IndraLab
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"Although the mechanisms of the anti-cancer activity of evodiamine have been well-studied, the precise mechanisms still remain unclear.It is known that the downregulation of WWOX leads to cytoplasmic β-catenin accumulation and the subsequent activation of the Wnt/β-catenin signaling pathway in HCC [4], while decreases in the activities of Akt and GSK-3β inhibit the expression of β-catenin."
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"Rg1 can reduce β-catenin expression and glycogen synthase kinase 3 beta (GSK3β) phosphorylation in the cytoplasm and can further reduce the protein expression of β-catenin in the nucleus via Ras-related C3 botulinum toxin substrate 1 (Rac1) and other factors; in addition, the binding of β-catenin to the transcription factor TCF-4 in the nucleus is reduced and ultimately inhibits c-Myc gene expression, which results in the reduction of β-galactosidase expression [40] (Figure 6)."
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"Our findings have demonstrated that SALL4 triggers the Wnt and beta-catenin signaling pathway and shRNA induced SALL4 inhibition can decrease Wnt3a and beta-catenin expression at both mRNA and protein levels, suggesting targeting SALL4 may be a promising new strategy to block Wnt and beta-catenin signaling pathway and EMT to prevent tumor metastasis in ESCC."
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"Although miR-34a-5p and miR-200a-3p were not selected in the screening (fold change ratio = -0.265 and -0.093, respectively), we also evaluated their regulatory activity as they were among the first miRNAs described as beta-catenin regulators.16, 17 Nine out of 26 miRNA candidates significantly decreased beta-catenin protein expression in Huh6 cells, which carry the beta-catenin missense G34V mutation."
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"We found that the treatment with RS-1 resulted in an increase in both the protein and mRNA expressions of β-catenin and C-myc in SGNs, while treatment with IWP-2 markedly reduced the expressions of β-catenin and C-myc in SGNs compared with the paclitaxel-only group (p < 0.05 or p < 0.01) (Figures 4(b) and 4(f))."
"Cleavage of beta-catenin was found to be caspase-dependent. Five cleavage products of beta-catenin were identified in vivo and after in vitro cleavage by caspase-3 . . . Functional analysis revealed that beta-catenin deletion constructs resembling the observed proteolytic fragments show a strongly reduced transcription activation potential when analyzed in gene reporter assays."
"Although Wnts act to stabilize beta-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3beta, and Axin1 or its homolog Axin2/Axil/conductin promotes beta-catenin phosphorylation and subsequent proteasomal degradation"
"Indeed, hamartin and tuberin co-immunoprecipitated with glycogen synthase kinase 3 beta and Axin, components of this complex in a Wnt-1-dependent manner. Our data suggest that hamartin and tuberin negatively regulate beta-catenin stability and activity by participating in the beta-catenin degradation complex."
"Enzastaurin also blocked phosphorylation of b-catenin at S33,37 phosphorylation sites essential for PKC-regulated proteasomal degradation (Figure 1C).18,19 Indeed, inhibition of translation using cycloheximide did not abrogate enzastaurin-induced up-regulation of b-catenin. These data support the hypothesis that enzastaurin inhibits degradation of b-catenin via abrogation of ubiquitination"
"A novel pathway for beta-catenin degradation was discovered involving mammalian homologs of Drosophila Sina (Siah), which bind ubiquitin-conjugating enzymes, and Ebi, an F box protein that binds beta-catenin independent of the phosphorylation sites recognized by beta-TrCP. A series of protein interactions were identified in which Siah is physically linked to Ebi by association with a novel Sgt1 homolog SIP that binds Skp1, a central component of Skp1-Cullin-F box complexes."
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"In addition, MA treatment elevated the protein expression levels of beta-catenin and its target proteins, including Cyclin D1, c-Myc and Survivin, as well as the gene expression levels of ZO-1, beta-catenin, Survivin and TCF-4, all of which could be down-regulated by the Wnt and beta-catenin pathway inhibitor XAV-939."
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"To evaluate the role of the canonical Wnt pathway in DC differentiation, we regulated the level beta-catenin in HPC using two GFP expressing vectors : beta-catenin shRNA to block the expression of beta-catenin (XREF_FIG); and a vector containing mutant beta catenin, which is resistant to ubiquitination and degradation and thus induces activation of the Wnt pathway."
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"To explore the possible role of beta-catenin, which normally is responsible for activation of LEF1 transcription, in palatogenesis, we treated normal palates undergoing EMT with sense and antisense (AS) beta-catenin oligonucleotide and found that AS beta-catenin significantly reduces beta-catenin protein levels compared with sense (XREF_FIG)."
