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)

Wilms' tumor, or nephroblastoma, is a developmental malignancy of the kidney that affects approximately 1 in 10,000 children between 1 and 6 years of age. Typically, the histology of nephroblastoma reveals a disorganized renal developmental process showing blastema and epithelia randomly interspersed in varying amounts of stroma. This developmental disruption is associated with the loss of function of the tumor suppressor gene WT-1. This gene, located on chromosome 11 at band p13, codes for a zinc finger protein that may act as a transcriptional repressor. Familial cases of Wilms' tumor fit Knudson's "two hit" model, according to which a germ line mutation of one WT-1 allele predisposes to the tumor while an additional somatic mutation of the other allele causes malignant transformation. Originally proposed for retinoblastoma, this model defines the nature of the tumor suppressor gene as a gene that is tumorigenic when inactivated. However, not all Wilms' tumor cases fit this model because the majority of Wilms' tumors do not show a mutation of WT-1. For Wilms' tumor, the loss of tumor suppression appears to be more complex than for retinoblastoma. Some of the mechanisms recognized to date involve dominant negative WT-1 mutations, interaction of the WT-1 gene product with other mutated transcription factors such as p53, loss of imprinting, and mutations of other tumor suppressor genes at 11p15 or other loci. Although classic Wilms' tumor is associated with good prognosis (85% survival), its anaplastic form is often fatal. Despite the plethora of knowledge gained in recent years, Wilms' tumor remains the center of attention for further investigation because it offers opportunities for studying normal kidney development, for understanding the molecular basis for clinically important anaplastic forms, as well as for elucidating the molecular mechanisms of tumor suppressor genes. To facilitate this task, Wilms' tumor heterotransplants have been established in nude mice. This provides an indefinite source of tumor tissue and a means to test their growth properties in response to drug treatments or molecular genetic manipulations. Furthermore, the establishment of stable Wilms' tumor cell lines is essential to investigating further the molecular basis of tumorigenesis using recombinant DNA technology.
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PMID:Nephroblastoma (Wilms' tumor): a model system of aberrant renal development. 780 6

The mdm2 gene encodes a zinc finger protein that negatively regulates p53 function by binding and masking the p53 transcriptional activation domain. Two different promoters control expression of mdm2, one of which is also transactivated by p53. We cloned and characterized the mdm2 gene from a murine 129 library. It contained at least 12 exons and spanned approximately 25 kb of DNA. Sequencing of the mdm2 gene revealed three nucleotide differences that resulted in amino acid substitutions in the previously published mdm2 sequence. Sequencing of normal BalbC/J DNA and the original cosmid clone isolated from the 3T3DM cell line revealed that they are identical, suggesting that the published sequence is in error at these three positions. In addition, we analyzed the expression pattern of mdm2 and found ubiquitous low-level expression throughout embryo development and in adult tissues. Analysis of mRNA from numerous tissues for several mdm2 spliced variants that had been identified in the transformed 3T3DM cell line revealed that these variants could not be detected in the developing embryo or in adult tissues.
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PMID:The organization and expression of the mdm2 gene. 866 Sep 94

The biological effects of the p53 tumor suppressor protein are elicited, at least in part, through sequence-specific transactivation of a battery of target genes. The differential display method was employed towards identifying additional p53 target genes, with emphasis on genes whose induction may contribute to p53-mediated apoptosis. We report here the cloning of a novel p53-inducible gene, designated PAG608. PAG608 transcripts are induced by DNA damage in a p53-dependent manner. PAG608 encodes a nuclear zinc finger protein, which appears to localize preferentially to nucleoli when expressed at moderate levels in transfected cells. Transient overexpression of PAG608 in human tumor-derived cells leads to distinctive changes in nuclear morphology, and can promote apoptosis. Together with additional p53 target genes, PAG608 may therefore play a role in mediating the biological activities of p53.
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PMID:A novel p53-inducible gene, PAG608, encodes a nuclear zinc finger protein whose overexpression promotes apoptosis. 925 Jun 82

