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 E6 protein of human papillomavirus (HPV) type 16 displays a number of activities when transfected into cultured cells, including transcriptional activation of several viral promoters and targeting of p53 for degradation. HPV 16E6 was found to function as a transcriptional repressor of the moloney murine leukemia virus long terminal repeat and the cytomegalovirus immediate early promoter. Although the degree of transcriptional repression was low, a dose-dependent two- to threefold decrease in promoter activity was consistently seen in cells expressing 16E6. HPV 16E6-dependent transcriptional repression was observed in C33a cells, which express mutant p53, and in Saos-2 cells, which lack p53. These results indicate that 16E6-dependent repression of promoter activity is unlikely to be mediated by p53.
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PMID:The E6 protein of human papillomavirus type 16 functions as a transcriptional repressor in a mechanism independent of the tumor suppressor protein, p53. 797 61

Many DNA tumor viruses express a protein that inhibits transcriptional activation by the tumor-suppressing transcription factor p53. We report that adenovirus E1B 55K represses p53-mediated activation by a mechanism not described previously. E1B 55K binds p53 without displacing it from its DNA-binding site. A fusion of E1B 55K to the GAL4 DNA-binding domain represses transcription from a variety of promoters with engineered upstream GAL4-binding sites. Mutations within E1B 55K that interfere with its transforming activity and its ability to inhibit p53-mediated trans-activation also interfere with transcriptional repression by the GAL4-55K fusion. These results demonstrate that E1B 55K functions as a direct transcriptional repressor that is targeted to p53-responsive genes by binding to p53.
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PMID:Adenovirus E1B oncoprotein tethers a transcriptional repression domain to p53. 829 38

WT1 is a tumor-suppressor gene expressed in the developing kidney, whose inactivation leads to the development of Wilms tumor, a pediatric kidney cancer. WT1 encodes a transcription factor which binds to the EGR1 consensus sequence, mediating transcriptional repression. We now demonstrate that p53, the product of a tumor-suppressor gene with ubiquitous expression, physically associates with WT1 in transfected cells. The interaction between WT1 and p53 modulates their ability to transactivate their respective targets. In the absence of p53, WT1 acts as a potent transcriptional activator of the early growth response gene 1 (EGR1) site, rather than a transcriptional repressor. In contrast, WT1 exerts a cooperative effect on p53, enhancing its ability to transactivate the muscle creatine kinase promoter.
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PMID:Physical and functional interaction between WT1 and p53 proteins. 838 68

Cross-linking membrane Ig (mIg) on B cells stimulates tyrosine phosphorylation of proteins involved in signal transduction including the mIg-associated proteins Ig-alpha and Ig-beta, the tyrosine kinases p53/p56lyn, p55blk, p59fyn, and PTK72, phosphatidylinositol 3-kinase, phospholipase C gamma 1 and gamma 2, and the mitogen-activated protein kinase. We now show that the p21ras GTPase-activating protein (GAP) is also a substrate for mIg-activated tyrosine kinases. p21ras is a key regulator of cell growth and GAP may act as both a regulator of p21ras activity and as a downstream effector of p21ras. We found that mIg cross-linking caused a rapid increase in tyrosine phosphorylation of GAP in the immature B cell line WEHI-231, the mature B cell lines BAL 17 and Daudi, and the IgG-bearing B cell line A20. In fibroblasts, tyrosine kinase activation causes GAP to associate with two other tyrosine-phosphorylated proteins, p62 and p190, which have homologies to an RNA-binding protein and a transcriptional repressor, respectively. Similarly, mlg cross-linking induced the association of GAP with a 62-kDa tyrosine-phosphorylated protein in BAL 17, WEHI-231, and Daudi cells. Anti-Ig treatment also increased the amount of a 190-kDa tyrosine-phosphorylated protein associated with GAP in WEHI-231 and Daudi cells. After separation by SDS-PAGE and transfer to nitrocellulose, the tyrosine-phosphorylated p62 and p190 present in anti-GAP immunoprecipitates from B cells were capable of binding radiolabeled recombinant GAP, as previously reported for the GAP-associated p62 and p190 from fibroblasts. The amount of p62 that could be detected in this way after immunoprecipitation with antiphosphotyrosine antibodies was much greater from anti-IgM-treated BAL 17 cells than from unstimulated BAL 17 cells. This probably reflects anti-Ig-induced tyrosine phosphorylation of p62. In any case, GAP, p62, and/or p190 may be involved in signal transduction by mIg in B cells.
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PMID:Targets of B lymphocyte antigen receptor signal transduction include the p21ras GTPase-activating protein (GAP) and two GAP-associated proteins. 841 71

The IE2 gene of human cytomegalovirus has been implicated in the development of coronary restenosis, and the gene product appears to inhibit p53-dependent transactivation. Here we describe an analysis of the IE2-p53 interaction. Repression of p53 function by IE2 requires two separable domains of IE2. The N terminus of IE2 interacts with p53. IE2 has little effect on the ability of p53 to bind specific DNA sequences. Reduction of the transactivation activity of p53 is caused by a transcriptional repression function contributed by the C-terminal domain of IE2. These findings suggest that IE2 may function as a transcriptional repressor, which is recruited to p53's target genes by interacting with p53.
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PMID:Human cytomegalovirus immediate-early protein IE2 tethers a transcriptional repression domain to p53. 863 58

