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

It has been reported recently that the wild-type p53 gene product can positively regulate the expression of a test gene adjacent to the enhancer-promoter elements of the murine muscle-specific creatine kinase (MCK) gene. This discussion reports the identification of a wild-type p53 protein-specific DNA-binding element located within the p53-responsive region of the MCK enhancer-promoter element. This p53 protein/DNA-binding element has been defined by DNase I footprint analysis, which identified a 50-bp region. This 50-bp sequence was sufficient to confer wild-type p53 responsiveness on a heterologous minimal promoter. The mutant forms of p53 protein are much less capable of stimulating this DNA element. This study has identified the first example of a naturally occurring wild-type p53-specific DNA-binding element that is able to mediate positive regulation of a test gene. The results suggest a biological function in gene regulation for the wild-type p53 protein that is lost or altered in the mutant p53 proteins.
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PMID:Wild-type p53 mediates positive regulation of gene expression through a specific DNA sequence element. 162 22

Expression of the p53 gene plays an important role in the regulation of cellular proliferation and malignant transformation. Overexpression of mutant forms of p53 is in fact a common feature of many transformed cells. Studies dealing with the transcriptional regulatory regions of the p53 gene indicate that, unlike most promoters transcribed by RNA polymerase II, the p53 promoter contains no TATA-like sequence upstream of the transcription start site. Here we demonstrate that the murine p53 promoter contains a cis-acting element that maps downstream to the transcription initiation site. The integrity of this element is required for high-level expression from the promoter in transformed cells. By DNase I protection and mobility-shift analysis, we show that a nuclear factor binds to this downstream element through the consensus recognition sequence for the helix-loop-helix (HLH)-containing proteins of the myc/MyoD family of transcriptional regulators. We propose that the activity of one or more members of this family of transcription factors is an important determinant in the expression of p53 and that at least one level of p53 overexpression in transformed cells may thus be due to aberrant expression of the relevant factor(s). Furthermore, the possibility that the regulation of expression of p53 occurs, in part, by means of a potential HLH-containing factor provides a possible mechanism for the suppression of proliferation by the MyoD family of transcriptional regulators.
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PMID:Expression from the murine p53 promoter is mediated by factor binding to a downstream helix-loop-helix recognition motif. 185 94

The SVT2 line of simian virus 40-transformed mouse cells expresses little or no wild-type-size A protein (T antigen). Instead, a variant form is produced in these cells that is larger than normal-size A protein. This variant form has an Mr of 100,000 (100K super-T antigen) and is found primarily in complexes with the host-cell-coded p53 protein. Binding of the 100K super-T antigen to simian virus 40 origin region DNA was assayed by immunoprecipitation of super-T antigen-DNA complexes and then digestion with DNase I. DNA sequences associated with super-T antigen were protected from digestion and retained in the immune complex, while unprotected sequences were digested and released. The 100K super-T antigen efficiently protects DNA sequences in the previously defined regions I and II (P. Tegtmeyer, B. A. Lewton, A. L. DeLucia, V. G. Wilson, and K. Ryder, J. Virol. 46:151-161, 1983). Within region II (the origin of replication), the pattern and size of protected fragments are identical for super-T antigen and purified wild-type A protein. Thus, even though super-T antigen is larger than wild-type A protein, both must bind with the same alignment on origin DNA. Furthermore, complexes between the host-cell-coded p53 protein and the 100K super-T antigen also retain the ability to bind in regions I and II.
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PMID:Origin binding by a 100,000-dalton super-T antigen from SVT2 cells. 299 42

p53 accumulates after DNA damage and arrests cellular growth. These findings suggest a possible role for p53 in the cellular response to DNA damage. We have previously shown that the C terminus of p53 binds DNA nonspecifically and assembles stable tetramers. In this study, we have utilized purified segments of human and murine p53s to determine which p53 domains may participate in a DNA damage response pathway. We find that the C-terminal 75 amino acids of human or murine p53 are necessary and sufficient for the DNA annealing and strand-transfer activities of p53. In addition, both full-length wild-type p53 and the C-terminal 75 amino acids display an increased binding affinity for DNA damaged by restriction digestion, DNase I treatment, or ionizing radiation. In contrast, the central site-specific DNA-binding domain together with the tetramerization domain does not have these activities. We propose that interactions of the C terminus of p53 with damaged DNA may play a role in the activation of p53 in response to DNA damage.
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PMID:The C-terminal domain of p53 recognizes DNA damaged by ionizing radiation. 756 53

