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)

Beta-catenin is a key mediator of the Wnt pathway, which plays a critical role in embryogenesis and oncogenesis. As a transcriptional activator, beta-catenin binds the transcription factors, T-cell factor and lymphoid enhancer factor, and regulates gene expression in response to Wnt signaling. Abnormal activation of beta-catenin has been linked to various types of cancer. In a yeast two-hybrid screen, we identified the four and a half of LIM-only protein 2 (FHL2) as a novel beta-catenin-interacting protein. Here we show specific interaction of FHL2 with beta-catenin, which requires the intact structure of FHL2 and armadillo repeats 1-9 of beta-catenin. FHL2 cooperated with beta-catenin to activate T-cell factor/lymphoid enhancer factor-dependent transcription from a synthetic reporter and the cyclin D1 and interleukin-8 promoters in kidney and colon cell lines. In contrast, coexpression of beta-catenin and FHL2 had no synergistic effect on androgen receptor-mediated transcription, whereas each of these two coactivators independently stimulated AR transcriptional activity. Thus, the ability of FHL2 to stimulate the trans-activating function of beta-catenin might be dependent on the promoter context. The detection of increased FHL2 expression in hepatoblastoma, a liver tumor harboring frequent beta-catenin mutations, suggests that FHL2 might enforce beta-catenin transactivation activity in cancer cells. These findings reveal a new function of the LIM coactivator FHL2 in transcriptional activation of Wnt-responsive genes.
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PMID:Identification of the LIM protein FHL2 as a coactivator of beta-catenin. 1246 81

The mammalian protein DEK has been implicated in multiple cellular processes, including transcriptional regulation, mRNA processing, and chromatin remodeling, and is associated with a number of clinical autoimmune and neoplastic conditions. The connection between DEK and cancer exists at multiple levels: (a) the t(6;9) chromosomal translocation that characterizes a subtype of acute myelogenous leukemia cases results in the formation of a DEK-CAN fusion oncoprotein; (b) a fragment of dek cDNA is capable of partially reversing the radiation-sensitive phenotype of fibroblasts cultured from ataxia-telangiectasia patients; and (c) increased levels of dek mRNA have been found to be associated with hepatocellular carcinoma, glioblastoma, and melanoma. Despite the growing list of cancer subtypes with a connection to DEK, the factors that mediate its expression have yet to be characterized. Here we undertake the analysis of DEK regulation by mapping the discrete elements within the proximal promoter that are responsible for constitutive transcription of dek in transformed cells. We find that functional elements include an inverted CCAAT box and a YY1 consensus binding site, and the introduction of point mutations into these sites markedly diminishes transcriptional activity. In addition, we identify the transcriptional activator NF-Y as a member of the CCAAT-binding complex, and verify binding of the transcription factor YY1 at its consensus site in the dek promoter. The discovery of NF-Y and YY1 as regulatory determinants of DEK expression is consistent with the well-documented roles of these two factors in cellular proliferation and transformation.
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PMID:YY1 and NF-Y binding sites regulate the transcriptional activity of the dek and dek-can promoter. 1248 38

ZBP-89 (ZNF148) is a Zinc finger Binding Protein of 89 kDa that binds GC-rich DNA elements. Originally, it was expression cloned using a DNA element mediating EGF regulation of the gastrin promoter. ZBP-89 functions as both a transcriptional activator and repressor. A variety of extracellular regulators including TGFbeta, retinoic acid and butyrate stimulate ZBP-89 gene expression. Butyrate activation of p21WAF1 is potentiated by ZBP-89 through the recruitment of the co-activator p300, while chronic stimulation by butyrate increases ZBP-89 gene expression correlating with cell differentiation. ZBP-89 stimulates growth arrest and apoptosis through its ability to bind the p21WAF1 promoter or its ability to form protein-protein interactions with p53. ZBP-89 protein is elevated in a variety of gastrointestinal cancers as well as the pancreas. In particular, ZBP-89 is normally expressed in pancreatic islets and ducts and in about 30% of pancreatic adenocarcinomas.
Int J Gastrointest Cancer 2002
PMID:Regulation of epithelial cell growth by ZBP-89: potential relevance in pancreatic cancer. 1262 18

