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)

The human Ku86 gene and an isoform, KARP-1 (Ku86 autoantigen related protein-1), encode overlapping, but differentially regulated, transcripts. Ku86 is constitutively transcribed at high levels and, although it plays a seminal role in DNA double-strand break repair, its expression is not induced by DNA damage. KARP-1, in contrast, is expressed constitutively only at low levels and its expression is induced by DNA damage in a p53-dependent fashion. The regulatory elements promoting KARP-1 gene expression and p53 responsiveness, however, were unknown. Here, we report that a strong DNase I hypersensitive site (DHS) resides approximately 25 kb upstream from the Ku86 promoter. This DHS is encompassed by a hypomethylated CpG island. Reporter assays demonstrated that this region corresponded to a promoter(s), which promoted transcription of peroxisomal trans-2-enoyl CoA reductase in the centromeric direction and KARP-1 in the telomeric direction. KARP-1 primer extension products were mapped to this CpG island in the correct transcriptional orientation confirming that KARP-1 transcription initiates from this site. Moreover, a p53 response element within the first intron of the KARP-1 transcriptional unit was identified using chromatin immunoprecipitation and antibodies specific to activated forms of p53. These data expand our understanding of this important DNA repair locus.
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PMID:Ku86 autoantigen related protein-1 transcription initiates from a CpG island and is induced by p53 through a nearby p53 response element. 1193 24

Several studies have shown that hexavalent chromium [Cr(VI)] induces apoptosis in a variety of in vitro test systems. We instilled intra-tracheally either saline or sodium dichromate (0.25 mg/kg body weight), for three consecutive days, to Sprague-Dawley rats. TUNEL analyses showed a marked increase of the apoptotic index in both bronchial epithelium and lung parenchyma of Cr(VI)-treated rats, but no effect was detected in their liver. In parallel, the expression of 13 out of 18 apoptosis-related genes, evaluated by cDNA array analysis, was significantly enhanced in rat lung. The overexpressed genes included c-Jun N-terminal kinases 1, 2 and 3, bcl-x, bcl-2-associated death promoter and bcl-2-related ovarian killer protein, caspases 1, 3 and 6, DNase I precursor, DNA topoisomerases I and II alpha, and poly(ADP-ribose) polymerase. The enhancement of p53 expression in the lung was borderline to statistical significance. Expressions of bcl-2, bax-alpha, mdm2 and DNA topoisomerase IIB were not enhanced to a significant extent in lung. No induction of gene expression was observed in rat liver. RT-PCR analyses confirmed that Cr(VI) enhances the expression of c-Jun N-terminal kinase 1, caspase 6, and DNase I precursor but not that of bcl-2 in lung, while none of these genes was overexpressed in the liver of Cr(VI)-treated rats. The lack of stimulation of apoptosis in the liver parallels the failure of Cr(VI) to produce genotoxic damage, as we previously observed under identical experimental conditions. These negative findings may be ascribed to reduction of Cr(VI) to Cr(III) when traveling from the respiratory tract to the liver. On the other hand, induction of apoptosis in the respiratory tract parallels the occurrence of genotoxic effects and oxidative DNA damage produced by Cr(VI) in the same tissue. As previously shown in another laboratory, Cr(VI) did not induce lung tumors after 30 months of administration of the same daily dose. Therefore, apoptosis is likely to provide a protective mechanism at a post-genotoxic stage of Cr(VI) carcinogenesis.
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PMID:Induction of apoptosis in the lung but not in the liver of rats receiving intra-tracheal instillations of chromium(VI). 1196 Sep 10

The ability of p53 to alter, at the transcriptional level, the gene expression of downstream targets is critical for its role as a tumor suppressor. Most models of p53 activation postulate the stepwise recruitment by p53 of coactivators, histone acetyltransferases, and/or chromatin remodeling factors to a promoter region to facilitate the subsequent access of the general transcriptional machinery required for transcriptional induction. We demonstrate here, however, that the promoter regions for the p53 target genes, p21, 14-3-3sigma, and KARP-1, exist in a constitutively open conformation that is readily accessible to DNase I. This conformation was not altered by DNA damage or by whether p53 was present or absent in the cell. In contrast, p53 response elements, which resided outside the immediate promoter regions, existed within DNase I-resistant chromatin domains. Thus, p53 activation of downstream target genes occurs without p53 inducing chromatin alterations detectable by DNase I accessibility at either the promoter or the response element. As such, these data support models of p53 activation that do not require extensive chromatin alterations to support cognate gene expression.
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PMID:Constitutive DNase I hypersensitivity of p53-regulated promoters. 1247 92

