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)

Sodium butyrate, a histone deacetylase inhibitor, has been shown to induce differentiation of many cancer cells and senescence-like state of human fibroblasts. Here we show that sodium butyrate also induces senescence-like state of NIH3T3 cells. The treated cells were blocked at G1 phase and featured morphologically like senescent cells with enlarged cytoplasm and multiple nuclei. The expression of p21(WAF/CIP1) (p21) increased after sodium butyrate treatment at transcriptional level. To analyze the induction of promoter activity, we isolated 4.6 kb of murine p21 promoter and inserted it upstream of a luciferase reporter gene. When this construct was transiently transfected into NIH3T3 cells, sodium butyrate enhanced the luciferase activity. p53 independency of sodium butyrate-inducible p21 promoter activity was confirmed by using the deletion mutants lacking p53 binding sites and p53 deficient cells in transfection experiments.
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PMID:Sodium butyrate induces NIH3T3 cells to senescence-like state and enhances promoter activity of p21WAF/CIP1 in p53-independent manner. 926 33

p53, a tumor suppressor and a transcription factor, has been shown to transcriptionally activate the expression of a number of important genes involved in the regulation of cell growth, DNA damage, angiogenesis, and apoptosis. In a computer search for other potential p53 target genes, we identified a perfect p53 binding site in the promoter of the human type IV collagenase (also called 72-kDa gelatinase or matrix metalloproteinase 2 [MMP-2]) gene. This p53 binding site was found to specifically bind to p53 protein in a gel shift assay. Transcription assays with luciferase reporters driven by the promoter or enhancer of the type IV collagenase gene revealed that (i) activation of the promoter activity is p53 binding site dependent in p53-positive cells but not in p53-negative cells and (ii) wild-type p53, but not p53 mutants commonly found in human cancers, transactivates luciferase expression driven by the type IV collagenase promoter as well as by a p53 site-containing enhancer element in the promoter. Significantly, expression of the endogenous type IV collagenase is also under the control of p53. Treatment of U2-OS cells, a wild-type p53-containing osteogenic sarcoma line, with a common p53 inducer, etoposide, induced p53 DNA binding and transactivation activities in a time-dependent manner. Induction of type IV collagenase expression followed the p53 activation pattern. No induction of type IV collagenase expression can be detected under the same experimental conditions in p53-negative Saos-2 cells. All these in vitro and in vivo assays strongly suggest that the type IV collagenase gene is a p53 target gene and that its expression is subject to p53 regulation. Our finding links p53 to a member of the MMP genes, a family of genes implicated in trophoblast implantation, wound healing, angiogenesis, arthritis, and tumor cell invasion. p53 may regulate these processes by upregulating expression of type IV collagenase.
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PMID:Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter. 934 94

Reversible inhibitors of the cell cycle such as the TGF-betas have been exploited to protect dividing cells from exposure to anticancer drugs and radiation. Here, rat embryo fibroblast (REF) lines expressing different p53 mutations were used to test whether the p53 growth arrest could also chemoprotect cells from high doses of anticancer drugs. Whereas the doubling times of the different REF lines at 37 degrees C were similar, cells bearing temperature-sensitive mutations (mouse 135V or human 143A) were growth arrested at 31 degrees C. Temperature-dependent p53 activity was associated with increased levels of MDM2 and p21/WAF1, and the induction of an integrated p53-responsive luciferase gene. The REF lines exhibited similar sensitivities to common anticancer drugs when grown at 37 degrees C. However, when exposed to the same agents following transient incubation at 31 degrees C, the p53-arrested cells exhibited a marked survival advantage as shown by colony-forming assays. Chemoprotection was not universal, in that colony formation was not enhanced significantly after treatment with cisplatin or 5-fluorouracil, two drugs which can cause cellular damage throughout the cell cycle. Like other negative growth regulators, an activated p53 checkpoint may mediate the survival of cells exposed to drugs that target DNA synthesis or mitosis.
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PMID:A p53 growth arrest protects fibroblasts from anticancer agents. 935 95

