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 transcriptional activator beta-catenin is the key mediator of the canonical Wnt signaling pathway. However, beta-catenin does not itself bind DNA, but functions via interaction with T-cell factor (TCF)/ lymphoid-enhancing factor (LEF) transcription factors. These proteins contain a high-mobility group (HMG) box that binds DNA in a sequence-specific manner. Thus, in the case of active Wnt signaling, beta-catenin activates, in cooperation with proteins of the TCF/LEF family, the expression of a wide variety of genes. To date, the list of established Wnt targets is far from complete. The establishment of plasmids harbouring reporter genes under control of the native promoter sequences provides a tool to validate novel putative Wnt targets by directly quantifying the beta-catenin-dependent activation of each specific gene. In this chapter, we describe how to generate such reporter plasmids using the MMP7 promoter as an example.
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PMID:Native promoter reporters validate transcriptional targets. 1909 50

Based on the capacity of mesenchymal stem cells (MSC) to differentiate into multiple cell types in vitro and in vivo, MCS may be a suitable source for cell therapy and regeneration strategies. A prerequisite for effective clinical applications of human MSC (hMSC) is a profound knowledge of signal transduction cascades that mediate processes like proliferation, targeted migration and differentiation. Recently, we identified the canonical Wnt signal transduction pathway as a key player in hMSC proliferation and invasion. To evaluate whether those findings are transferable to the equivalent counterparts in mice, we studied important steps in the wingless/int-1 (Wnt) signal transduction pathway in mouse MSC (mMSC) and mMSC carrying a T cell specific transcription factor (TCF)/lymphoid enhancer binding factor (LEF)-reporter transgene. We found that the induction of the canonical Wnt pathway resulted in the up-regulation of the known Wnt target gene cyclin D1, closely associated with an enhanced proliferation capacity of mMSC. Interestingly, the expression of the Wnt target gene membrane type 1-matrix metalloproteinase (MT1-MMP) was diminished in mMSC upon Wnt3a stimulation, which came along with an impaired invasion. In line with these findings, MMP-2 and MMP-9 expression levels in mMSC were also decreased after Wnt3a treatment. In contrast, inhibition of Wnt signalling by the knockdown of the transcriptional activator beta-catenin resulted in an up-regulation of MT1-MMP and mMSC invasion. By comparing these findings with the settings in hMSC, major differences in Wnt-regulated MMP expression were observed in mMSC. Thus, our data advice caution when mouse model systems represent the pre-clinical validation of MSC-mediated therapeutical approaches.
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PMID:Wnt signalling in mouse mesenchymal stem cells: impact on proliferation, invasion and MMP expression. 1941 84

beta-catenin functions as both a structural protein and a transcriptional activator. In this study, we examined the expression of beta-catenin in human cirrhotic livers, and administered adenoviruses carrying the beta-catenin or DeltaTCF4 genes to cirrhotic rats to investigate the role of beta-catenin in the development of liver cirrhosis development. beta-catenin expression was associated with liver cirrhosis development in cirrhotic human and rat liver. beta-catenin adenovirus was capable of accelerating cirrhosis progress but this progression was unaffected by administration of DeltaTCF4 adenovirus. beta-catenin was mainly located in the intercellular regions between liver cells and was highly concentrated in the hepatic sinusoid wall, where alpha-smooth muscle actin (SMA) was also mainly distributed. The binding of beta-catenin to alpha-SMA was also increased in cirrhotic liver. Portal vein blood pressure was significantly increased in the group administered beta-catenin adenovirus, but not in that receiving DeltaTCF4 adenovirus. These results suggest that high concentrations of beta-catenin at the hepatic intercellular membrane and the hepatic sinusoid wall contribute to hepatic hyperpiesia in liver cirrhosis patients. beta-catenin functions as a structural molecule, but not as a signaling molecule, during liver cirrhosis development.
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PMID:Overexpression of beta-catenin is responsible for the development of portal hypertension during liver cirrhosis. 1946 46

The lymphoid enhancer factor 1 (Lef-1) belongs to the nuclear transducers of canonical Wnt-signalling in embryogenesis and cancer. Lef-1 acts, in cooperation with beta-catenin, as a context-dependent transcriptional activator or repressor, thereby influencing multiple cellular functions such as proliferation, differentiation and migration. Here we report that an increased Lef-1 expression in human pancreatic cancer correlates with advanced tumour stages. In pancreatic tumours, two different transcripts of Lef-1 have been detected in various stages, as demonstrated by RT-PCR analysis. One transcript was identified as the full length Lef-1 (Lef-1 FL), whereas the second, shorter transcript lacked exon VI (Lef-1 Deltaexon VI) compared to the published sequence. Comparative analysis of these two Lef-1 variants revealed that they exhibit different cellular effects after transient expression in pancreatic carcinoma cells. Forced expression of Lef-1 Deltaexon VI inhibited E-cadherin expression in a beta-catenin-independent way. Increased amounts of Lef-1 Deltaexon VI resulted in reduced cellular aggregation and increased cell migration. Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation. Our findings indicate that expression of alternatively spliced Lef-1 isoforms is involved in the determination of proliferative or migratory characteristics of pancreatic carcinoma cells.
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PMID:Lef-1 isoforms regulate different target genes and reduce cellular adhesion. 1965 74

