Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wilms' tumor suppressor gene WT1 encodes a zinc finger transcription factor, whose expression inhibits the growth of the RM1 Wilms' tumor cell line. Transient transfection of WT1 constructs into 3T3 or 293 cells results in transcriptional repression of a number of cotransfected promoters containing the early growth response gene 1 consensus sequence. We now show that WT1 has properties of a transcriptional activator in RM1 cells, an effect that may be associated with the presence of a mutated p53 gene in these cells. Stable transfection of wild-type WT1 into RM1 cells results in induction of endogenous insulin-like growth factor 2 (IGF2) but not of other previously postulated WT1-target genes. The induction of IGF2 is dramatically enhanced by WT1 mutants encoding an altered transactivation domain. We conclude that IGF2 is a potentially physiological target gene for WT1 and that its induction may contribute to the growth-stimulating effects of WT1 variants.
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PMID:WT1 induces expression of insulin-like growth factor 2 in Wilms' tumor cells. 755 24

The earliest characterized events during induction of tubulogenesis in renal anlage include the condensation or compaction of metanephrogenic mesenchyme with the concurrent upregulation of WT1, the gene encoding the Wilms tumor transcriptional activator/suppressor. We report that basic fibroblast growth factor (FGF2) can mimic the early effects of an inductor tissue by promoting the condensation of mesenchyme and inhibiting the tissue degeneration associated with the absence of an inductor tissue. By in situ hybridization, FGF2 was also found to mediate the transcriptional activation of WT1 and of the hepatocyte growth factor receptor gene, c-met. Although FGF2 can induce these early events of renal tubulogenesis, it cannot promote the epithelial conversion associated with tubule formation in metanephrogenic mesenchyme. For this, an undefined factor(s) from pituitary extract in combination with FGF2 can cause tubule formation in uninduced mesenchyme. These findings support the concept that induction in kidney is a multiphasic process that is mediated by more than a single comprehensive inductive factor and that soluble molecules can mimic these inductive activities in isolated uninduced metanephrogenic mesenchyme.
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PMID:Basic fibroblast growth factor can mediate the early inductive events in renal development. 775 67

We report expression of the wt1 (Wilms' tumor) gene by cultured human melanoma cells. Using RNA polymerase chain reaction analysis, wt1 transcripts were detected in 7 of 9 melanoma cell lines but not in 5 normal melanocyte strains. In Northern blot analysis, steady-state wt1 mRNA levels were found in 2 of 4 melanoma lines but not in normal melanocytes. Sequence analysis of the wt1 cDNA expressed by melanoma cell line WM 902-B revealed the presence of 4 previously published splice variants but no evidence for mutations in the coding region. Previous work has shown that WT1 modulates transcription after binding to the early growth response (EGR)-1 sites present in the platelet-derived growth factor (PDGF)-A chain promoter; the PDGF-A chain gene is known to be expressed by various melanoma cell lines. Based on these findings, we studied the relationship of wt1 and PDGF-A chain gene expression in melanoma cell lines. Co-expression of the wt1 and the PDGF-A chain genes was observed in 2 melanoma cell lines with mutated p53 but not in 2 melanoma cell lines with wild-type p53; this result is consistent with a previous report showing that, in the context of absent or mutated p53, WT1 acts as a transcriptional activator, whereas in the presence of wild-type p53 it acts as a repressor.
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PMID:Expression of the wt1 Wilms' tumor gene by normal and malignant human melanocytes. 792 8

The human Wilms tumour suppressor gene, WT1, encodes a zinc-finger protein which can function as a transcriptional activator or suppressor. This study reports the analysis of the human WT1 gene promoter, and demonstrates that high levels of WT1 expression lead to autosuppression of the WT1 promoter. Deletion analyses of the promoter region implicate sequences 5' and 3' of the transcriptional start site as being crucial in WT1 autosuppression. Loss or alteration of this function of WT1 may be important in tumourigenesis.
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PMID:Autoregulation of the human WT1 gene promoter. 804 5

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

The tumour suppressor gene WT1 encodes a transcription factor expressed in tissues of the genito-urinary system. Inactivation of this gene is associated with the development of Wilms tumour a pediatric kidney cancer. We show that WT1 is also expressed at high levels in many supportive structures of mesodermal origin in the mouse. We also describe a case of adult human mesothelioma, a tumour derived from the peritoneal lining, that contains a homozygous point mutation within WT1. This mutation, within the putative transactivation domain, converts the protein from a transcriptional repressor of its target sequence to a transcriptional activator. The role of WT1 in normal development thus extends to diverse structures derived from embryonic mesoderm and disruption of WT1 function contributes to the onset of adult, as well as pediatric, tumours.
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PMID:The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma. 840 92