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 plays a major role in the induction of G1 cell cycle arrest following DNA damage and is known to be regulated by p53-dependent and -independent pathways. Here, we show that p21WAF1/CIP1 transcription is also regulated, independently of p53, by the cis elements that are located downstream of the transcription start site. A cDNA fragment of approximately 180 bp, located 260 bases 3' to the translation termination codon of p21WAF1/CIP1 cDNA, was cloned in both the sense and antisense orientations downstream of the CMV promoter, upstream of the SV40 promoter, and both upstream and downstream of the p21WAF1/CIP1 promoter in the plasmids carrying the luciferase reporter gene. The constructs were transiently transfected in human breast carcinoma cells MCF-7 and MDA-MB-468 and a Syrian hamster smooth muscle cell line DDT1MF2 and were found to elicit 2-3-fold or higher repression of luciferase activities. By using overlapping deletions of the above 180-bp fragment, we identified a 48-bp subfragment that contains putative cis element(s) that participate in the transcriptional repression of the p21WAF1/CIP1 gene. The overlapping subfragments bind, in vitro, to specific proteins present in the nuclear extracts of MDA-MB-468 and DDT1MF2 cells. We, therefore, propose that additional mechanism(s) exist that regulate expression of the cellular p21WAF1/CIP1 and may contribute to p21WAF1/CIP1-dependent control of the cell cycle.
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PMID:Transcriptional repression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 gene mediated by cis elements present in the 3'-untranslated region. 937 14

A family of related connexin genes encodes the subunit gap junction proteins that form intercellular channels in different tissues. Connexin40 (Cx40) is one of these proteins, and it exhibits limited expression only in a few cells of the cardiovascular system. To begin to analyze Cx40 expression, we isolated a 3.3-kb rat Cx40 cDNA by hybridization screening of a bacteriophage library prepared from BWEM cells and isolated corresponding mouse genomic clones from a bacterial artificial chromosome library. Restriction mapping, sequencing, and comparison to the rat cDNA showed that the mouse Cx40 gene contained a short first exon, an 11.4-kb intron, and a second exon containing the complete coding region and 3'-UTR. Exon I contained only 1 base that differed between rat and mouse. Primer extension experiments yielded a single band and confirmed the position of the transcriptional start site. We obtained 1.2 kb of sequence 5' of the transcriptional start site and 400 bp 3' of exon I. Exon I was closely preceded by a consensus TATA box. The flanking sequences contained a number of potential transcription factor binding sites (including AP-1, AP-2, SP1, TRE, and p53). To identify transcriptional regulatory elements in the Cx40 promoter region, a series of DNA deletion fragments flanking exon I was prepared, subcloned adjacent to a luciferase reporter gene, and used for transient transfections of BWEM, SHM, and N2A cells. The resulting luciferase activity determinations suggested that an area of 300 bp 5' of the transcription start site acted as a basal promoter for Cx40 and that there was a strong negative regulatory element in the region from +100 to +297.
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PMID:Mouse connexin40: gene structure and promoter analysis. 940 66

The present study represents a continuation of previous works in which we observed that lung carcinomas co-expressing MDM2 protein and p53 mutants (mt p53) exhibited more aggressive behaviour. In the above studies, we suggested a 'gain of function' mechanism of mt p53 proteins based on the fact that the MDM2 gene possesses a p53-responsive element (MDM2-p53RE). In this study, to prove our hypothesis, we selected 12 cases from a series of 51 bronchogenic carcinomas. In these 12 cases, we examined the ability of the expressed mt p53 to bind the MDM2-p53RE and correlated the findings with MDM2 expression. Furthermore, we constructed four of these p53 mutants and studied their transactivation properties by co-transfecting them with a reporter plasmid carrying MDM2-p53RE in the p53 null non-small-cell lung carcinoma cell line (NSCLC) H1299. We observed mutant p53 protein DNA-binding activity, which depended on the nature and the position of the amino acid substitution. The fact that the cases with DNA-binding activity were accompanied with MDM2 protein isoforms' overexpression is indicative of a 'gain of function' phenotype. This hypothesis was enforced by the findings of the transfection experiments, which revealed that certain p53 mutants enhanced the expression of the luciferase reporter gene either directly or indirectly via a dominant positive effect on the wild-type p53. In conclusion, this work is one first attempt to examine if the deregulation of the p53/MDM2 autoregulatory feedback loop is due to novel properties of certain p53 mutants in the specific environment of a subset of bronchogenic carcinomas.
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PMID:Effects of p53 mutants derived from lung carcinomas on the p53-responsive element (p53RE) of the MDM2 gene. 947 31

p53 triple mutants (120N/121G/277H, 120H/121G/ 277H, 120S/121G/277H and 120H/121G/277Y) have altered sequence specificity in bandshift assays in vitro and transcription assays in vivo. These mutants activate transcription from the site TTT CATG AAA but not from wild type sites. The triple mutants activate more strongly than p53 with a single 277Y mutation. The TTT site matches the wild type p53 consensus at only 4/10 positions and is not recognised by wild type p53. 277Y mutations have been described in human tumours, and Ewing tumour cells expressing this mutant from the endogenous p53 locus selectively activate transcription from transfected luciferase reporters regulated by TTT-mutant p53 binding sites. p53 mutants with altered sequence specificity have potential advantages for cancer gene therapy: if used to activate transcription of conditionally toxic genes they would allow tumour-targeting by p53, which acts as a sensor for the malignant state, but place control over cell killing in the hands of the clinician. Rare tumours expressing such mutants from the endogenous p53 locus could be targeted directly with p53-regulated suicide vectors, but for most tumours both the p53 mutant and the reporter would need to be encoded by the virus.
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PMID:Use of transcription reporters with novel p53 binding sites to target tumour cells expressing endogenous or virally transduced p53 mutants with altered sequence-specificity. 948 17

