IndraLab
Statements
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"Disassembly of the destruction complex can block β-catenin degradation that results in the translocation of the accumulated β-catenin into the nucleus, where β-catenin binds to the lymphoid enhancer factor/T-cell factor (LEF/TCF) family of transcription factors and triggers the protooncogene-induced transcription of several target genes, such as c-myc, MDR1, OCT4, and cyclin D1 (refs. xref – xref )."
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"Further, chromatin immunoprecipitation (ChIP) assays demonstrate that both beta-catenin and Lef1 bind directly to the neurogenin promoter, and luciferase reporter assays demonstrate that beta-catenin is directly involved in the regulation of neurogenin 1 and possibly other proneural genes when neural stem cells are cultured in the presence of FGF2."
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"We performed ChIP assay and found that ARA014418 treatment increased the levels of co-immunoprecipitated cis-elements of LEF1/TCF-1 and LEF1/TCF-2 by β-catenin (Figure 7A), suggesting inhibition of GSK-3β enhances the binding of β-catenin to LEF1/TCF elements.To determine the effect of ARA014418 on PME-1 expression in primary cultured cortical neurons, we treated the neurons with various concentrations of ARA014418 for 4.5 hr and analyzed mRNA level of PME-1 by qPCR."
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"Subsequently beta-catenin interacts with members of the lymphoid enhancer factor 1/T-cell factor (LEF1/TCF) family, resulting in a functional transcription factor complex and the expression of downstream target genes. xref , xref The non-canonical Wnt ligands also bind to FZD family receptors, and ROR2 and RYK co-receptors. xref - xref The non-canonical signaling pathways include three pathways (Wnt/Ca 2+ , Wnt/G protein, and Wnt/PCP signaling pathways) and non-canonical signaling regulates cell polarity and movement. xref - xref Among the five Wnt antagonist families (secreted frizzled-related protein (sFRP), Wnt inhibitory factor 1 (Wif1), Xenopus Cerberus, Wise and Dickkopf (DKK) families) the DKK family consists of four main members (DKK1-4) which contain two distinct cysteine-rich domains. xref , xref Our lab has studied several Wnt antagonist genes and these function in renal cancer. xref - xref Previously DKK4 has been thought to act as an inhibitor of Wnt/beta-catenin signaling in colorectal cancer. xref , xref Recently two groups found that DKK4 expression was increased in colon cancer tissues compared to matched normal colon tissues and DKK4 was induced by activated beta-catenin, although DKK4 itself significantly inhibited TCF/LEF reporter activity in colon cancer cell lines. xref , xref As far as we know, there have been no reports regarding DKK4 and renal cancer."
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"In line with our previous findings that DBC1 enhances LEF1-β-catenin complex formation on WREs of β-catenin targets including a Wnt-inducible transcription factor PROX1 involved in colon cancer progression xref , DBC1 increases LEF1-β-catenin interaction on the MACC1 enhancer, and loss of DBC1 reduced the occupancy of LEF1, TCF4, and β-catenin on the MACC1 enhancer."
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"On the other hand, interactions between Runx2 and beta-catenin and Lef1 inhibit Runx2 mediated activation of osteocalcin [XREF_BIBR], and Runx3 was recently shown to attenuate tumorogenic beta-catenin signaling via direct physical interactions with both beta-catenin and TCF4 [XREF_BIBR]."
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"Wnt and beta-catenin pathway activation is characterized by (i) stabilization of cytoplasmic beta-catenin upon receptor engagement by Wnt ligands, (ii) beta-catenin nuclear translocalion, (iii) beta-catenin interaction with lymphoid enhancer binding factor-1 and T-cell factor-1 (LEF and TCF) transcription factors, and (iv) stimulation of target genes XREF_BIBR, XREF_BIBR."
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"Β-catenin may increase FoxO transcriptional activity and competitively limit β-catenin interaction with members of the lymphoid enhancer factor/T cell factor family. xref This may lead to cell injury, since β-catenin has been demonstrated to be necessary for protection against Aβ toxicity in neuronal cells. xref "
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"Chromatin immunoprecipitation (ChIP) analysis also showed that the T-cell factor (TCF)4, which is one of the transcription factors of the lymphoid enhancer factor (LEF)/TCF family that binds to stabilized β-catenin to regulate Wnt signalling xref , is bound to the promoter of Irs1 xref ."