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti- carbonic anhydrase, diuretic, hypoglycemic and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial antitumor activity in vitro and in vivo. Although they have a common chemical motif of aromatic/heterocyclic or amino acid sulfonamide, there are a variety of mechanisms of their antitumor action, such as carbonic anhydrase inhibition, cell cycle perturbation in the G1 phase, disruption of microtubule assembly, functional suppression of the transcriptional activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition among others. Some of these compounds selected via elaborate preclinical screenings or obtained through computer-based drug design, are currently being evaluated in clinical trials. The review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed as effective tumor cell growth inhibitors, or for the treatment of different types of cancer. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Thus, at least two clinically used HIV protease inhibitors possess sulfonamide moieties in their molecules, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with less toxicity or activity against drug-resistant viruses. Several non nucleoside HIV reverse transcriptase or HIV integrase inhibitors containing sulfonamido groups were also reported. Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. Most compounds with antiviral activity possessing this mechanism of action incorporate in their molecules primary sulfonamide groups. Some small molecule chemokine antagonists acting as HIV entry inhibitors also possess sulfonamide functionalities in their scaffold.
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PMID:Anticancer and antiviral sulfonamides. 1267 81

The tumor suppressor p53 is the most frequently mutated gene in human tumors. In response to DNA damage, aberrant growth signals, or chemotherapeutic drugs, p53 is stabilized and induces apoptosis and/or cell cycle arrest. While the mechanisms of p53-dependent apoptosis are not well understood, p53-dependent cycle arrest is primary mediated by the CDK inhibitor p21. p53 is a transcriptional activator and it is not surprising that a majority of p53 mutations occur in the core DNA binding domain and affect DNA binding and transactivation of p53 targets in tumors. We used the capability of p53 to activate transcription for developing a new assay that permits rapid determination of the status of p53 in cancer cell lines of different origin. Our strategy involved using a retrovirus containing a p53-regulated lacZ reporter gene that was introduced into colon and breast tumor cell lines to determine p53 status. Simple staining for beta-galactosidase allowed us to confirm that the colon cancer cell lines LIM1215 and HCT116, as well as the breast cancer cell line MCF7. have wild-type p53, and the colon cancer cell line Caco-2 as well as breast cancer cell lines MDA-MB-435 and MDA-MB-231 have mutant p53. This method may be applied to novel cell lines of any origin with unknown status of p53.
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PMID:A new method for determining the status of p53 in tumor cell lines of different origin. 1272 31

Prostaglandin E(2) (PGE(2)) has been implicated as an inducer of angiogenesis in human colon cancer. Here, we demonstrate that PGE(2) exposure induces the expression of vascular endothelial growth factor (VEGF) mRNA in HCT116 human colon carcinoma cells that is mediated by the transcriptional activator hypoxia-inducible factor 1 (HIF-1). PGE(2) exposure induces the phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Pharmacologic inhibition of ERK phosphorylation blocks the induction of VEGF mRNA and HIF-1alpha protein expression in response to PGE(2) stimulation. Inhibition of C-SRC tyrosine kinase activity also blocks PGE(2)-induced HIF-1alpha protein and VEGF mRNA expression without blocking ERK phosphorylation. In contrast, phosphorylation of AKT is dependent on ERK and C-SRC activity. Thus, the activity of multiple signal transduction pathways is required for the HIF-1-mediated induction of VEGF expression in colon cancer cells exposed to PGE(2).
Cancer Res 2003 May 01
PMID:Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. 1272 58

The presence and transcriptional expression of Epstein-Barr virus (EBV)-encoded genes, oestrogen receptor (ER) status and degree of lymphocyte infiltration were evaluated in 15 mastectomy-removed breast cancer samples, mostly of ductal origin. With regard to these parameters, the tumours were heterogeneous. Viral genes, including EBNA1 - a universal EBV marker - and others, selected in part on the basis of expression in other EBV-associated carcinomas and/or presence in an epithelial cell immortalising subfragment p31 of viral DNA, were detected in up to 40% of the breast malignancies. The small viral RNAs, EBERs, were not observed. In culture, p31 EBV DNA, alone among EBV fragments, stimulated the growth of human breast-milk epithelial cells. There was no correlation between viral and ER expression and tumours were heterogeneous with regard to their invasive lymphocytes: of three studied in detail, one contained none, another had (mainly) T-lymphocyte aggregates on the tumour periphery, and a third (BC 12) was infiltrated with both T- and B-lymphocytes. BC 12 differed in several aspects from other malignancies in expressing a transcriptional activator (BZLF1) associated with overcoming virus latency, and failing to express a viral oncogene, BARF1. Arguments are given for EBV as a protagonist cocarcinogen in some breast malignancies.
Br J Cancer 2003 Jul 07
PMID:Epstein-Barr virus gene expression in human breast cancer: protagonist or passenger? 1283 11