The quaternary structure of the adenovirus early region 1B 54K protein has been examined under denaturing and nondenaturing conditions. In the presence of SDS the protein has a strong tendency to form disulfide-linked high-molecular-weight polymers. Under nondenaturing, but reducing, conditions the in vitro-translated 54K polypeptide forms oligomers (probably tetramers) of molecular weight approximately 2 x 10(5). After subcellular fractionation of Ad12 early region 1-transformed cells, the 54K E1B protein present in the cytoplasm had a molecular weight similar to that determined for the in vitro-translated material. However, two populations of the viral protein could be distinguished in the nucleus-one of a size similar to that seen in the cytoplasm and the other of appreciably higher molecular weight (approximately 2 x 10(6)). No difference in migration pattern was observed after treatment of the nuclear extract with DNase I or RNase. A proportion of the Ad12 E1B 54K protein in both the high- and the low-molecular-weight populations in the nucleus was found to form a complex with p53, and it is therefore concluded that the very high molecular weight derives from interaction with an, as yet, unidentified component.
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PMID:The quaternary structure of the adenovirus 12 early region 1B 54K protein. 787 36

We have examined the occurrence of apoptotic cell death in formalin-fixed, paraffin-embedded human gastric carcinoma specimens by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) method. The specificity of the TUNEL signals was confirmed by the omission of either TdT or biotinylated dUTP as negative controls, and by pretreatment with DNase I as a positive control. Careful observation of routine hematoxylin and eosin-stained sections showed a few tumor cells with apoptosis, especially in well-differentiated carcinomas. Intense TUNEL signals were frequently observed even in ordinary, non-pyknotic nuclei of tumor cells, and occasionally also in nuclear fragments corresponding to apoptotic bodies. Apoptotic indices (number of apoptotic cells/total number of tumor cells) ranged between 7.7 and 14.5% (mean, 10.9%) in nine well-differentiated carcinomas and between 2.7 and 7.5% (mean, 4.0%) in five which were poorly differentiated, the mean number being significantly higher in the former (P < 0.01). No apparent correlation was found between apoptosis and the expression of proliferating cell nuclear antigen, P53 or Le(y) in the present study. This high frequency of apoptosis, implying cell loss, may be related to the slow-growing nature of well-differentiated carcinomas. Poorly differentiated carcinomas, including scirrhous gastric carcinomas, showed a lower incidence of apoptosis, indicating the existence of an escape mechanism from the process.
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PMID:Apoptotic cell death in human gastric carcinoma: analysis by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. 796 Nov 23

A novel transcription factor binding element in the human p53 gene promoter has been characterized. It lies about 100 bp upstream of the major reported start site for human p53 gene transcription. On the basis of DNase I footprinting studies, electromobility shift assay patterns, sequence specificity of binding, the binding pattern of purified transcription factors, effects of specific antibodies, and methylation interference analysis we have identified the site as a composite element which can bind both YY1 and NF1 in an independent and mutually exclusive manner. The site is conserved in the human, rat, and mouse p53 promoters. The occupancy of the site varies in a tissue-specific manner. It binds principally YY1 in nuclear extracts of rat testis and spleen and NF1 in extracts of liver and prostate. This may facilitate tissue-specific control of p53 gene expression. When HeLa cells were transiently transfected with human p53 promoter-chloramphenicol acetyltransferase reporter constructs, a mutation in this composite element which disabled YY1 and NF1 binding caused a mean 64% reduction in basal p53 promoter activity. From mutations which selectively impaired YY1 or NF1 binding and the overexpression of YY1 or NF1 in HeLa cells we concluded that both YY1 and NF1 function as activators when bound to this site. In transient cotransfections E1A could induce the activity of the p53 promoter to a high level; 12S E1A was threefold as efficient as 13S E1A in this activity, and YY1 bound to the composite element was shown to mediate 55% of this induction. Overexpressed YY1 was shown to be able to synergistically activate the p53 promoter with E1A when not specifically bound to DNA. Deletion of an N-terminal domain of E1A, known to be required for direct E1A-YY1 interaction and E1A effects mediated through transcriptional activator p300, blocked the E1A induction of p53 promoter activity.
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PMID:YY1 and NF1 both activate the human p53 promoter by alternatively binding to a composite element, and YY1 and E1A cooperate to amplify p53 promoter activity. 881 7