The putative Wilms tumor suppressor gene, wt1, encodes a zinc-finger protein that binds to the DNA sequence 5'-GCGGGGGCG-3'. We previously reported that WT1 has separable domains that function either to activate or suppress transcription. We now have identified a second WT1 binding sequence (5'-TCCTCCTCCTCCTCTCC-3') 3' to the transcription initiation site of the platelet-derived growth factor A-chain gene by DNase I footprinting and gel mobility shift assays. WT1 requires both 5' and 3' binding sites for transcriptional suppression; however, WT1 functions as a transcriptional activator when it binds to either the 5' or 3' site alone. This second WT1 binding sequence functions equally well as the previously identified 5'-GCGGGGGCG-3' sequence when analyzed in transient transfection assays. A core DNA sequence recognized by WT1 was defined by using related synthetic oligonucleotides. We also identified sequences similar to the WT1 binding site within the promoter regions of five other growth-related genes and demonstrated that each of these sequences also binds WT1 in gel mobility shift assays. These results thus identify a second WT1 binding site and suggest that additional growth-related genes may be transcriptionally influenced by WT1.
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PMID:A second transcriptionally active DNA-binding site for the Wilms tumor gene product, WT1. 841 28

We recently reported that the putative tumor suppressor gene product WT1 interacts with a 5'-flanking DNA sequence 5'-GCGGGGGCG-3' within the platelet-derived growth factor A-chain gene and abolishes its promoter activity, suggesting that WT1 functions as a transcriptional suppressor of the platelet-derived growth factor A-chain gene. We now show that WT1 functions also as a transcriptional activator. Using chimeric reporter plasmids, we demonstrated that WT1 requires both 5' and 3' binding sites relative to transcription start site for transcriptional repression; however, when WT1 binds to either the 5' or the 3' site alone, WT1 functions to activate transcription. We truncated the wt1 gene and established that amino acid residues 84-179 are required for transcriptional suppression, whereas amino acid residues 180-294 contain a domain that mediates transcriptional activation. These results establish that WT1 has regulatory domains that function either to activate or suppress transcription and suggest the possibility that WT1 functions as an activator and not as a suppressor of selected gene transcription.
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PMID:The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains. 848 16

The product of the p53 tumor suppressor gene has a well-documented activity as a transcriptional activator, and several studies indicate that this function is at least in part essential for the ability of p53 to suppress cellular proliferation. However, there is growing evidence that some activities of wild-type p53 may be independent of its trans-activation function; in fact, recent investigations have indicated that the transcriptional repression function of p53, rather than its trans-activation function, may be influential in p53-mediated apoptosis. The focus of this study has been on the identification of genes that exhibit decreased expression during p53-dependent apoptosis, and therefore represent potential p53-repressed genes influential in programmed cell death. This report identifies the gene encoding the microtubule-associated protein MAP4 as one whose mRNA and protein expression decrease in cells following induction of wild-type p53. Importantly, decreased MAP4 expression following p53 induction can be inhibited by molecules that prevent p53-mediated transcriptional repression and apoptosis, such as the adenovirus E1B-19K protein and the Wilms tumor gene product WT1. Additionally, overexpression of MAP4 in cells induced to undergo p53-dependent apoptosis significantly delays this process, indicating that the negative regulation of this gene by p53 may be influential in the rapid progression of apoptosis.
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PMID:Wild-type p53 negatively regulates the expression of a microtubule-associated protein. 895 98

We performed deletion analysis of WT1-reporter constructs containing up to 24 kilobases of 5'-flanking and first intron WT1 sequence in stably transfected cultured cells as an unbiased approach to identify cis elements critical for WT1 transcription. Although not a tissue-specific element, a proximate 9-base pair CTC repeat accounted for approximately 80% of WT1 transcription in this assay. Enhancer activity of the element and mutated versions correlated completely with their ability to form a DNA-protein complex in gel shifts. Antibody supershift, oligonucleotide competition, and Southwestern studies indicated that the CTC-binding factor is the transcriptional activator Sp1. Sp1 binds the CTC repeat with an affinity, KD = 0.37 nM, at least as high as the consensus GC box. Similar CTC repeats are found in promoters of other growth-related genes. Because Sp1 is important for WT1 expression, we examined Sp1 immunohistochemistry in fetal and adult kidney. In a pattern that precedes that of WT1 message, Sp1 immunostaining was highest in uninduced mesenchyme, early tubules, developing podocytes, and mature glomeruli, but was minimal in mature proximal tubules. This work suggests abundant Sp1 may be a prerequisite for WT1 expression, and that Sp1 may have a wider role in nephrogenesis.
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PMID:Sp1 is a critical regulator of the Wilms' tumor-1 gene. 900 35


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