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"Given the ability of DeltaNDeltaCbetacatenin to act in a dominant negative fashion in interfering with the activity of functional Lef1 and betacatenin complexes in keratinocytes in vitro, we then turned towards using this transgene to assess the consequences of diminished Wnt signaling on hair organogenesis and postnatal cycling."
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"Nuclear β-catenin binds to and activates T cell factor (TCF) and lymphoid enhancer-binding (LEF) TFs, which directly bind to specific DNA sequences, enhancing the transcription of genes such as Cyclin D, c-Myc, and Axin2 and inhibiting transcription of other genes such as E-cadherin and the tumor suppressor p53 [ xref , xref ]."
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"To determine whether the beta, catenin, LEF1, and TCF complex might directly regulate Cacna1g, Cacna2d2, Kcna6, Kcnh8, Drd3, Gabra3, Glra1, Grid2, and Calb2, we analyzed the in vivo binding of beta-catenin to LEF1 and TCF motifs within the CNSs using a chromatin immunoprecipitation (ChIP) assay with designed primers."
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"Nuclear β-catenin binds to and activates T cell factor (TCF) and lymphoid enhancer-binding (LEF) TFs, which directly bind to specific DNA sequences, enhancing the transcription of genes such as Cyclin D, c-Myc, and Axin2 and inhibiting transcription of other genes such as E-cadherin and the tumor suppressor p53 [19,25]."
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"Subsequently β-catenin interacts with members of the lymphoid enhancer factor 1/T-cell factor (LEF1/TCF) family, resulting in generation of a functional transcription factor complex and the expression of downstream target genes. [ xref ] Non-canonical Wnt ligands bind to FZD family receptors, and ROR2 and RYK co-receptors.[ xref – xref ] This signaling is mainly involved in cytoskeletal reorganization during cancer cell invasion and metastasis.[ xref ][ xref ] At present, five Wnt antagonist families have been described, namely, secreted frizzled-related protein (sFRP), Wnt inhibitory factor 1 (Wif1), Xenopus Cerberus, Wise and Dickkopf (DKK) families.[ xref ]"
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"Our results clearly demonstrated that endogenous β-catenin and endogenous LEF-1/TCF proteins in mesenchymal FosER cells were able to form a transcriptionally active complex, which could be increased further upon ectopic expression of β-catenin and LEF-1 without additional signals."
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"Jerky also recruits β-catenin to chromatin, and promotes the association of β-catenin and LEF1, resulting in the induction of Wnt target gene expression.( xref , xref ) We found that RUNX3 increases the occupancy of the TCF4/β-catenin complex in KatoIII cells, suggesting that RUNX3 plays a role in the stabilization of the TCF4/β-catenin complex on the Wnt target gene promoter like TBL1 and Jerky."
"Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1"
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"Finally, based on the fact that certain vertebrate TCFs encode either repressor or activator function and that repressive TCF proteins have higher affinities for Gro/TLE, a model has been proposed by which Gro/TLE in complex with repressive TCFs (e.g., TCF3) is released upon Wnt signaling, allowing for the recruitment of activating TCFs (e.g., LEF1) bound to β-catenin [18]."
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"Maetzel et al ( xref ) firstly demonstrated that a proteolytic fragment of EpCAM containing EpICD forms a complex with β-catenin and LEF-1, which translocates to the nucleus and activates the transcription of genes associated with cell proliferation, such as c-Myc and cyclins A and E, thereby promoting oncogenesis ( xref ) ( xref )."
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"Mammalian Dpr1/Dact inhibits expression of Wnt-responsive reporters through its promotion of Dvl degradation in a lysosome-dependent pathway, and by inhibiting the binding of LEF1 with β-catenin, but promoting the binding of LEF1 with a corepressor, histone deacetylase 1 (HDAC1) xref , xref ."
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"The extended N-terminal region of Lef-1 binds to β-catenin using most of the conserved sequence motif Dxθθxφx 2–7 E. There are relatively few direct contacts between Lef-1 residues 11–18 and β-catenin, which include a salt bridge between Asp12 and Arg515, and the backbone carbonyl oxygen of Gly11 forms a hydrogen bond with Arg582 ( xref )."