Epidermal keratinocytes undergo a process of terminal differentiation or cornification that in many aspects resembles apoptosis. It is characterized by the elimination of cell nuclei within the granular layer, whereas the cytoplasm is transformed into horn cells. Premature death of keratinocytes can be induced by extrinsic factors such as UV irradiation. We investigated the time-dependent expression of apoptotic marker proteins in the skin of one healthy human volunteer after irradiation with a fourfold minimal erythema dose (MED) of UVB. The data were supplemented by including healthy skin areas of biopsies from patients UVB-irradiated for therapeutic reasons. Punch biopsies were analysed by in situ end-labelling (ISEL) for DNA strand breaks and by immunohistochemistry for expression of p53, bcl-2, active caspase-3 and its proform, and deoxyribonuclease I (DNase I). Keratinocytes with pyknotic nuclei were first detected 6 h after UVB exposure, and apoptotic keratinocytes (sunburn cells) 12 h after exposure. These aggregated to sunburn bodies after 24 h. In control skin, nuclei with DNA strand breaks were only occasionally detected in the granular layer but 6 h after UVB irradiation in the spinous layer. After 12 h, many sunburn cells were ISEL-positive and positively stained for active caspase-3, P53, and DNase I. Morphometric evaluation of the immunohistochemical data demonstrated that maximal upregulation of P53, DNase I and activation of caspase-3 occurred 12 h after irradiation and in advance of the peak of apoptotic cell death reached after 24 h as verified by ISEL. In contrast, strong Bcl-2 immunostaining appeared restricted to presumed melanocytes and basal cells but was not increased after UVB irradiation.
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PMID:Premature keratinocyte death and expression of marker proteins of apoptosis in human skin after UVB exposure. 1275 86

Butyric acid, one of the short-chain fatty acids produced by microbial fermentation in the colon, exhibits antiproliferative activities in various cancer cell lines. The initial objective of the study was to assess whether the effect of sodium butyrate (NaB) on cell growth differed by p53 status of the cells. Four human colorectal adenocarcinoma cell lines were used: HT29 (p53 point mutation), Caco2 (p53 truncation), LS513 (p53 wild type), and Lovo (p53 wild type). NaB significantly inhibited cell growth in all four cell lines. NaB arrested HT29 and LS513 cells in G0/G1 and Caco2 and Lovo in G2-phase. A second objective was to determine whether NaB similarly affected the cyclin-dependent kinase inhibitor, p21WAF1/CIP1. In all cell lines, p21 mRNA levels were immediately elevated after NaB exposure, and p21 protein levels were increased within 6 h. NaB increased p21 promoter activity in both Caco2 and Lovo, suggesting p53 independence. NaB did not influence p21 mRNA stability. Although three DNase I hypersensitivity sites were identified in the region of the p21 gene, induction of p21 mRNA by NaB was not accompanied by relaxation of the chromatin in the region of the p21 gene.
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PMID:Sodium butyrate inhibits cell growth and stimulates p21WAF1/CIP1 protein in human colonic adenocarcinoma cells independently of p53 status. 1469 Jul 97

Burkitt's lymphoma is invariably associated with chromosomal translocations that juxtapose the c-myc proto-oncogene with regulatory elements of the immunoglobulin heavy (IgH) or light chain loci resulting in the deregulation of c-myc expression. However, the enhancer elements mediating c-myc deregulation in vivo remain largely unidentified. To investigate the role of the IgH 3'-enhancers in c-myc deregulation, we used gene targeting to generate knock-in mice in which four DNase I hypersensitive regions from the murine IgH 3'-region were integrated into the 5'-region of the c-myc locus. The IgH 3'-enhancers induced the up-regulation of c-myc expression specifically in B cells of IgH-3'-E-myc mice. After approximately 10 months, the mice developed a Burkitt-like B cell lymphoma with the phenotype of B220+, IgM+, and IgD(low). Analysis of immunoglobulin gene rearrangements indicated that the lymphoma cells were of clonal origin. The presence of a rapidly expanding population of B cells in the spleen and bone marrow of young knock-in mice at 2-4 months of age was observed. Premalignant splenic B cells of knock-in mice showed higher spontaneous and induced apoptosis; however, malignant B cells were more resistant to apoptosis. The p53-ARF-Mdm2 pathway was disabled in half of the lymphomas examined, in most cases through Mdm2 overexpression. Although c-myc expression was increased in premalignant B cells, the promoter shift from P2 to P1 was observed only in malignant B cells. Our studies demonstrate that the IgH 3'-enhancers play an important role in c-myc deregulation and B cell lymphomagenesis in vivo.
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PMID:Regulatory elements in the immunoglobulin heavy chain gene 3'-enhancers induce c-myc deregulation and lymphomagenesis in murine B cells. 1568 98

