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

Transcriptional activity of p53 was monitored by cotransfection of pCMV expression vectors containing wild-type and mutant p53 cDNAs into the p53-null H1299 lung cancer cells along with luciferase reporter plasmids containing different p53 target sequences in the 5' regulatory region: fragment A of the ribosomal gene cluster (RGC); p53 consensus sequence (p53CON); or a tandemly linked RGC+p53CON sequence. Our results show: (1) wild-type p53 stimulates the transcription of reporter genes with p53CON and RGC in their 5' region while most p53 mutants occurring in human cancers have lost this activity; (2) the R273H mutant retains transcriptional activity for the p53CON sequence but not RGC; (3) some mutants are temperature-sensitive for the transcriptional activity with the p53CON but not the RGC sequence; (4) p53 mutants vary in their ability to inhibit wild-type p53 transactivation but there is no difference between p53CON and RGC sequences; (5) lung cancer cells with endogenous mutant p53 proteins (M246I in H23 cells and R248L in H322 cells) retain transcriptional activity for the p53CON but not the RGC sequence. We conclude that p53 DNA target sequences vary in their response to mutant p53 proteins, and that p53 mutants vary in several transactivation related functions.
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PMID:Heterogeneity of transcriptional activity of mutant p53 proteins and p53 DNA target sequences. 833 41

Wild-type p53 was shown to function as a transcription factor. The N-terminal region of the protein contains the transcription activation domain, while the C terminus is responsible for DNA binding. Localization of the DNA-binding domain of the p53 protein to the highly conserved carboxy-terminal region suggests that the interaction of p53 with DNA is important for its function. We have developed a strategy for studying the DNA sequence specificity of p53-DNA binding that is based on random sequence selection. We report here on the isolation of murine genomic DNA clones that are specifically bound by the wild-type p53 protein but are not bound by mutant p53 protein forms. The isolated p53 target gene contains the unique DNA-binding sequence GACACTGGTCACACTTGGCTGCTTAGGAAT. This fragment exhibits promoter activity as measured by its capacity to activate transcription of the chloramphenicol acetyltransferase reporter gene. Our results suggest that p53 directly binds DNA and functions as a typical transcription factor.
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PMID:Isolation and characterization of DNA sequences that are specifically bound by wild-type p53 protein. 844 83

Deferoxamine (DFO)-induced iron deprivation caused an increase in p53 expression in ML-1 and Raji cells. In ML-1 cells, with express wild type p53, p53 protein levels were transiently increased 6 h after addition of 10(-4)M DFO. In Raji cells, which carry a mutant p53 allele, p53 increased 6 h after addition of 10(-4)M DFO and remained elevated for 24 h. Growth inhibition was observed in both cell types 6 h after addition of 10(-4)M DFO. In both cells, p53 mRNA levels did not increase following incubation with DFO, suggesting that increased p53 expression is the result of a post-transcriptional mechanism. Although increases in wild type p53 protein in ML-1 cells resulted in increases in a p53 target gene, p21cipl/wafl/sdil, this effect was not observed in Raji cells which express a mutant p53 protein.
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PMID:Iron deprivation results in an increase in p53 expression. 859 Jun 32

We used clone 6 cells (rat embryo fibroblasts transformed by the temperature sensitive mutant p53val135 and an activated H-ras-gene (Michalovitz et al., 1990)), growth arrested at 32 degrees C, as a model to analyse whether and how transformed cells, growth-arrested by an overexpressed wild-type p53, might overcome p53-mediated growth inhibition. When clone 6 cells were kept at 32 degrees C for about 2 weeks, foci of cells appeared which grew temperature-independent. Analysis of individual clones of such cell demonstrated that the ectopically expressed tsp53-gene had not been altered by an additional mutation, but that the tsp53 in these cells at 32 degrees C had lost its ability to upregulate expression of the p53 target genes waf1 and mdm2. This loss of p53-specific transactivation correlated with nuclear exclusion of the tsp53 at 32 degrees C, which was most likely mediated by cytoplasmic retention of the tsp53 protein via short-lived anchor proteins. Cytoplasmic retention of the tsp53 at 32 degrees C was also observed in PC12 pheochromocytoma cells ectopically expressing tsp53val135, there occurring without specific selection. Also in these cells nuclear exclusion of the tsp53 correlated with loss of p53 mediated growth inhibition. Nuclear exclusion of p53 thus might serve as an epigenetic mechanism to eliminate the growth-inhibitory function of p53.
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PMID:Abrogation of wild-type p53 mediated growth-inhibition by nuclear exclusion. 862 96