"In human colon carcinoma SW480 cells, activation of the Gq pathway inhibits beta-catenin signaling as determined by transcriptional reporter and cell proliferation assays. Ca(2+) release from internal stores results in nuclear export and calpain-mediated degradation of beta-catenin in the cytoplasm"
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"Prevention of β-catenin degradation allows the cytoplasmic level of β-catenin to increase, causing increased translocation of β-catenin into the nucleus, which allows interaction with the TCF/LEF transcription factors leading to enhanced canonical Wnt target gene transcription [99]."
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"Finally, this meta-analysis, including 6238 cases from 34 studies, revealed that beta-catenin overexpression in the nucleus (HR : 1.50 [95% CI : 1.08-2.10]) or reduced expression of beta-catenin in the membrane (HR : 1.33 [95% CI : 1.15-1.54]) significantly correlated with lower 5-year overall survival (OS)."
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"Three small molecules -- Inhibitor of beta-Catenin And TCF4 (ICAT), niclosamide, and XAV939 -- have been shown to strongly and specifically reduce levels of active beta-catenin in vitro by inhibiting beta-catenin stabilization and downstream beta-catenin signaling (TCF/LEF reporter activity)."
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"E2F1 is a potent and specific inhibitor of beta-catenin and T-cell factor (TCF)-dependent transcription, and E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC)/GSK3-independent manner, reducing the expression of key beta-catenin targets XREF_BIBR."
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"Pharmacological inhibition of GSK3 or beta-catenin knockdown with shRNAs decreased the levels of phosphorylated-beta-catenin, ankyrinG, and voltage gated sodium channels at the AIS, both " in vitro " and " in vivo ", therefore diminishing neuronal excitability as evaluated via sodium current amplitude and action potential number."
"Signalling initiated by secreted WNT, through Frizzled receptors, leads to phosphorylation of the protein Dishevelled (DSH), which inhibits phosphorylation of ?-Cat by GSK3?.GSK3? activity can also be inhibited by direct interaction with the glycogen-synthase-kinase-3-binding protein (GBP).As a consequence, ?-Cat is not phosphorylated, avoids destruction and enters the nucleus where it heterodimerizes with members of the TCF/LEF transcription factor family to activate downstream target genes."
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"The mechanism involved 4 aspects : 1,25 (OH) 2D3 and VDR suppress transcriptional activity of beta-catenin and TCF, 1,25 (OH) 2D3 represses mRNA expression of the beta-catenin target gene of Gli1 but induces the beta-catenin target gene PADI1 in vitro, VDR ablation reduces beta-catenin target genes involved in hair differentiation in vivo, and 1,25 (OH) 2D3/VDR suppresses the transcriptional activity of beta-catenin and represses the mRNA expression of Gli1 [XREF_BIBR]."
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"The inhibition of TNKS sustained the life of axin and surged the extent of the devastation complex of β-catenin, which led decrease levels of β-catenin and increased the levels of phosphorylated β–catenin triggering inhibition of the Wnt/β-catenin driven proliferation of cancer cells ."
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"We found that the treatment with Wnt agonist RS-1 resulted in an increase in both the protein and mRNA expressions of β-catenin and C-myc in SGNs, while treatment with Wnt antagonist IWP-2 markedly reduced the expressions of β-catenin and C-myc in SGNs compared with the paclitaxel-only group."
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"Various beta-catenin and TCF inhibitors, most of them belonging to low molecular-weight inhibitors, downregulate the expression of beta-catenin and TCF-responsive genes and disrupt the interaction of element binding protein (CBP) with beta-catenin [XREF_BIBR] or disrupt beta-catenin and TCF complexes directly [XREF_BIBR]."
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"In vitro, WIF1 suppresses beta-catenin expression in osteosarcoma cell lines and induces differentiation of primary human osteoblasts, and in primary human osteosarcoma samples, silencing of WIF1 is associated with increased proliferation, increased beta-catenin expression, and loss of differentiation, implying that de-repression of Wnt signaling plays a positive role in osteosarcoma pathogenesis."
"Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation and inactivation of GSK3beta, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of beta-catenin The activation of Akt results in the phosphorylation of a number of downstream substrates such as glycogen synthase kinase (GSK3) It has been shown that GSK3 plays an important role in the Wnt pathway by regulating the degradation of -catenin Recently, a specific protein-protein interaction between -catenin and AR was identified by us and others (22, 23). Through this interaction, -catenin augments the ligand-dependent activity of AR in prostate cancer cells."
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"Therefore, HDAC3 could be a key positive regulator of β-catenin stability in leukemic cells.There is evidence that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the immunomodulatory enzymes cyclooxygenase-1/cyclooxygenase-2 (COX1/COX2), antagonize β-catenin expression and the stemness of leukemic cells [31,32,33,34]."