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"In addition, recent data demonstrates that at the onset of anagen, HG exchanging Tcf3/Tcf4 for Lef1 at the super-enhancers, and then Lef1 forms the nuclear complex with β-catenin after activation of WNT signaling (as a consequence of BMP inhibition) which drives HG committed progenitors ( xref ; xref ; xref )."
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"We demonstrated that LEF1 and β-catenin bind to and regulate MIR17HG promoter activity, and that activation of the Wnt/β-catenin pathway increases the MIR17HG promoter activity as well as the endogenous expression of miR-17-92 cluster, whereas inactivation of the Wnt/β-catenin pathway reduces miR-17-92 cluster expression."
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"Based on these insights, new therapeutic opportunities have been explored by investigators who show that small-molecule WNT-pathway inhibitors, which inhibit the interaction between beta-catenin and LEF1, selectively induce cell death in AML cell lines and primary AML blasts [XREF_BIBR]."
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"Moreover, when the endogenous Smad7 was repressed by specific small interfering RNA, TGF-beta-induced increase of activated p38, Akt phosphorylated on Ser473, glycogen synthase kinase 3beta phosphorylated on Ser9 was prevented, as well as the TGF-beta-induced association between beta-catenin and LEF1."
"Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors."
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"Residues 11–18 adopt a conformation different from the equivalent portions of other Tcfs, which may be due to differences in lattice packing, as neighboring molecules of β-catenin interact with some of this region of Lef-1. (Interestingly, pLef-1 Cys16 forms a disulfide bond with β-catenin Cys350 from a lattice neighbor, even though its conformation is the same in the non-phosphorylated structure.) It is also possible that some of the difference arises from the insertion of Pro13 between two acids that are otherwise adjacent in sequence in the other Tcfs ( xref ); Lef-1 Asp12 forms a salt bridge with β-catenin Arg515 ( xref ), whereas the equivalent interaction is absent in other TCF–β-catenin structures."
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"Activation of the Wnt and beta-catenin pathway is characterized by 1) stabilization of cytoplasmic beta-catenin after receptor engagement by Wnt ligands; 2) beta-catenin nuclear translocation, 3) beta-catenin interaction with lymphoid enhancer binding factor-1 and T-cell factor-1 (LEF and TCF) transcription factors; and 4) stimulation of target genes."
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"Taken together, our results suggest that HQ induced hematotoxicity in bone marrow mononuclear cells is associated with dysregulation of Akt/GSK-3beta/beta-catenin signaling due to the dissociation of beta-catenin and LEF -1 complex, and LiCl and IGF-1 may be two potential agents to ameliorate HQ induced hematotoxicity."
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"XREF_BIBR - XREF_BIBR Although it is well established that the formation of nuclear beta-catenin and LEF1 complexes has a crucial role in the activation of Wnt target genes, the details of the regulatory mechanisms of beta-catenin activity and its interaction with LEF1 are still under investigation."
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"Dact proteins have been shown to also modulate Wnt signaling mediators in a ligand independent fashion : Dact proteins shuttle between the nucleus and cytoplasm, and can block nuclear beta-Catenin function by disrupting beta-Catenin and Lef1 complexes and enhancing Lef1-HDAC interaction [XREF_BIBR]."
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"In this study, we show that the beta-catenin and Lef -1 complex is capable of binding to the Jagged-1 promoter in vitro at positions -1933, -1635 and possibly -1083 relative to the translation start site (XREF_FIG and XREF_SUPPLEMENTARY) making these plausible sites for transcriptional interactions between Jagged-1 and the canonical Wnt pathway."
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"Consistent with the model in which beta-catenin acetylation enhances its binding to LEF1 and leads to increased chromatin occupancy of LEF1 by stabilizing LEF1, beta, and catenin complex, XREF_BIBR, XREF_BIBR our results further showed that DBC1 enhances the interaction of beta-catenin with LEF1 (XREF_FIG) and is required for efficient recruitment of LEF1 and beta-catenin to their target chromatin regions (XREF_FIG), probably through protecting beta-catenin from SIRT1 mediated deacetylation (XREF_FIG)."