To investigate the effect of p53 tumor suppressor gene loss in the mouse skin model of multistage carcinogenesis, p53 knockout mice, generated by gene targeting (p53 -/-), were mated to transgenic mice expressing v-rasHa (HK1.ras), v-fos (HK1.fos), or human transforming growth factor alpha+HK1.TGFalpha) exclusively in the epidermis, by means of a keratin K1-based targeting vector (HK1). HK1-p53 transgenic progeny expressing wild-type p53 alleles (p53 +/+) or hemizygous for the p53 knockout allele (p53+/-) were identical to parental HK1 lines and exhibited neonatal epidermal hyperplasia or wound-associated hyperplasia in adults, together with spontaneous or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced benign papillomas. Mating to p53-/- did not lead to the expected tumorigenesis in adults. Instead, whereas HK1.ras or HK1.TGFalpha transgenic mice null for p53 (HK1.ras-p53-/- and HK1.TGFalpha-p53-/-, respectively) retained the neonatal epidermal hyperplasia phenotype, in adults, spontaneous and TPA-promoted papilloma formation was blocked. Similarly, wound-associated epidermal hyperplasia/hyperkeratosis, a hallmark of adult HK1.fos phenotypes, was completely absent in HK1.fos-p53 -/- mice. Histological, immunofluorescence, and bromodeoxyuridine labeling analysis of neonatal or adult epidermis in HK1-p53 transgenic genotypes +/+, +/-, and -/- for p53 revealed no obvious differences in morphology, expression of keratinocyte differentiation markers, or mitotic index attributed to p53 loss. To determine whether the paradoxical absence of papillomas centered on up-regulation of p53 target genes, WAF1/CIP1/p21 RNA expression levels were examined in TPA promotion experiments. WAF1/CIP1/p21 expression increased in response to TPA promotion in all HK1-p53 transgenic genotypes regardless of p53 status. However, in HK1-p53 null genotypes, although TPA-induced, p53-independent WAF1/CIP1/p21 expression was observed, no large increase in expression was associated with the observed paradoxical tumorigenesis block. These data suggest that epidermis is somewhat resistant to the neoplastic effects of p53 loss, possibly possessing several compensatory systems. Alternatively, there may be a requirement forp53 expression in response to TPA or a wound-promotion stimulus in mouse epidermis.
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PMID:Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor alpha. 881 35

The E6 gene of tumor-associated types of human papillomaviruses codes for a functional antagonist of p53. Overexpression of E6 from heterologous promoters can block p53-mediated cellular responses to DNA damage, such as transcriptional stimulation of p53 target genes and cell-cycle arrest in G1. In contrast, genotoxic treatment of HPV-positive cancer cells, which express the E6 gene from chromosomally integrated viral copies, results in increased expression of the p53 target gene p21WAF1 and, in several cell lines, induction of G1 arrest. In the present study, we show that treatment with genotoxic agents, such as mitomycin C and cisplatin, leads to strong repression of viral E6/E7 oncogene expression in HPV16- and HPV18-positive cervical carcinoma cell lines. Kinetic analyses revealed that reduction of E6/E7 expression was not a prerequisite for induction of p21WAF1. We furthermore found that the apoptosis-promoting bax gene could be induced by genotoxic stress in some, but not all, HPV-positive cancer cell lines. Treatment with DNA-damaging agents eventually resulted in apoptotic cell death of HPV-positive cancer cells, irrespective of their capacity to induce the p53 target gene bax. These results support the notion that HPV-positive cancer cells can exhibit intact cellular responses to genotoxic stress, which may involve p53-dependent and -independent biochemical pathways. The ability of HPV-positive cancer cells to induce apoptotic cell death in response to DNA damage could provide a molecular explanation for the therapeutic effects of genotoxic agents in the treatment of cervical cancer.
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PMID:Cellular responses of HPV-positive cancer cells to genotoxic anti-cancer agents: repression of E6/E7-oncogene expression and induction of apoptosis. 894 23