The transcriptional activator beta-catenin is the primary mediator of the canonical Wnt signaling pathway and is frequently upregulated in many types of human cancer. Recent studies have suggested that the interaction of beta-catenin and its cofactor, B-cell lymphoma 9 (BCL9), is crucial for its transcriptional activity. Targeting this interaction using small molecules will improve our understanding of the beta-catenin/Wnt signaling pathway and may lead to the development of a new class of anticancer drugs. In this study, we developed a fluorescence polarization (FP)-based BCL9 binding assay. Using our initial FP assay, we performed extensive mutational analysis on four critical hydrophobic residues in the BCL9 peptide and determined the precise region in BCL9 responsible for binding to beta-catenin. These results led to further optimization of our FP assay, making it amenable for high-throughput screening (HTS). We also developed and validated a complementary surface plasmon resonance (SPR)-based binding assay and showed that our synthetic BCL9-based peptides are capable of fully inhibiting the binding of beta-catenin to wild-type BCL9 protein. Our studies provide not only further insight into the interaction between BCL9 and beta-catenin but also quantitative and reliable biochemical binding assays for the discovery of potent and specific small-molecule inhibitors of this interaction.
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PMID:Analysis of the interaction of BCL9 with beta-catenin and development of fluorescence polarization and surface plasmon resonance binding assays for this interaction. 1971 4

Legionella pneumophila is the causative agent of human Legionnaires' disease. L. pneumophila has been shown to induce apoptosis of T-cells and this may be important pathologically and clinically. The present study has determined the molecular mechanisms underlying L. pneumophila-induced apoptosis, which were unclear. Wild-type L. pneumophila and flagellin-deficient Legionella, but not L. pneumophila lacking a functional type IV secretion system Dot/Icm, replicated in T-cells. However, apoptosis was efficiently induced in T-cells only by wild-type L. pneumophila, and not flagellin-deficient or Dot/Icm-deficient Legionella. Induction of apoptosis involved activation of the initiator caspase 9 and effector caspase 3. Infection with L. pneumophila inhibited phosphorylation of Akt (also known as protein kinase B) and the Akt substrate GSK3beta (glycogen synthase kinase 3beta), and reduced the levels of beta-catenin, a transcriptional activator regulated by GSK3beta. It also caused the activation of the pro-apoptotic protein Bax and inhibited the expression of the anti-apoptotic protein XIAP (X-linked inhibitor of apoptosis) via inhibition of the Akt pathway. In conclusion, L. pneumophila induces mitochondria-mediated T-cell apoptosis through inhibition of the Akt/GSK3beta signalling pathway.
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PMID:Inhibition of Akt/GSK3beta signalling pathway by Legionella pneumophila is involved in induction of T-cell apoptosis. 2134 58

Kaiso is a dual-specificity POZ-ZF transcription factor that regulates gene expression by binding to sequence-specific Kaiso binding sites (KBS) or methyl-CpG dinucleotide pairs. Kaiso was first identified as a binding partner for the epithelial cell adhesion regulator p120(ctn). The p120(ctn)/Kaiso interaction is reminiscent of the beta-catenin/TCF interaction and several studies have suggested that Kaiso is a negative regulator of the Wnt/beta-catenin TCF signaling pathway. To gain further insight into Kaiso's function, we performed a yeast two-hybrid screen using the Kaiso POZ domain as bait. This screen identified the POZ-ZF protein, Znf131, as a Kaiso-specific binding partner. GST pull-down assays confirmed that the interaction is mediated via the POZ domain of each protein, and co-immunoprecipitation experiments further supported an in vivo Kaiso-Znf131 interaction. Using a Cyclic Amplification and Selection of Targets (CAST) approach, we identified the 12-base pair DNA palindrome sequence GTCGCR-(X)(n)-YGCGAC as a potential Znf131 binding element (ZBE). In vitro studies using electrophoretic mobility shift assay (EMSA) demonstrated that Znf131 binds the ZBE via its zinc finger domain. Znf131 DNA-binding specificity was confirmed using competition assays and ZBE mutational analyses. An artificial promoter-reporter construct containing four tandem copies of the ZBE was constructed and used to assess Znf131 transcriptional properties. We observed dose-dependent transcriptional activation of this artificial promoter-reporter by Znf131 in both epithelial and fibroblast cells, suggesting that Znf131 is a transcriptional activator. Kaiso overexpression significantly decreased the Znf131-mediated transcriptional activation, and interestingly, co-expression of the Kaiso-specific interaction partner p120(ctn) relieved Kaiso's inhibition of Znf131-mediated transcriptional activation. These findings indicate that Znf131 is a transcriptional activator, a less common function of POZ-ZF proteins, that is negatively regulated by its heterodimerization partner Kaiso.
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PMID:Kaiso regulates Znf131-mediated transcriptional activation. 2030 51