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"The cytoplasmic accumulation of β-catenin after activation of Wnt signaling, or the release of β-catenin due to the loss of E-cadherin, which allow the interactions between β-catenin and LEF-1, can induce the upregulation of Snail, Slug, Twist and mesenchymal markers such as fibronectin ( xref ; xref )."
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"The role of beta-catenin in anoikis is also attributable to the activation of the Wnt pathway, in which beta-catenin interacts with transcription factor lymphoid enhancer binding factor 1 (LEF-1) to regulate gene expression and subsequently inhibit anoikis [XREF_BIBR - XREF_BIBR]."
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"The downregulation of APC contributes to nuclear accumulation of β-catenin, which subsequently interacts with the lymphoid enhancing factor/T cell factor (TCF) transcription factor to activate the transcription of target genes including c-Myc, cyclin D1, and matrix metalloproteinase 7 (MMP7) [ xref ]."
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"To quantitatively measure the ability of GATA4 to block interaction between β-catenin and LEF1/TCF1, we turned to bimolecular fluorescence complementation assay 34 by fusing β-catenin and LEF1/TCF1 to N- and C-terminal half of firefly luciferase respectively, such that when these fusion proteins were expressed in HepG2 cells, luciferase activity is a direct readout for interaction between β-catenin and LEF1/TCF1."
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"Elevated beta-catenin levels in colorectal cancer caused by mutations in beta-catenin or by the adenomatous polyposis coli molecule, which regulates beta-catenin degradation, result in the binding of beta-catenin to LEF-1 and increased transcriptional activation of mostly unknown target genes."
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"However, unlike embryonic development in which uniform upper dermal Wnt signaling precedes hair morphogenesis ( xref ; xref ; xref ) we could not detect Wnt activity in the upper dermis prior to hair germ formation by either β-catenin or LEF-1 immunohistochemistry or with a Wnt-responsive reporter ( xref , data not shown)."
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"These results agree with the currently-accepted model that β-catenin associates with DNA-bound LEF1 and functions as a scaffold protein to recruit additional coactivators, such as CARM1 and p300, each of which makes a unique and specific contribution to the highly complex transcriptional initiation process."
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"Isothermal titration calorimetry revealed that β-catenin binds to non-phosphorylated or CK2 phosphorylated Lef-1 with the same affinity, which is consistent with the absence of phosphoSer40 interactions in the crystal structure of phosphorylated Lef-1 N-terminal domain bound to β-catenin."
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"Despite the finding that transcription factor LEF-1 interacts with β-catenin to activate their target genes, such as EMT-related gene SNAI2 xref , and induces EMT, we found that not only full-length LEF-1 but also LEF-1 lacking the N-terminal β-catenin–binding domain can induce EMT."
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"Despite the finding that transcription factor LEF-1 interacts with beta-catenin to activate their target genes, such as EMT related gene SNAI2 XREF_BIBR, and induces EMT, we found that not only full-length LEF-1 but also LEF-1 lacking the N-terminal beta-catenin-binding domain can induce EMT."
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"Mammalian Dpr1 and Dact inhibits expression of Wnt responsive reporters through its promotion of Dvl degradation in a lysosome dependent pathway, and by inhibiting the binding of LEF1 with beta-catenin, but promoting the binding of LEF1 with a corepressor, histone deacetylase 1 (HDAC1) XREF_BIBR, XREF_BIBR."
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"Elevated levels of DVL3 have also been reported in nonsmall cell lung carcinoma. xref CSNK2A2 (overexpressed 11-fold) is a highly conserved and ubiquitous serine/threonine kinase, over-expressed in many tumors including prostate. xref Cytoplasmic CSNK2A2 opposes the inhibitory role of GSK3B by phosphorylating and activating DVL and β-catenin, while nuclear CSNK2A2 enhances β-catenin:LEF1 transactivation of Wnt target genes. xref Its nuclear localization was previously reported as a poor prognostic indicator in prostate cancer, xref potentially through its promotion of AR-dependent transcription. xref Downstream component of the pathway, transcription factor LEF1 was also significantly over-expressed and has recently shown to promote AR expression and consequently enhance growth and invasion ability of prostate cancer cells in vitro . xref "
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"To determine whether the in silico identified LEF-1 and TCF binding sequences physically bind to the beta-catenin and Lef -1 complex in vitro, we conducted a competitive electrophoretic mobility-shift assay (EMSA) with a radioactively labeled consensus LEF-1 and TCF strong binding probe and duplex oligonucleotides covering the potential sites in target promoters."