The human epidermal growth factor receptor (EGFR) promoter is activated by both wild-type and tumor-derived mutant p53. In this communication, we demonstrate that EGFR promoter sequence requirements for transactivation by wild-type and mutant p53 are different. Transient-expression assays with EGFR promoter deletions identified a wild-type human p53 response element, 5'-AGCTAGACGTCCGGGCAGCCCCCGGCG -3', from positions --265 to --239. Electrophoretic mobility shift analysis and DNase I footprinting assays indicated that wild-type p53 binds sequence specifically to the response element. Using circularly permuted DNA fragments containing the p53-binding site, we show that wild-type p53 binding induces DNA bending at this site. We further show that the EGFR promoter is also activated by tumor-derived p53 mutants p53-143A, p53-175H, p53-248W, p53-273H, and p53-281G. However, the transactivation by mutant p53 does not require the wild-type p53-binding site. The minimal EGFR promoter from positions --104 to --20 which does not contain the wild-type p53-binding site is transactivated by the p53 mutants but not by the wild-type protein, showing a difference in the mechanism of transactivation by wild-type and mutant p53. Transactivation of the EGFR promoter by p53 may represent a novel mechanism of cell growth regulation.
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PMID:Transcriptional activation of the human epidermal growth factor receptor promoter by human p53. 888 30

The testis is a tissue of high proliferative activity. In this organ, sperm cells (spermatozoa) are produced from stem cells (spermatogonia) by two consecutive steps of cell multiplication and spermatid cytodifferentiation. Mitotic proliferation of spermatogonia generates primary spermatocytes which enter meiosis, leading to the generation of spermatids. The number of cells entering meiosis is held constant, since outnumbering spermatogonia or premeiotic spermatocytes are eliminated by apoptosis (programmed cell death). During apoptosis, the nuclear chromatin is internucleosomally degraded by the activity of a Ca2+, Mg2+-dependent endonuclease. Recent data indicate that deoxyribonuclease I (DNase I) is identical to the apoptotic endonuclease responsible for the internucleosomal DNA degradation. Previous results using primers specific for rat parotid DNase I in a polymerase chain reaction have demonstrated the presence of DNase I-specific gene transcripts in rat testis. We have therefore analysed the presence of DNase I in rat testis by immunohistochemistry and biochemical procedures. The presence of DNase I-like endonucleolytic activity was verified enzymatically. DNase I immunoreactivity was detected in the nuclei of a few spermatogonia and premeiotic spermatocytes, but within the acrosomic vesicle of all spermatids and spermatozoa. In situ hybridisation revealed the accumulation of DNase I-specific gene transcripts in a small number of spermatogonia and/or premeiotic spermatocytes, but in a large number of spermatids. The occurrence of apoptotic DNA fragmentation was investigated by in situ end-labelling (ISEL) of free 3'-OH DNA ends and gave positive nuclear staining of only very few spermatogonia. No positive ISEL staining was observed in maturing spermatids and/or spermatozoa. These data support the notion that, within the seminiferous epithelium, the number of primary spermatocytes entering meiosis is controlled by apoptosis. In addition, they demonstrated that mature sperm cells are equipped with an endonuclease that might be used for DNA degradation during their elimination at later stages of their life span. The expression and distribution of the tumour suppressor gene product, p53, was analysed by immunostaining. Strong p53 immunoreactivity was observed in the nuclei of a number of spermatogonia, of some premeiotic spermatocytes and probably in all spermatids. Thus, p53 expression appeared to parallel that of DNase I. In contrast, p53 immunoreactivity was absent in mature spermatozoa present in the lumen of the testicular tubules or the ductus epididymidis. It is therefore proposed that at later stages of spermatid maturation most probably before their release as mature spermatozoa-the p53 gene product was either degraded or retained in residual bodies, since p53 immunoreactivity was found to be concentrated within these organelles.
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PMID:Distribution of deoxyribonuclease I (DNase I) and p53 in rat testis and their correlation with apoptosis. 891 66

A detailed investigation of how nucleosomes are formed and arranged on the DNA sequence is a prerequisite to understanding the molecular mechanisms of DNA-dependent processes such as transcription, replication, DNA repair, and mutagenesis. In this report we analyzed the chromatin structure of exons 5-8 of the p53 gene in human fibroblasts. We mapped at the nucleotide level the positions of DNase I and micrococcal nuclease cleavage sites in permeabilized cells. Areas of clear DNase I protection, which would be indicative of the binding of sequence-specific proteins, were not detected. Instead, the micrococcal nuclease and DNase digestion patterns suggested that this region was covered by nucleosomes and that two areas spanning exons 5 and 6 are occupied preferentially. These nucleosomes could influence DNA damage distribution, repair of certain lesions, and other aspects of the mutagenesis process in p53 sequences.
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PMID:A high-resolution analysis of chromatin structure along p53 sequences. 898 12


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