We previously reported the identification of mZac, a novel mouse zinc finger protein that shared with p53 the ability to regulate concomitantly apoptosis and cell cycle progression. We describe here the isolation, chromosomal localization, and functional in vitro characterization of its human homolog. hZAC is a widely expressed zinc finger protein that reveals transactivation and DNA-binding activity. hZAC inhibits tumor cell growth through induction of apoptotic cell death and G1 arrest. Thus hZAC, like its mouse counterpart, displays antiproliferative properties through pathways known to be central to the activity of p53. We mapped hZAC on chromosome 6q24-q25, a region frequently deleted in many solid tumors. Indeed, allelic loss at 6q24-q25 has been shown in breast and ovary cancers, melanomas, astrocytomas, and renal cell carcinomas. Furthermore, Abdollahi et al. [Abdollahi, A., Godwin, A. K., Miller, P. D., Getts, L. A., Schultz, D. C., Tagushi, T., Testa, J. R. & Hamilton, T. C. (1997) Cancer Res. 57, 2029-2034] recently isolated ZAC through its loss of expression in a surface epithelial ovary tumor model and accordingly named it Lot for "lost on transformation." In view of these observations, the functional properties we report here provide further arguments to consider hZAC as a tumor suppressor gene candidate.
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PMID:hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer. 967 65

Poly(ADP-ribose) polymerase (PARP) is a DNA binding zinc finger protein that catalyzes the transfer of ADP-ribose residues from NAD(+) to itself and different chromatin constituents, forming branched ADP-ribose polymers. The enzymatic activity of PARP is induced upon DNA damage and the PARP protein is cleaved during apoptosis, which suggested a role of PARP in DNA repair and DNA damage-induced cell death. We have generated transgenic mice that lack PARP activity in thymocytes owing to the targeted expression of a dominant negative form of PARP. In the presence of single-strand DNA breaks, the absence of PARP activity correlated with a strongly increased rate of apoptosis compared to cells with intact PARP activity. We found that blockage of PARP activity leads to a drastic increase of p53 expression and activity after DNA damage and correlates with an accelerated onset of Bax expression. DNA repair is almost completely blocked in PARP-deficient thymocytes regardless of p53 status. We found the same increased susceptibility to apoptosis in PARP null mice, a similar inhibition of DNA repair kinetics, and the same upregulation of p53 in response to DNA damage. Thus, based on two different experimental in vivo models, we identify a direct, p53-independent, functional connection between poly(ADP-ribosyl)ation and the DNA excision repair machinery. Furthermore, we propose a p53-dependent link between PARP activity and DNA damage-induced cell death.
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PMID:DNA excision repair and DNA damage-induced apoptosis are linked to Poly(ADP-ribosyl)ation but have different requirements for p53. 1095 67

The EB-1 cell line is a stable transfectant of EB, a p53 null colon carcinoma cell line, with an inducible promoter controlling expression of a wild type p53 cDNA. The induced p53 is transcriptionally active and gives rise to apoptosis in these cells. Using this cellular model for presence or absence of the transcription factor p53 and transactivated genes, the Suppression Subtractive Hybridization (SSH) technique permitted the isolation of 17 mRNA candidates (GIPs-Genes induced by p53), whose expression appears to be p53-dependent. Identity has been established for nine of the 17 isolated candidates. These are HGFL/MSP, Zap-70, APOBEC2, Ponsin/SH3P12/CAP/FLAF2, CDCrel2b/H5/Pnutl2, IgG, lats 2, cytokeratin 15 and PIG-3 (quinone oxidoreductase). The latter gene is the only GIP previously demonstrated to be p53 regulated. Of the eight remaining GIPs, six correspond to Unigene clusters. One candidate, GIP #1, is significantly homologous (72% identity) to a chicken zinc finger protein, CTCF, which binds to insulator elements and thus attenuates enhancer cross-talk between physically adjacent promoters. The p53-dependent expression of GIPs was confirmed by dependence of expression upon induction of wt p53 expression in the EB-1 cellular model and by up-regulation following activation of an endogenous wt p53 by treatment with adriamycin. Oncogene (2000) 19, 3978 - 3987.
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PMID:Isolation and characterization of sixteen novel p53 response genes. 1096 54

