Disease relevance of Ctnnb1

• Gene expression patterns in perivenous hepatocytes and Ctnnb1 mutated hepatoma cells were strongly correlated: 96.5% of the genes present in both datasets were regulated in the same direction [1].
• In colon cancer, decreased E-cadherin/beta-catenin association is causally linked to increased beta-catenin-regulated gene expression and increased cellular division [2].
• To address this question, we used the transmissible murine colonic hyperplasia model to measure changes in beta-catenin abundance, nuclear partitioning, target gene (c-myc and cyclin D1) expression, and subcellular distribution [2].
• These results suggest that the reduced APC protein level increases intestinal polyp multiplicity through quantitative stimulation of the beta-catenin/T-cell factor transcription [3].
• The adenomatous polyposis coli (APC) gene, whose mutations are responsible for familial adenomatous polyposis, is a major negative controller of the Wnt/beta-catenin pathway [3].
• The expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized beta-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in beta-catenin-induced lymphomas [4].
• We found that although loss of alphaE-catenin resulted in disruption of intercellular adhesion and hyperplasia in the developing brain, beta-catenin signaling was not altered [5].

Psychiatry related information on Ctnnb1

• Although an association between the product of the familial Alzheimer's disease (FAD) gene, presenilin 1 (PS1), and beta-catenin has been reported recently, the cellular consequences of this interaction are unknown [6].
• In addition, exploratory behavior by mice resulted in a similar cleavage of beta-catenin, as well as activation of the Tcf signaling pathway, in hippocampal neurons [7].

High impact information on Ctnnb1

• The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector beta-catenin [8].
• Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of beta-catenin [8].
• Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly [9].
• Prevailing dogma is that cadherins are linked to the actin cytoskeleton through beta-catenin and alpha-catenin, although the quaternary complex has never been demonstrated [10].
• Monomeric alpha-catenin binds more strongly to E-cadherin-beta-catenin, whereas the dimer preferentially binds actin filaments [9].

Chemical compound and disease context of Ctnnb1

• In total, mutations of the Trp53, Hras1 and/or Catnb genes were identified in 15 out of 17 1,3-butadiene-induced mammary adenocarcinomas [11].
• Carnosol inhibits beta-catenin tyrosine phosphorylation and prevents adenoma formation in the C57BL/6J/Min/+ (Min/+) mouse [12].
• Activation of the beta-catenin/Lef-Tcf pathway is obligate for formation of primitive endoderm by mouse F9 totipotent teratocarcinoma cells in response to retinoic acid [13].
• In summary, we show that CN-induced chemical anoxia activates c-Src and induces its translocation to cell-cell junctions where it binds to and phosphorylates beta-catenin and p120 [14].
• Colonic adenocarcinomas rapidly induced by the combined treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate in male ICR mice possess beta-catenin gene mutations and increases immunoreactivity for beta-catenin, cyclooxygenase-2 and inducible nitric oxide synthase [15].
• Neither acute lithium nor beta-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior [16].

Biological context of Ctnnb1

• Beta-catenin is essential for cadherin-based cell adhesion and Wnt/Wingless growth factor signaling [17].
• beta-Catenin is an essential molecule in Wnt/wingless signaling, which controls decisive steps in embryogenesis [18].
• beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin [18].
• The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound beta-catenin (Catnb) and has a key role in cell-fate determination [19].
• Our results imply that constitutive activation of the Apc/beta-catenin signaling pathway results in differentiation defects in tissue homeostasis, and possibly underlies tumorigenesis in the colon and other self-renewing tissues [19].

Anatomical context of Ctnnb1

• If beta-catenin is deleted after hair follicles have formed, hair is completely lost after the first hair cycle [18].
• Further analysis demonstrates that beta-catenin is essential for fate decisions of skin stem cells: in the absence of beta-catenin, stem cells fail to differentiate into follicular keratinocytes, but instead adopt an epidermal fate [18].
• We provide genetic and molecular evidence that the ability and sensitivity of ES cells to differentiate into the three germ layers is inhibited by increased doses of beta-catenin by specific Apc mutations [19].
• Our data demonstrate that beta-catenin function is essential in anterior-posterior axis formation in the mouse, and experiments with chimeric embryos show that this function is required in the embryonic ectoderm [20].
• N-cadherin-dependent cell-cell contact regulates Rho GTPases and beta-catenin localization in mouse C2C12 myoblasts [21].

Associations of Ctnnb1 with chemical compounds

• Beta-catenin detected in Triton X-100-soluble (cytosolic) cellular fractions was enriched 4.3 +/- 0.9 (SD)-fold, whereas a modest decrease of 0.9 +/- 0.09 (SD)-fold was recorded in Triton X-100-insoluble (cytoskeletal) fractions [2].
• In contrast to the effects of Wnt-1, v-Src does not modulate the uncomplexed population of beta-catenin. p120(cas) is phosphorylated on tyrosine by v-Src, and this is accompanied by a significant decrease in the level of uncomplexed p120(cas) as well as a change in behavior of p120(cas) upon biochemical fractionation [22].
• Glycogen Synthase Kinase-3 Inactivation and Stabilization of beta-Catenin Induce Nephron Differentiation in Isolated Mouse and Rat Kidney Mesenchymes [23].
• Direct metabolic regulation of beta-catenin activity by the p85alpha regulatory subunit of phosphoinositide 3-OH kinase [24].
• This regulation occurs at the level of glycogen synthase kinase 3 (GSK3), a serine/threonine kinase that marks beta-catenin to enter a destruction pathway [24].
• Conditions that increased basal beta-catenin levels, such as lithium chloride treatment or repression of caveolin-1 expression, were shown to enhance the effects of strain [25].