Extensive apoptosis occurs in the nervous system of mouse embryos homozygous mutant for a targeted disruption of the retinoblastoma (Rb) gene. This cell death is present in both the central (CNS) and peripheral nervous systems (PNS) and is associated with abnormal S phase entry of normally post-mitotic neurons. Aberrant proliferation in the CNS correlates with increased free E2F DNA binding activity and increased expression of cyclin E, an E2F target gene and critical cell cycle regulator. Cell death in the CNS is accompanied by increased levels of the p53 tumor suppressor gene product and increased expression of the p53 target gene, p21Waf-1/Cip-1. However, induction of p53 is not observed in the PNS of Rb-mutant embryos, nor does loss of p53 function inhibit cell death in the PNS. Surprisingly, p21Waf-1/Cip-1 is induced in the sensory ganglia of Rb-mutant embryos in a p53-independent manner. Although loss of p53 gene function prevents cell death in the CNS of Rb-mutant embryos, it does not restore normal proliferative control.
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PMID:Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. 894 40

The p53 protein binds sites of primary DNA damage via its C-terminus. This interaction in some way activates sequence-specific binding (via the central core domain) and transactivation of p53 target genes. We now show that interaction with non-specific DNA, but not specific DNA targets, induces selective proteolysis of p53 to give a 40 kDa fragment, comprising the core plus C-terminus, and a 35 kDa conformationally intact core domain. Proteolytic cleavage was limited and yielded roughly equivalent proportions of full length p53 and the 40 kDa and 35 kDa fragments. Significantly, both 40 kDa and 35 kDa products were activated for sequence-specific DNA binding. Similar p53-related products were induced by exposure of cells to DNA damage. We propose that some functions of p53 can be activated by proteolytic processing and that this may be important in the cellular response to DNA damage.
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PMID:Interaction with damaged DNA induces selective proteolytic cleavage of p53 to yield 40 kDa and 35 kDa fragments competent for sequence-specific DNA binding. 895 Sep 74

Rat embryo fibroblasts transformed with HPV-16 E7 and the Ha-ras oncogene (ER clones) fall into two distinct groups based on their endogenous p53 status, wild-type or mutant. We have taken advantage of such clones in order to study the p53 target genes by the differential display method of RNA fingerprinting. We have identified a cDNA clone, clone 16, that recognises a large transcript on Northern blots. The clone 16 transcript is overexpressed in ER cell lines that express wild-type p53 compared with ER cell lines that express mutant p53. Similar to the waf1/p21 gene, which is transcriptionally activated in cells treated with ionizing radiation in a p53-dependent manner, the clone 16 transcript was also induced in response to cell irradiation. The sequence of clone 16 exhibits a high homology to two members of RAL retroviral-like elements.
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PMID:A transcript exhibiting homology to endogenous rat retroviral-like elements is regulated by p53. 900 Jan 48

p53, a tumor suppressor gene, functioning as a transcription factor, has been recently shown in a cell free system to be subject to redox (reduction/oxidation) regulation. Oxidants or metal chelating reagents disrupt wildtype p53 conformation and decrease or abolish its DNA binding activity, while reductants restore wildtype conformation and increase DNA binding. We have extended these observations to intact cell systems by using luciferase transactivation assay in two murine tumor cell lines, both harboring endogenous wildtype p53. The results showed that none of these in vitro active reagents, except 1,10-phenanthroline (OP) has a significant effect on p53 transactivation activity. OP, a metal chelator and p53 inactivator in cell free systems, however, induces p53 transactivation activity as well as sequence-specific DNA binding in a dose dependent manner. OP also differentially induces endogenous expression of several known p53 target genes such as Waf-1 and Mdm-2, but not Bax, Gadd45, and PCNA. Increased p53 activity induced by OP is not due to elevated p53 mRNA nor to protein levels. Furthermore, the OP-induced p53 transcriptional activation is not due to its potential DNA intercalating activity, but mainly due to its metal chelating activity. OP was also found to induce dramatically apoptotic cell death in these tumor cells harboring wildtype p53, to a less extent in MEF cells from p53 knockout mice and not at all in Saos-2 cells without p53 or Rb. We concluded from this study that (a) unlike what has been seen in vitro, OP induces p53 activity in intact cells (b) OP activates p53 transcriptional activity without increasing p53 protein; and (c) activation of p53 may contribute to apoptosis, but is not required.
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PMID:Activation of p53 transcriptional activity by 1,10-phenanthroline, a metal chelator and redox sensitive compound. 905 35


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