The Gfi-1 protooncogene encodes a nuclear zinc-finger protein that carries a novel repressor domain, SNAG, and functions as a position- and orientation-independent active transcriptional repressor. The Gfi-1 repressor allows interleukin 2 (IL-2)-dependent T cells to escape G1 arrest induced by IL-2 withdrawal in culture and collaborates with c-myc and pim-1 for the induction of retrovirus-induced lymphomas in animals. Here we show that overexpression of Gfi-1 also inhibits cell death induced by cultivation of IL-2-dependent T-cell lines in IL-2-deficient media. Similarly, induction of Gfi-1 in primary thymocytes from mice carrying a metal-inducible Gfi-1 transgene inhibits cell death induced by cultivation in vitro. The protein and mRNA levels of the proapoptotic regulator Bax are down-regulated by Gfi-1 in both immortalized T-cell lines and primary transgenic thymocytes. The repression is direct and depends on several Gfi-1-binding sites in the p53-inducible Bax promoter. In addition to Bax, Gfi-1 also represses Bak, another apoptosis-promoting member of the Bcl-2 gene family. Therefore, Gfi-1 may inhibit apoptosis by means of its repression of multiple proapoptotic regulators. The antiapoptotic properties of Gfi-1 provide a potential explanation for its strong collaboration with c-myc during oncogenesis.
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PMID:The Gfi-1 protooncoprotein represses Bax expression and inhibits T-cell death. 896 93

DNA topoisomerase II (topo II) is an essential nuclear enzyme involved in major cellular functions such as DNA replication, transcription, recombination, and mitosis. While an elevated level of topo II alpha is associated with cell proliferation, wild-type (wt) p53 inhibits the expression of various growth-stimulatory genes. To determine if p53 downregulates topo II alpha gene expression, a murine cell line, (10)1val, that expresses a temperature-sensitive p53 was utilized. The (10)1val cells had significantly lower levels of topo II alpha mRNA and protein following incubation for 24 h at 32 degrees C (p53 with wt conformation) than at 39 degrees C (p53 with mutant conformation). The effect of p53 on the human topo II alpha gene promoter was determined by using luciferase reporter plasmids containing varying lengths of the topo II alpha promoter transiently cotransfected into p53-deficient (10)1 cells together with wt or mutant p53 expression plasmids. Transcription from the full-length (bp -557 to +90) topo II alpha promoter was decreased 15-fold by wt p53 in a concentration-dependent manner, whereas mutant p53 exerted much weaker inhibition. Consecutive deletion of the five inverted CCAAT elements (ICEs) from the topo II alpha promoter reduced both the basal promoter activity and wt p53-induced suppression. Transcription of the minimal promoter (-32 to +90), which contains no ICE, was slightly stimulated by wt or mutant p53 expression. When point mutations were introduced into the most proximal ICE (-68), the inhibitory effect of wt p53 was alleviated and stimulation of topo II alpha expression resulted. Our study suggests that wt p53 functions as a transcriptional repressor of topo II alpha gene expression, possibly through a functional interaction with specific ICEs. Inactivation of wt p53 may reduce normal regulatory suppression of topo II alpha and contribute to abortive cell cycle checkpoints, accelerated cell proliferation, and alterations in genomic stability associated with neoplasia.
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PMID:Inhibition of DNA topoisomerase II alpha gene expression by the p53 tumor suppressor. 897 19

One reason for the failure of chemotherapy is the overexpression of the multidrug resistance gene, MDR1. The product of this gene is the multidrug transporter P-glycoprotein, an ATP-dependent pump that extrudes drugs from the cytoplasm. Some tumors inherently express P-glycoprotein, whereas others acquire the ability to do so after exposure to certain chemotherapeutic agents, often by the mechanism of gene amplification. Classical Wilms' tumors (nephroblastoma) typically respond to therapy and have a good prognosis. On the contrary, anaplastic Wilms' tumors are generally refractory to chemotherapy. These anaplastic variants are rare (4.5% of all Wilms' tumors reported in the United States), aggressive, and often fatal forms of tumor, which are commonly thought to result from the progression of classical Wilms' tumors. To investigate the basis for this differential response to therapy, we examined a number of classical and anaplastic Wilms' tumors for the expression of the MDR1 gene by immunohistochemical and mRNA analysis. Classical Wilms' tumors consistently did not express P-glycoprotein except in areas of tubular differentiation, as in normal kidney. Similarly, two of three anaplastic tumors failed to show P-glycoprotein expression. In contrast, cultured cells derived from a third anaplastic tumor, W4, exhibited strong P-glycoprotein expression and were drug resistant in vitro. Southern analysis revealed that W4 cells contained a single copy of the MDR1 gene per haploid genome similar to normal cells, demonstrating that the overexpression of MDR1 was not caused by gene amplification. Transcriptional activation of the MDR1 gene would be in keeping with the concept that p53 might act as a transcriptional repressor of the MDR1 gene.
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PMID:Anaplasia and drug selection-independent overexpression of the multidrug resistance gene, MDR1, in Wilms' tumor. 912 18

The Wilms tumor gene WT1 has been implicated in the early development of the kidney. Mutations in WT1 are found in a small fraction of Wilms tumor, a pediatric nephroblastoma, and Denys-Drash syndrome, characterized by genitourinary abnormalities. The WT1 gene product functions as a transcriptional repressor of growth factor-related genes. The kidney is one of the major sites of insulin action in vivo and expresses high levels of insulin receptors (IR). IR expression has been detected during early embryogenesis, suggesting that it may play a role in development. We investigated whether two WT1 splice variants lacking or including a three-amino-acid (KTS) insertion between the third and fourth zinc finger in the DNA-binding domain could repress the IR promoter in vitro. We show that the +KTS variant effectively represses promoter activity under all conditions tested but the -KTS variant was only able to repress in the presence of cotransfected C/EBP beta or a dominant-negative p53 mutation. Deletional mapping indicated that distinct regions of the IR promoter mediated the effects of the two isoforms and DNaseI footprint analysis identified potential WT1 binding sites within these regions.
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PMID:Differential effects of Wilms tumor WT1 splice variants on the insulin receptor promoter. 944 65


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