p63, a homolog of the tumor suppressor p53, plays an important role in the formation of stratified epithelium such as those in the epidermis of the skin. The p63 gene gives rise to multiple functionally distinct protein isoforms, including the DeltaNp63 class of isoforms, which lacks the N-terminal transactivation domain and is synthesized from an internal promoter. DeltaNp63 proteins are the predominant isoforms expressed in keratinocytes and are thought to be important for maintenance of the proliferative capacity of these cells. Here, we have examined the transcriptional control mechanisms that govern the expression DeltaNp63 in keratinocytes. We first performed DNase I hypersensitive site mapping and demonstrated that the promoter region of DeltaNp63 is in open chromatin state in keratinocytes. To identify the cis-elements that regulate DeltaNp63, we have performed transient transfection assays in keratinocytes with several DeltaNp63 promoter constructs. This identified a short evolutionarily conserved fragment that harbors most of the transcriptional activity of the DeltaNp63 promoter. Biochemical studies of this element have revealed critical roles for CCAAT-box-binding factor (CBF/NF-Y) and Sp1/Sp3 family of proteins. In addition, our data suggest that DeltaNp63 is recruited to and can activate its own promoter, possibly through protein-protein interactions, thus providing an auto-regulatory loop of self-regulation. These studies support the notion that unique and distinct pathways control the expression of individual p53 family members and their various isoforms.
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PMID:Defining the regulatory elements in the proximal promoter of DeltaNp63 in keratinocytes: Potential roles for Sp1/Sp3, NF-Y, and p63. 1664 95

In mammals, small multigene families generate spliceosomal U snRNAs that are nearly as abundant as rRNA. Using the tandemly repeated human U2 genes as a model, we show by footprinting with DNase I and permanganate that nearly all sequences between the enhancer-like distal sequence element and the initiation site are protected during interphase whereas the upstream half of the U2 snRNA coding region is exposed. We also show by chromatin immunoprecipitation that the SNAPc complex, which binds the TATA-like proximal sequence element, is removed at metaphase but remains bound under conditions that induce locus-specific metaphase fragility of the U2 genes, such as loss of CSB, BRCA1, or BRCA2 function, treatment with actinomycin D, or overexpression of the tetrameric p53 C terminus. We propose that the U2 snRNA promoter establishes a persistently open state to facilitate rapid reinitiation and perhaps also to bypass TFIIH-dependent promoter melting; this open state would then be disassembled to allow metaphase chromatin condensation.
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PMID:Human U2 snRNA genes exhibit a persistently open transcriptional state and promoter disassembly at metaphase. 1837 97

Many genes involved in cell cycle control have promoters that bind the heterotrimeric transcription factor NF-Y. Several minor-groove binding drugs have been shown to block interactions of transcription factors with cognate DNA-binding sequences. We showed previously that noncovalent minor-groove binding agents block interactions of NF-Y with the promoter of topoisomerase IIalpha (topo IIalpha). In this study, we investigated the ability of GWL-78, a pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugate, to inhibit the binding of NF-Y to DNA. Electrophoretic mobility shift assays showed that GWL-78 could displace NF-Y bound to several CCAAT motifs within promoters of genes involved in cell cycle progression. DNase I footprinting of the topo IIalpha promoter confirmed binding of GWL-78 to AT-rich sequences corresponding to the preferred binding site of NF-Y. Incubation with GWL-78 resulted in displacement of NF-Y binding to DNA. Chromatin immunoprecipitation assays on the topo IIalpha promoter showed that GWL-78 was able to enter the nucleus and interact with specific DNA sequences. Treatment of NIH3T3 cells with GWL-78 resulted in a block of cell cycle progression, which did not involve activation of p53. Thus, agents such as GWL-78 may be useful in modulating transcription and blocking cellular proliferation.
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PMID:Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78. 1848 19

The glutathione S-transferase P1 (GSTP1) is involved in multiple cellular functions, including phase II metabolism, stress response, signaling, and apoptosis. The mechanisms underlying the significantly high GSTP1 expression in many human tumors are, however, currently not well understood. We report here that the GSTP1 gene is a heretofore unrecognized downstream transcriptional target of the tumor suppressor p53. We identified a p53-binding motif comprising two consecutive half-sites located in intron 4 of the GSTP1 gene and is highly homologous to consensus p53-binding motifs in other p53-responsive genes. Using a combination of electrophoretic mobility shift assay and DNase I footprinting analyses, we showed that wild-type p53 protein binds to the GSTP1 p53 motif and luciferase reporter assays showed the motif to be transcriptionally functional in human tumor cells. In a temperature-sensitive p53-mutant cells, levels of both p21/WAF1 and GSTP1 gene transcripts increased time dependently when cells were switched from the inactive mutant state to the wild-type p53 state. Small interfering RNA-mediated reduction of p53 expression resulted in a specific decrease in GSTP1 expression and in tumor cells with mutated p53; adenovirally mediated expression of wild-type p53 increased GSTP1 expression significantly. In a panel of early-passage brain tumor cultures from patients, high levels of GSTP1 transcripts and protein were associated with wild-type p53 and, conversely, low GSTP1 levels with mutant p53. p53 expression knockdown by small interfering RNA increased cisplatin sensitivity. The ability of wild-type p53 to transcriptionally activate the human GSTP1 gene defines a novel mechanism of protecting the genome and, potentially, of tumor drug resistance.
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PMID:Identification and functional characterization of the human glutathione S-transferase P1 gene as a novel transcriptional target of the p53 tumor suppressor gene. 1850 28


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