The Hepatitis B Virus X (HBx) protein of hepatitis B virus plays a major role in hepatocellular carcinoma. It has been reported that the mutation and disruption of PTEN, a known tumor suppressor and a negative regulator of phosphatidylinositol 3'-kinase/AKT might be involved in tumor progression. However, the relationship between HBx and PTEN expression in hepatocellular carcinoma (HCC) development is not fully understood. This study reports on an investigation of whether PTEN expression in HBx-transfected cells is modulated by HBx or not. HBx decreased the expression of PTEN in HBx-transfected cells, as evidenced by Western as well as Northern blot analysis. In addition, AKT was found to be activated by HBx, as evidenced by not only the phosphorylation of AKT at serine 473 but by the phosphorylation of the exogenous substrate histone H2B as well, and these were specifically blocked by the presence of wortmannin. Moreover, The growth rate of HBx-transfected liver cells was higher than that of Chang and Chang-pEGFP cells. HBx had no effect on the expression of p53, a known transcriptional activator of PTEN. However, we confirmed that the binding of the p53 protein to p53 binding site-oligo of PTEN promoter is decreased in HBx-transfected liver cells by electrophoretic mobility shift analysis and, in addition, that HBx disrupts p53-mediated PTEN transcription, as evidenced by a PTEN promoter assay. Therefore, we conclude that HBx in liver cells down-regulates the expression of PTEN and activates AKT. This constitutes the first report to demonstrate that HBx has an effect on the p53-mediated transcription of PTEN, which, in turn, is associated with tumor suppression.
Cancer Res 2003 Jul 01
PMID:Hepatitis B Virus X protein modulates the expression of PTEN by inhibiting the function of p53, a transcriptional activator in liver cells. 1283 24

There are many sources of genetic diversity, ranging from programmed mutagenesis in antibody genes to random mutagenesis during species evolution or development of cancer. We propose that mutations in DNA sequence-specific transcription factors that target response elements (REs) in many genes can also provide for rapid and broad phenotypic diversity, if the mutations lead to altered binding affinities at individual REs. To test this concept, we examined the in vivo transactivation capacity of wild-type human and murine p53 and 25 partial function mutants. The p53s were expressed in yeast from a rheostatable promoter, and the transactivation capacities toward >15 promoter REs upstream of a reporter gene were measured. Surprisingly, there was wide variation in transactivation by the mutant p53s toward the various REs. This is the first study to address directly the impact of mutations in a sequence-specific transcription factor on transactivation from a wide array of REs. We propose a master gene hypothesis for phenotypic diversity where the master gene is a single transcriptional activator (or repressor) that regulates many genes through different REs. Mutations of the master gene can lead to a variety of simultaneous changes in both the selection of targets and the extent of transcriptional modulation at the individual targets, resulting in a vast number of potential phenotypes that can be created with minimal mutational changes without altering existing protein-protein interactions.
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PMID:Functional mutants of the sequence-specific transcription factor p53 and implications for master genes of diversity. 1290 20

MLL fusion proteins are leukemogenic, but their mechanism is unclear. Induced dimerization of a truncated MLL immortalizes bone marrow and imposes a reversible block on myeloid differentiation associated with upregulation of Hox a7, a9, and Meis1. Both dimerized MLL and exon-duplicated MLL are potent transcriptional activators, suggesting a link between dimerization and partial tandem duplication of DNA binding domains of MLL. Dimerized MLL binds with higher affinity than undimerized MLL to a CpG island within the Hox a9 locus. However, MLL-AF9 is not dimerized in vivo. The data support a model in which either MLL dimerization/exon duplication or fusion to a transcriptional activator results in Hox gene upregulation and ultimately transformation.
Cancer Cell 2003 Sep
PMID:Dimerization of MLL fusion proteins immortalizes hematopoietic cells. 1452 54


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