The aim of this study was to investigate whether IGF I induction of p53 expression and p21 promoter require activation of MAP kinase in cardiac muscle cells. Compared to cardiomyocytes transfected with control vector, activation of MAP kinase by IGF I was decreased by approximately 60-70% in the cells transfected with dominant negative MAP kinase Y185. Transfection with Y185 also resulted in decreased induction of p53 mRNA by IGF I (70% reduction). In the cells transfected with a wildtype p21WAF1/CIP1 promoter construct, activation of luciferase reporter gene by IGF I was decreased in the cells co-transfected with Y185. To further confirm these findings, cells were preincubated with PD98059, a specific MAP kinase kinase inhibitor. As expected, PD98059 inhibited induction of p53 mRNA and p21WAF1/CIP1 promoter by IGF I. These data indicate that transcriptional activation of p53 and p21WAF1/CIP1 by IGF I involves MAP kinase pathway in cardiomyocytes, and thus link MAP kinase to negative modulation of the cell cycle in cardiac muscle cells.
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PMID:IGF I induction of p53 requires activation of MAP kinase in cardiac muscle cells. 958 14

Cathepsin D (CD), the major intracellular aspartyl protease, is a mediator of IFN-gamma and TNF-alpha induced apoptosis. Using subtractive hybridization screening we isolated CD as an upregulated transcript in PA1 human ovarian cancer cells undergoing adriamycin-induced apoptosis. CD mRNA levels increased in wild-type p53-expressing PA1, ML1 leukemia and U1752 lung cancer cells but not in mutant p53-expressing cells following adriamycin exposure. Overexpression of CD inhibited growth of colon, liver, and ovarian cancer cells. CD protein expression was increased by exposure of ML1 cells to etoposide, adriamycin or gamma-radiation. Inhibition of CD protease with Pepstatin A suppressed p53-dependent apoptosis in lymphoid cells, suggesting a possible role for CD in p53-dependent cell death. CD-/- fibroblasts were found to be more resistant to killing by adriamycin and etoposide, as compared to CD+/+ cells. Two p53 DNA-binding sites located in the CD-promoter specifically bound to p53 protein in vitro and appeared to mediate transactivation of a CD-promoter luciferase-reporter during p53-dependent apoptosis. These observations link CD protease to p53-dependent tumor suppression and chemosensitivity.
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PMID:Potential role for cathepsin D in p53-dependent tumor suppression and chemosensitivity. 961 26

The developmentally regulated H19 gene displays several remarkable properties: expression of an apparently non-translated mRNA, genomic imprinting (maternal allele only expressed), relaxation of the imprinting and/or epigenetic lesions demonstrated in some tumors. Despite several observations after relaxation of imprinting status of the gene, data on trans and cis-acting factors required for the human H19 gene expression are still missing. As a first approach to address identification of factors involved in the regulation of the gene, we found that cells from a p53 antisense-transfected HeLa clone displayed increased amounts of H19 transcripts when compared to the non-transfected cells. Moreover, a HeLa clone stably transfected with a temperature sensitive (ts) 143 Ala p53 mutant exhibited temperature-dependent regulation of H19 expression. This preliminary indication of the repressing effect of the p53 protein on H19 expression has been confirmed by transient cotransfection experiments in HeLa cells, using luciferase surrogate constructs under the control of the 823 bp sequence immediately upstream of the transcription start point of the H19 gene, and different constructs containing sense, antisense or a ts 143 Ala mutant p53 cDNA. We observed an increase of H19 promoter-driven activity in transient cotransfections with the antisense p53 cDNA and the temperature sensitive mutant p53 at the non-permissive temperature, but a decrease with sense wild-type p53 cDNA. Furthermore, the cotransfection experiments were repeated in a cell line lacking endogenous p53. (Calu 6 cells) and the results provided additional evidence for a down regulation of the expression of the H19 gene by the p53 protein.
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PMID:The H19 TATA-less promoter is efficiently repressed by wild-type tumor suppressor gene product p53. 962 May 57


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