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"Regarding the putative role of the LEF1 gene in hernia, it has been shown that the LEF1 protein constitutively associates with beta-catenin which mediates the action of the anti-mullerian hormone (AMH) [XREF_BIBR], itself involved in the gubernaculum swelling reaction that occurs during the first phase of testicular descent [XREF_BIBR, XREF_BIBR]."
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"Elevated beta-catenin levels in colorectal cancer caused by mutations in beta-catenin or by the adenomatous polyposis coli molecule, which regulates beta-catenin degradation, result in the binding of beta-catenin to LEF-1 and increased transcriptional activation of mostly unknown target genes."
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"The use of this type of library has identified erythropoieitin (EPO) mimetics (promote EPO receptor dimerization), inhibitors of Myc and Max dimerization, inhibitors of LEF-1 and beta-catenin dimerization, inhibitors of the binding of the protease MMP-2 to alphavbeta3 integrin, and inhibitors of HIV protease."
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"Together, these results suggest that DBC1 functions as a positive regulator of β-catenin by inhibiting SIRT1-mediated deacetylation and repression of β-catenin through blocking the interaction between β-catenin and SIRT1, thereby enhancing the association of β-catenin with LEF1 and promoting β-catenin-mediated transcription ( xref )."
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"Wnt/β-catenin pathway activation is characterized by (i) stabilization of cytoplasmic β-catenin upon receptor engagement by Wnt ligands, (ii) β-catenin nuclear translocalion, (iii) β-catenin interaction with lymphoid enhancer-binding factor-1/T-cell factor-1 (LEF/TCF) transcription factors, and (iv) stimulation of target genes xref , xref ."
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"Our model ( xref ) details the proposed steps for Rac1 involvement in canonical Wnt signaling: (1) activation (GTP-loading) of Rac1 reduces its association with the plasma membrane and causes active Rac1–β-catenin complexes to dissociate from the membrane, (2) these active Rac1–β-catenin complexes translocate to the cytoplasm and nucleus, (3) active Rac1 mediates the phosphorylation of β-catenin at S191 and S605 via JNK2 kinase in the cytoplasm and possibly the nucleus, and (4) the newly phosphorylated β-catenin preferentially binds to LEF-1 to boost gene transactivation."
"Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus."
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"The association of Ep-ICD with FHL2 and Wnt pathway components - β-catenin and Lef-1 forms a nuclear complex that binds DNA at Lef-1 consensus sites and induces gene transcription, leading to increased cell proliferation and has been shown to be oncogenic in immunodeficient mice [ xref ]."
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"The bioinformatic analysis revealed an array of putative nuclear factor-binding sites, including two potential LEF1/TCF like elements located on -349 bp – -333 bp and +19 bp – +35 bp (Figure 2A), on which β-catenin acts as co-activator of TCF transcription factors to regulate the transcription of target genes.To determine whether β-catenin binds to the LEF1/TCF elements of PME-1 promoter, we performed the ChIP assay in SH-SY5Y cells."
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"In normal epithelial cells, the inhibitory effect of E-cadherin against tumorigenesis is maintained by sequestering the binding of β-catenin to lymphoid enhancer factor (LEF)/T cell factor (TCF); this process could impede the transcription of genes involved in the proliferation-associated Wnt signaling pathway xref ."
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"Furthermore, the degradation of E-cadherin and the release of beta-catenin to cytosol were accompanied by the formation of nuclear beta-catenin and LEF -1 complex, demonstrating the dissociation of beta-catenin from E-cadherin may be responsible for the activation of beta-catenin and LEF -1 transcription complex."
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"To confirm that the compounds inhibit LEF-1 and beta-catenin DNA binding, EMSA assays were performed with immunoprecipitated beta-catenin and a 32 P labeled double stranded deoxyoligonucleotide (5 '-CCCTTTGATCTTACC-3 ') containing the LEF-1 consensus binding site in the presence of varied concentrations of the compounds."