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"To confirm the role of beta-catenin and Wnt signaling in mediating myoblast phenotype induced by inhibition of GSK-3beta activity, we treated the cells either with beta-catenin RNAi to inhibit beta-catenin expression, or with DKK-1 (Dickkopf related protein-1), an established antagonist of canonical Wnt signaling."
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"By western blotting RGD treatment increased levels of active β-catenin, which was blocked by ILK inhibition, thus supporting a role for the regulation of active β-catenin levels via ILK in primary human MSCs (Fig. 2B).3.3
EGF-induced activation of beta-catenin may be unique to MSCs."
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"Additionally, after CTNNB1 siRNA applied to reduce the beta-catenin expression, we found the EMT like morphology induced by heat treatment disappeared, and the differences in migration, EMT markers and transcription factors between heated and non heated SUM-1315 and ZR-75-1 cells also diminished."
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"In early attempts to identify the function of APC, it was found that APC could directly interact with beta-catenin and decrease levels of cytoplasmic beta-catenin [XREF_BIBR - XREF_BIBR], whereas mutations of APC found in human colorectal cancer lead to accumulation of beta-catenin [XREF_BIBR, XREF_BIBR]."
"Importantly, mutations of FBW7 were found in three out of ten ovarian cancer cell lines analysed, indicating that mutations of FBW7 might be responsible for elevated levels of Cyclin E in this tumor The mammalian SCFb-Trcp (b-transducin repeat-containing protein) has been implicated in the regulation of at least two different signal transduction pathways, Wnt/Wingless and NF-kB, by mediating the ubiquitinylation and degradation of the transcriptional coactivator bcatenin and the NF-kB inhib itor IkB, respectively"
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"Mechanistically, Acp5 selectively bound and dephosphorylated β-catenin at serine (Ser) 33 and threonine (Thr) 41 in the cytoplasm, and then reduced the degradation of β-catenin, which enhanced the levels of β-catenin in the nucleus to promote fibroblast differentiation, proliferation and migration."
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"More importantly, pharmacological activation of Wnt and beta-catenin signaling restored the shear stress suppressed beta-catenin expression in LCSCs, and abolished the shear stress altered sphere forming ability, chemotherapeutic drug sensitivity, cancer stem cell marker expression, Young 's modulus and in vivo tumorigenicity potential of LCSCs."
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"Inhibition of beta-catenin degradation blocked chondrogenesis [XREF_BIBR] and expression of stabilized beta-catenin in chondrocytes led to severe chondrodysplasia and dramatic inhibition of chondrocyte differentiation [XREF_BIBR], suggesting that Wnt and beta-catenin signaling is under strict regulation during chondrocyte differentiation and excessive signaling activity caused chondrogenesis defects."
"We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo."
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"Results demonstrated beta-catenin knock-down not only inhibited beta-catenin expression under high-glucose conditions (P < 0.01) but also resulted in a further degree of MALAT1 down-regulation (P < 0.01), suggesting that nuclear translocated beta-catenin might be involved in the progression of MALAT1 expression."
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"The present study extends those previous findings by showing that the activation of PKCalpha by a novel agonist, CGK062, promotes beta-catenin degradation in three cancer cell lines - PC3 (prostate cancer), SNU475 (hepatoma), and SW480 (colon cancer) -which display aberrant up-regulation of the intracellular beta-catenin level."
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"Mechanistic experiments show that Acp5 is upregulated by TGF-β1 in a TGFβR1/Smad3-dependent manner, after which Acp5 selectively dephosphorylates p-β-catenin at Ser33 and Thr41 in the cytoplasm, reducing the degradation of β-catenin, by which the levels of β-catenin in the nucleus are enhanced, promoting fibroblast differentiation, proliferation and migration."
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"Meanwhile, AGE (100 microg/ml) activated GSK3beta kinase at 8-48 h. AGE (100 microg/ml) dose-dependently (75-100 microg/ml) decreased beta-catenin protein expression but AGE did not decrease beta-catenin protein expression until 48 h. SB216763 (a GSK3beta inhibitor) and GSK3beta shRNA attenuated AGE (100 microg/ml)-inhibited cell proliferation and protein expression of beta-catenin and cyclin D1 at 48 h. SB216763 also attenuated AGE induced type IV collagen."
"Phosphorylation of the S100A6-binding domain of Sgt1 by casein kinase II was inhibited by S100A6, a result suggesting that the role of S100A6 binding is to regulate the phosphorylation of Sgt1. These findings suggest that protein ubiquitination via Sgt1-dependent pathway can be regulated by S100 proteins. Because S100A6 and some other S100 proteins can interact with CacyBP/SIP and Sgt1, these S100 proteins could regulate both pathways in a similar fashion. The defects in ubiquitination and degradation of -catenin"