Physical interactions of Ctnnb1

• DeltaNp63alpha also associates with and blocks activation of the adenomatous polyposis coli (APC) destruction complex that targets free cytoplasmic beta-catenin for degradation [26].
• T cell factor / lymphocyte enhancer factor (Tcf/Lef) transcription factors complex with the transcriptional co-activator beta-catenin to transduce Wnt signals in a variety of developmental systems [27].
• Although beta-catenin interacts tightly with E-cadherin, it does not seem to be associated with either desmoglein I or with isolated desmosomes [28].
• In addition, the regulatory subunit p85alpha directly binds beta-catenin, but the role of this interaction in the context of the lipid kinase regulation of beta-catenin signaling is unknown [24].
• Beta-catenin physically interacts through its Armadillo repeats with the C-terminal transactivation domain of Sox9 [29].
• SFRP2 stabilizes beta-catenin, activates its target genes, and enhances cell proliferation [30].
• Sox9 binds to beta-catenin and components of the beta-catenin "destruction complex," glycogen synthase kinase 3 and beta-transducin repeat containing protein, to promote their nuclear localization [31].

Enzymatic interactions of Ctnnb1

• Beta-catenin is a major tyrosine-phosphorylated protein during mouse oocyte maturation and preimplantation development [32].
• In addition, the expression of mutated PS1 elevated the level of phosphorylated beta-catenin, which is targeted to the ubiquitin/proteasome pathway [33].

Co-localisations of Ctnnb1

• Both SMAD3 and beta-catenin co-localized to the nucleus after TGF-beta treatment [34].
• Furthermore, beta-catenin colocalized with transcription factor LEF-1 in the nucleus, and coprecipitated with LEF-1-related proteins from cell extracts [35].
• Consistent with these data, chromatin immunoprecipitation assays from either embryocarcinoma cells or from the tail bud of embryos revealed that LEF1 and beta-catenin co-localize with the Cdx4 promoter [36].
• The tumor suppressor protein APC colocalizes with beta-catenin in the colon epithelial cells [37].

Regulatory relationships of Ctnnb1

• Thus, PS1 adds to the molecules that are known to regulate the rapid turnover of beta-catenin [38].
• In this study, we found that TGF-beta rapidly induced beta-catenin protein levels and signaling in murine neonatal sternal primary chondrocytes [34].
• Previous work has shown that the transcriptional regulator beta-catenin can translocate to the nuclei when cells are stimulated with the type 1 insulin-like growth factor (IGF-1) [39].
• Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2 [40].
• The inability of Gadd45a-null keratinocytes to suppress beta-catenin may contribute to the resulting observation of increased MMP expression and activity along with significantly faster keratinocyte migration in Matrigel in vitro and accelerated wound closure in vivo [26].
• As Wt1 conditional knockout in Sertoli cells causes similar phenotypes to our stabilized beta-catenin mutants, we then investigated the relationship of Wt1 and beta-catenin in Sertoli cells and found Wt1 inhibits beta-catenin signaling in these cells during testis development [41].

Other interactions of Ctnnb1

• Regulated exchange of HDAC1/beta-catenin converts Pitx2 from repressor to activator, analogous to control of TCF/LEF1 [42].
• We show that beta-catenin is required genetically downstream of tabby/downless and upstream of bmp and shh in placode formation [18].
• Beta-catenin is a central player in the Wnt pathway and in cadherin-mediated cell adhesion [20].
• Three proteins identified by quite different criteria in three different systems, the Drosophila segment polarity gene armadillo, the human desmosomal protein plakoglobin, and the Xenopus E-cadherin-associated protein beta-catenin, share amino acid sequence similarity [28].
• Finally, we show an altered response to Wnt signaling and impaired ubiquitination of beta-catenin in the absence of PS1, a phenotype that may account for the increased stability in PS1-deficient cells [38].
• E-cadherin downregulates beta-catenin/Tcf-mediated transcriptional activity by sequestrating beta-catenin into E-cadherin cell-adhesion complexes even in the presence of activated Wnt signaling [43].
• We propose that in motile cells beta-catenin is recruited by IQGAP1 and N-cadherin to active membrane ruffles, wherein beta-catenin mediates the internalization and possible recycling of the membrane-associated proteins N-cadherin and APC [44].
• Spatial restriction of Ripply2 to the anterior PSM is ensured by the Wnt3a/beta-catenin-mediated repression of Ripply2 in posterior PSM [45].

Analytical, diagnostic and therapeutic context of Ctnnb1

• Liver-specific loss of beta-catenin results in delayed hepatocyte proliferation after partial hepatectomy [46].
• These defects in cell adhesion and tissue organization are explained by loss of E-cadherin and beta-catenin localization to cell adhesion sites in both cell culture and in the intact embryos [47].
• beta-Catenin functions as a transducer of Wnt signals to the nucleus, where it interacts with the T cell factor (TCF) family of DNA binding proteins to regulate gene expression [48].
• Subcutaneous injection of EGF or TGF-beta1 before wounding of TCF-beta-gal mice resulted in larger scars and fibroblasts within these wounds that strongly stained for beta-galactosidase, indicating significant beta-catenin transcriptional activity in vivo [49].
• Almost 90% (34/38) of all tumors from PCB 153-treated animals contained Catnb mutations, which compares to approximately 45% (17/37) of tumors in the control group [50].

References