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"During a high-throughput screening the approved FDA diuretic ethacrynic acid was found to down-regulate Wnt and beta-catenin signaling by inhibiting the formation of the beta-catenin and Lef -1 complex [XREF_BIBR, XREF_BIBR] in chronic lymphocytic leukemia (CLL) cells, although at a low IC 50."
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"Some studies reported promising results in APC mutated CRC cell lines [XREF_BIBR, XREF_BIBR], whilst others showed that nuclear beta-catenin bound to LEF-1 and TCF transcription factors would be protected from degradation such that TNKSi treatment would not be effective [XREF_BIBR]."
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"Activation of the Wnt/β-catenin pathway is characterized by 1) stabilization of cytoplasmic β-catenin after receptor engagement by Wnt ligands; 2) β-catenin nuclear translocation, 3) β-catenin interaction with lymphoid enhancer-binding factor-1/T-cell factor-1 (LEF/TCF) transcription factors; and 4) stimulation of target genes ( xref – xref )."
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"Because Wnt3a preferentially induces the full-length form of LEF-1, which includes the N-terminal beta-catenin interaction domain, this mechanism ensures mutually interdependent binding of LEF-1 and beta-catenin to chromatin and enables rapid and synchronous activation of downstream target genes."
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"Consistent with the model in which β-catenin acetylation enhances its binding to LEF1 and leads to increased chromatin occupancy of LEF1 by stabilizing LEF1–β-catenin complex, xref , xref our results further showed that DBC1 enhances the interaction of β-catenin with LEF1 ( xref ) and is required for efficient recruitment of LEF1 and β-catenin to their target chromatin regions ( xref ), probably through protecting β-catenin from SIRT1-mediated deacetylation ( xref )."
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"By qPCR analysis, RUNX2, ALP, and SPARC, which are associated with osteogenic differentiation, were significantly increased 2.47 ± 0.73-fold ( p = 0.011), 2.57 ± 0.09-fold ( p = 0.004), and 2.13 ± 0.60-fold ( p = 0.018), respectively; LEF1 and β-catenin, which are associated with the Wnt/β-catenin pathway, were increased 1.89 ± 0.45-fold ( p = 0.012) and 2.22 ± 0.51-fold ( p = 0.017), respectively (Fig. xref a)."
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"During hair follicle development in the mouse, epithelial cells of the ectoderm secrete Wnt3a, leading to nuclear accumulation of beta-Catenin, and mesenchymal cells secrete Noggin, which activates the Lef1 transcription factor; Lef1 can subsequently form a heterodimer with beta-Catenin to regulate transcription of target genes XREF_BIBR."
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"Β-catenin may increase FoxO transcriptional activity and competitively limit β-catenin interaction with members of the lymphoid enhancer factor/T cell factor family [ xref ] and β-catenin also has been demonstrated to be necessary for protection against amyloid toxicity in neuronal cells [ xref ]."
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"Regarding the putative role of the LEF1 gene in hernia, it has been shown that the LEF1 protein constitutively associates with β-catenin which mediates the action of the anti-mullerian hormone (AMH) [ xref ], itself involved in the gubernaculum swelling reaction that occurs during the first phase of testicular descent [ xref , xref ]."
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"In relation to this, it is notable that although lymphoid enhancer factor/TCF7 transcription factors associate with β-catenin in canonical wnt signaling leading to the transcription of its target genes, SATB1 has recently been shown to competitively influence the TCF7 binding to β-catenin ( xref )."
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"The present study shows for the first time that LEF-1 associates with E2F1 and further beta-catenin independently activates the E2F responsive reporter gene by attenuating the interaction between E2F1 and Histone deacetylase 1 (HDAC1), which indicates that LEF-1, except for its function in Wnt signaling, may play a distinct role via activating the transcription of E2F1."
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"Recent studies indicate that increased levels of beta-catenin correlate with the downregulation of the Wnt and beta-catenin pathway due to the proteasomal degradation of beta-catenin and the subsequent decrease in cyclin D [XREF_BIBR], as the cyclin D1 gene might be a target of the beta-catenin and LEF -1 complex [XREF_BIBR]."