X-linked inhibitor of apoptosis protein (XIAP) is a potent modulator of programmed cell death. XIAP specifically binds and inhibits the function of caspase-3, -7, and -9, key effector proteases of apoptosis. We recently isolated, by yeast two-hybrid screening, a novel 34-kDa zinc finger protein, XIAP-associated factor 1 (XAF1). Both the caspase inhibiting and the anti-apoptotic abilities of XIAP were found to be blocked by overexpressed XAF1. Here, we report the isolation and characterization of the human XAF1 gene. The xaf1 gene consists of seven exons spanning 18 kb. Fluorescence in situ hybridization analysis localized the xaf1 locus at 17p13.2, telomeric to the p53 gene. The xaf1 locus was further refined to YAC 746C10, approximately 3 cM distal to TP53. Microsatellite analysis of the xaf1 locus using the NCI 60 cell line panel revealed significantly decreased heterozygosity at all three polymorphic markers tested, suggesting that allelic loss of the xaf1 gene is prevalent in cancer cell lines. Examination of the same NCI cell line panel for xaf1 RNA expression demonstrated that cancer cell lines exhibited very low levels of mRNA relative to normal human liver. In contrast, XIAP mRNA levels were relatively high in the majority of cancer cell lines tested. We propose that a high level of XIAP to XAF1 expression in cancer cells may provide a survival advantage through the relative increase of XIAP anti-apoptotic function.
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PMID:Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. 1108 68

The transition from preimplantation to postimplantation development leads to the initiation of complex cellular differentiation and morphogenetic movements, a dramatic decrease in cell cycle length, and a commensurate increase in the size of the embryo. Accompanying these changes is the need for the transfer of nutrients from the mother to the embryo and the elaboration of sophisticated genetic networks that monitor genomic integrity and the homeostatic control of cellular growth, differentiation, and programmed cell death. To determine the function of the murine zinc finger protein ZFR in these events, we generated mice carrying a null mutation in the gene encoding it. Homozygous mutant embryos form normal-appearing blastocysts that implant and initiate the process of gastrulation. Mutant embryos form mesoderm but they are delayed in their development and fail to form normal anterior embryonic structures. Loss of ZFR function leads to both an increase in programmed cell death and a decrease in mitotic index, especially in the region of the distal tip of the embryonic ectoderm. Mutant embryos also have an apparent reduction in apical vacuoles in the columnar visceral endoderm cells in the extraembryonic region. Together, these cellular phenotypes lead to a dramatic development delay and embryonic death by 8 to 9 days of gestation, which are independent of p53 function.
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PMID:Requirement for the murine zinc finger protein ZFR in perigastrulation growth and survival. 1128 66

In this review, we summarize design strategies for generating proteins with desired sequences such as long contiguous base pairs and diverse sequence specificities based on the nature of Cys(2)-His(2) zinc finger proteins. Recent progress towards artificial DNA binding proteins has been achieved by structure-based design processes and by selection strategies. Indeed, a multi-zinc finger protein with an 18 (or 27)-base pair address, and new zinc finger proteins for diverse DNA target sites (TATA-box and p53 binding site) have been created successfully. Such novel zinc finger proteins will probably be useful tools in molecular biology and potentially in human medicine.
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PMID:Design of novel zinc finger proteins: towards artificial control of specific gene expression. 1129 73

Experimental studies of complete mammalian genes and other genetic domains are impeded by the difficulty of introducing large DNA molecules into cells in culture. Previously we have shown that GST-Z2, a protein that contains three zinc fingers and a proline-rich multimerization domain from the polydactyl zinc finger protein RIP60 fused to glutathione S-transferase (GST), mediates DNA binding and looping in vitro. Atomic force microscopy showed that GST-Z2 is able to condense 130-150 kb bacterial artificial chromosomes (BACs) into protein-DNA complexes containing multiple DNA loops. Condensation of the DNA loops onto the Z2 protein-BAC DNA core complexes with cationic lipid resulted in particles that were readily transferred into multiple cell types in culture. Transfer of total genomic linear DNA containing amplified DHFR genes into DHFR(-) cells by GST-Z2 resulted in a 10-fold higher transformation rate than calcium phosphate co-precipitation. Chinese hamster ovarian cells transfected with a BAC containing the human TP53 gene locus expressed p53, showing native promoter elements are active after GST-Z2-mediated gene transfer. Because DNA condensation by GST-Z2 does not require the introduction of specific recognition sequences into the DNA substrate, condensation by the Z2 domain of RIP60 may be used in conjunction with a variety of other agents to provide a flexible and efficient non-viral platform for the delivery of large genes into mammalian cells.
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PMID:Condensation by DNA looping facilitates transfer of large DNA molecules into mammalian cells. 1132 83


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