The interaction between tumor cells and the stroma environment has crucial effects on tumor cell invasive behavior. As a major component of the stroma, collagen plays a key role on cellular adhesion and epithelial-mesenchymal transition (EMT). Recently, we found that collagen type I is significantly up-regulated in gastric cancer tissues compared with their adjacent non-neoplastic tissues. However, whether collagen type I contributes to gastric cancer invasion and metastasis is not clear. Herein we show that, collagen type I induces cell scattering and cytoskeleton rearrangement, prompts cell migration and proliferation, which indicates that collagen type I is involved in promoting gastric cancer invasion and metastasis. Collagen type I is able to reduce cell-cell adhesion and enhance migration by inducing disassembly of the E-cadherin/catenin complex in gastric carcinoma cells, which is related to tyrosine phosphorylation of beta-catenin. Tyrosine phosphorylation of beta-catenin dissociates it from E-cadherin and actin cytoskeleton and facilitates its entry into the nucleus, where beta-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. In conclusion, collagen type I contributes to invasion and metastasis by regulating beta-catenin tyrosine phosphorylation and nuclear translocation to promote migration and proliferation of gastric carcinoma cells.
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PMID:Collagen type I regulates beta-catenin tyrosine phosphorylation and nuclear translocation to promote migration and proliferation of gastric carcinoma cells. 2037 37

beta-Catenin is a bifunctional protein participating in both cell adhesion and canonical Wnt signaling. In cell adhesion, it bridges the transmembrane cadherin and the actin-binding protein alpha-catenin and is essential for adherens junction formation, whereas in canonical Wnt signaling, it shuttles between the cytosol and nucleus and functions as an essential transcriptional activator. Schmidtea mediterranea beta-catenin-1 was identified as a determinant of antero-posterior polarity during body regeneration by mediating Wnt signaling. Here we show that S. mediterranea beta-catenin-2 is specifically expressed in epithelial cells in the gut and pharynx, where it has a putative role in mediating cell adhesion. We show evidence that planarian beta-catenin-1 and -2 have distinct biochemical properties. beta-Catenin-1 can interact with the components of the canonical Wnt signaling pathway but not with alpha-catenin, whereas beta-catenin-2 interacts with cell adhesion molecules, including E-cadherin and alpha-catenin, but not with Wnt signaling components. Consistent with their specific function, beta-catenin-1 is a potent transcriptional activator, whereas beta-catenin-2 has no transcriptional activity. Protein sequence alignment also indicates that the planarian beta-catenin-1 and -2 retain distinct critical residues and motifs, which are in agreement with the differences in their biochemical properties. At last, phylogenetic analysis reveals a probable Platyhelminthes- specific structural and functional segregation from which the monofunctional beta-catenins evolved. Our results thus identify the first two monofunctional beta-catenins in metazoans.
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PMID:Complete functional segregation of planarian beta-catenin-1 and -2 in mediating Wnt signaling and cell adhesion. 2051 47

Beta-catenin (CTNNB1) directs ectodermal appendage spacing by activating ectodysplasin A receptor (EDAR) transcription, but whether CTNNB1 acts by a similar mechanism in the prostate, an endoderm-derived tissue, is unclear. Here we examined the expression, function, and CTNNB1 dependence of the EDAR pathway during prostate development. In situ hybridization studies reveal EDAR pathway components including Wnt10b in the developing prostate and localize these factors to prostatic bud epithelium where CTNNB1 target genes are co-expressed. We used a genetic approach to ectopically activate CTNNB1 in developing mouse prostate and observed focal increases in Edar and Wnt10b mRNAs. We also used a genetic approach to test the prostatic consequences of activating or inhibiting Edar expression. Edar overexpression does not visibly alter prostatic bud formation or branching morphogenesis, and Edar expression is not necessary for either of these events. However, Edar overexpression is associated with an abnormally thick and collagen-rich stroma in adult mouse prostates. These results support CTNNB1 as a transcriptional activator of Edar and Wnt10b in the developing prostate and demonstrate Edar is not only important for ectodermal appendage patterning but also influences collagen organization in adult prostates.This article has an associated First Person interview with the first author of the paper.
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PMID:Edar is a downstream target of beta-catenin and drives collagen accumulation in the mouse prostate. 3074 37


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