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"In this scenario, tumor cells with activated EpCAM i.e. the released EpICD associates with FHL2, β-catenin which form a nuclear complex with Lef-1 and induces transcription of genes associated with cell proliferation. (Figure xref ; Schematic diagram modified from Maetzel D et al., 2009) [ xref ]."
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"Hes-1 has recently also been identified as a direct transcriptional target of beta-catenin and Tcf-4-dependent Wnt signaling in CRC XREF_BIBR and our EMSA data supports this notion by clearly identifying Hes-1 -528 as a binding site for the beta-catenin and Lef -1 complex (XREF_SUPPLEMENTARY)."
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"Based on these insights, new therapeutic opportunities have been explored by investigators who show that small-molecule WNT-pathway inhibitors, which inhibit the interaction between β-catenin and LEF1, selectively induce cell death in AML cell lines and primary AML blasts [ xref ]."
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"10 As a complex, Smad2/3-Smad 4 are then able to enter the nucleus of the epithelial cell and increase transcription of LEF-1, a member of the T-cell family of transcription factors that binds with beta-catenin suppressing transcription of epithelial markers such as E-cadherin and promoting transcription of mesenchymal markers such as vimentin and N-cadherin."
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"Intermittent PTH is a pathway agonist, thus, the accumulated β-catenin binds to T-cell-specific transcription factor (TCF) and lymphoid enhancing factor (LEF), displacing the Groucho repressor gene, and thereby allowing the transcription of Wnt-specific osteoblast differentiation genes. xref "
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"The sum effect of MMP inhibitors demonstrated that NO induced activation of MMP may cause the degradation of E-cadherin and the subsequent dissociation of beta-catenin, thereby contributing to the cytosolic accumulation of beta-catenin and nuclear formation of beta-catenin and LEF -1 complex."
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"Combined with the established role of the Wnt signaling pathway in adult hippocampal neurogenesis together with the known association between Lef1 and beta-catenin, our results here suggest that Lef1 is an important part of the Wnt controlled regulation of neural precursor function in the adult dentate gyrus."
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"Since these RMS cell lines express the full-length LEF1 isoform of 44 kDa, whereas the truncated isoform lacking the β-catenin binding site (31 kDa and 23 kDa; see [ xref , xref ]) were barely detected (Figure xref ), we conclude that these cell lines express functional LEF1 that can interact with β-catenin."
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"Because Wnt3a preferentially induces the full-length form of LEF-1 ( xref ), which includes the N-terminal β-catenin interaction domain, this mechanism ensures mutually interdependent binding of LEF-1 and β-catenin to chromatin and enables rapid and synchronous activation of downstream target genes."
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"Moreover, β-catenin, a protein found at cell–cell adherens junctions, has been shown to play a role in both linking the actin cytoskeleton to the cadherin class of homophilic cell adhesion receptors as well as directly transducing Wnt/ Wingless signals ( xref ; xref ; xref ); Wnt/Wingless signaling results in the nuclear accumulation of a β-catenin-Lef-1 transcription factor complex that binds the promoter regions of several genes (Behrens, et al., 1996; Huber, et al., 1996 b )."
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"These results suggest that DBC1 is required for efficient binding of LEF1 to its regulatory regions and/or for stable association of LEF1 with β-catenin, which strongly enhances the binding of LEF1 to chromatin, xref and thereby facilitates the occupancy of p300 and Pol II on the regulatory regions of LEF1–β-catenin target genes."
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"Because proinflammatory cytokine induced cartilage degradation appears to involve WNT and beta-catenin signaling and increased WNT and beta-catenin signaling has been implicated in the initiation and progressive deterioration of cartilage degeneration, we hypothesized that small molecule inhibitors of the interaction between beta-catenin and TCF4 and Lef1 could be used to prevent cytokine induced cartilage degradation."
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"Β-catenin which is then subsequently translocate to the nucleus interacts with T-cell factor and lymphoid enhancer factor (TCF/LEF)-family transcription factors ( xref ; xref ), initiating transcription of a set of pro-inflammatory, proliferative genes and oncogenes, such as CCND1 and MYC ( xref )."