin3 histone deacetylase complex, while Yng1 and Yng2 are subunits of the NuA3 and NuA4 histone acetyltransferase complexes, respectively. We also show that the three different ING proteins have opposite roles in transcriptional activation by p53 in vivo. These effects are linked to the presence of each ING in its respective chromatin modifying complex, since mutation of the corresponding catalytic subunit gave similar results. Depletion of Pho23/Rpd3 leads to increased p53-dependent transcription in vivo while depletion of Yng2 abrogates it. Surprisingly, deletion of YNG1 or SAS3 leads to increased transcriptional activation by p53. These data suggest that the NuA3 complex can function in gene-specific repression, an unusual role for a histone acetyltransferase complex. They also demonstrate the key specific role of ING proteins in different chromatin modifying complexes and their opposite functions in p53-dependent transcription.
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PMID:Opposite role of yeast ING family members in p53-dependent transcriptional activation. 1267 25

By using the hepatic stellate cell (HSC) as a paradigm for cells that undergo long term re-programming of NF-kappaB-dependent transcription, we have determined a novel mechanism by which mammalian cells establish their basal NF-kappaB activity. Elevation of NF-kappaB activity during HSC activation is accompanied by induction of CBF1 expression and DNA binding activity. We show that the transcriptional repressor CBF1 interacts with a dual NF-kappaB/CBF1-binding site (kappaB2) in the IkappaBalpha promoter. Nucleotide substitutions that disrupt CBF1 binding to the kappaB2 site result in an elevation of IkappaBalpha promoter activity and loss of responsiveness of the promoter to a transfected CBF1 reporter vector. Overexpression of CBF1 in COS1 cells was associated with markedly reduced IkappaBalpha protein expression and elevated NF-kappaB DNA binding activity. CBF1-induced repression of IkappaBalpha promoter activity was reversed in HSC transfected with the Notch1 intracellular domain (NICD). The ability of NICD to enhance IkappaBalpha gene transcription was confirmed in COS1 cells and was found to be dependent on an intact RAM domain of NICD that has been shown previously to help mediate the interaction of NICD with CBF1. One of the mechanisms by which NICD is thought to convert CBF1 into an activator of transcription is via the recruitment of transcriptional co-activators/histone acetylases to gene promoters. Co-transfection of HSC with NICD and p53 caused a diminution of IkappaBalpha promoter activity, by contrast overexpression of p300 enhanced IkappaBalpha promoter function. Taken together, these data suggest that basal IkappaBalpha expression (and as a consequence NF-kappaB activity) is under the control of the various components of the CBF1/Notch signal transduction pathway.
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PMID:Basal expression of IkappaBalpha is controlled by the mammalian transcriptional repressor RBP-J (CBF1) and its activator Notch1. 1270 Feb 42

We identified and characterized two new ING family genes, p29ING4 and p28ING5,coding for two proteins of 249 and 240 amino acids, respectively. Both p29ING4 and p28ING5 proteins have a plant homeodomain finger motif also found in other ING proteins, and which is common in proteins involved in chromatin remodeling. p29ING4 or p28ING5 overexpression resulted in a diminished colony-forming efficiency, a decreased cell population in S phase, and the induction of apoptosis in a p53-dependent manner. Both p29ING4 and p28ING5 activate the p21/waf1 promoter, and induce p21/WAF1 expression. p29ING4 and p28ING5 enhance p53 acetylation at Lys-382 residues, and physically interact with p300, a member of histone acetyl transferase complexes, and p53 in vivo. These results indicate that p29ING4 and p28ING5 may be significant modulators of p53 function.
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PMID:p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. 1275 Feb 54

Transcription involves molecular interactions between general and regulatory transcription factors with further regulation by protein-protein interactions (e.g. transcriptional cofactors). Here we describe functional interaction between DNA-binding transcription factor and histone chaperone. Affinity purification of factors interacting with the DNA-binding domain of the transcription factor Sp1 showed Sp1 to interact with the histone chaperone TAF-I, both alpha and beta isoforms. This interaction was specific as Sp1 did not interact with another histone chaperone CIA nor did other tested DNA-binding regulatory factors (MyoD, NFkappaB, p53) interact with TAF-I. Interaction of Sp1 and TAF-I occurs both in vitro and in vivo. Interaction with TAF-I results in inhibition of DNA-binding, and also likely as a result of such, inhibition of promoter activation by Sp1. Collectively, we describe interaction between DNA-binding transcription factor and histone chaperone which results in negative regulation of the former. This novel regulatory interaction advances our understanding of the mechanisms of eukaryotic transcription through DNA-binding regulatory transcription factors by protein-protein interactions, and also shows the DNA-binding domain to mediate important regulatory interactions.
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PMID:Functional interaction of the DNA-binding transcription factor Sp1 through its DNA-binding domain with the histone chaperone TAF-I. 1275 64

BRCA1 is a central component of the DNA damage response mechanism and defects in BRCA1 confer sensitivity to a broad range of DNA damaging agents. BRCA1 is required for homologous recombination and DNA damage-induced S and G(2)/M phase arrest. We show here that BRCA1 is required for ATM- and ATR-dependent phosphorylation of p53, c-Jun, Nbs1 and Chk2 following exposure to ionizing or ultraviolet radiation, respectively, and is also required for ATM phosphorylation of CtIP. In contrast, DNA damage-induced phosphorylation of the histone variant H2AX is independent of BRCA1. We also show that the presence of BRCA1 is dispensable for DNA damage-induced phosphorylation of Rad9, Hus1 and Rad17, and for the relocalization of Rad9 and Hus1. We propose that BRCA1 facilitates the ability of ATM and ATR to phosphorylate downstream substrates that directly influence cell cycle checkpoint arrest and apoptosis, but that BRCA1 is dispensable for the phosphorylation of DNA-associated ATM and ATR substrates.
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PMID:A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. 1277

DNA methylation in the promoter of certain genes is associated with transcriptional silencing. Methylation affects gene expression directly by interfering with transcription factor binding and/or indirectly by recruiting histone deacetylases through methyl-DNA-binding proteins. In this study, we demonstrate that the human lung cancer cell line H719 lacks p53-dependent and -independent p21(Cip1) expression. p53 response to treatment with gamma irradiation or etoposide is lost due to a mutation at codon 242 of p53 (C-->W). Treatment with depsipeptide, an inhibitor of histone deacetylase, was unable to induce p53-independent p21(Cip1) expression because the promoter of p21(Cip1) in these cells is hypermethylated. By analyzing luciferase activity of transfected p21(Cip1) promoter vectors, we demonstrate that depsipeptide functions on Sp1-binding sites to induce p21(Cip1) expression. We hypothesize that hypermethylation may interfere with Sp1/Sp3 binding. By using an electrophoretic mobility shift assay, we show that, although methylation within the consensus Sp1-binding site did not reduce Sp1/Sp3 binding, methylation outside of the consensus Sp1 element induced a significant decrease in Sp1/Sp3 binding. Depsipeptide induced p21(Cip1) expression was reconstituted when cells were pretreated with 5-aza-2'-deoxycytidine. Our data suggest, for the first time, that hypermethylation around the consensus Sp1-binding sites may directly reduce Sp1/Sp3 binding, therefore leading to a reduced p21(Cip1) expression in response to depsipeptide treatment.
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PMID:Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter. 1277 51

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


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