Disease relevance of Ctnnb1

• In contrast, Ctnnb1 mutations were completely absent in 23 PhIP-induced mammary tumors, in accordance with recent work showing that human breast carcinomas lack mutations in CTNNB1 [1].
• Activating mutations in the beta-catenin (CTNNB1) gene corresponding to N-terminal phosphorylation sites in the protein have been implicated in the development of human colon cancer [1].
• Whether beta-catenin plays a role in the controlled proliferative and migratory responses to injury, eg, of vascular endothelial cells during neovascularization after myocardial infarction (MI), is not known [2].
• In colon tumors, beta-catenin gene mutations were found in two of three adenomas (67%) and 26 of 28 adenocarcinomas (93%), with a total incidence of 90% (28 of 31 adenomas plus adenocarcinomas) [3].
• This study examined the major components of adherens junctions, E-cadherin, alpha-catenin, beta-catenin, and actin, during the initial phase of experimental pancreatitis [4].

High impact information on Ctnnb1

• Mechanistically, we show that quiescent blood vessels contain a complex involving Flk, VE-cadherin, and beta-catenin that is transiently disrupted by VEGF injection [5].
• Here, we demonstrate that beta-catenin, which mediates interactions between cadherins and the actin cytoskeleton, moves from dendritic shafts into spines upon depolarization, increasing its association with cadherins. beta-catenin's redistribution was mimicked or prevented by a tyrosine kinase or phosphatase inhibitor, respectively [6].
• In Y654F-expressing neurons, the PSD-95 or associated synapsin-I clusters were larger than those observed in either wild-type-beta-catenin or also Y654E-expressing neurons [6].
• E-cadherin/beta-catenin complexes disintegrated and reassembled completely in parallel on immunoprecipitation experiments [4].
• Thus, beta-catenin binding to the whole cytoplasmic domain of E-cadherin correlates with efficient and targeted delivery of E-cadherin to the lateral plasma membrane [7].

Chemical compound and disease context of Ctnnb1

• Representatively, a key redox-status regulatory protein, manganese superoxide dismutase, up-regulated in IEC6 cells expressing stabilized beta-catenin protein, was overexpressed in adenoma and adenocarcinoma cells of familial adenomatous polyposis patients in parallel with the accumulation of beta-catenin [8].
• In this study, mutations in the region corresponding to N-terminal phosphorylation sites (codons 1-51) of the rat Ctnnb1 gene were investigated in 20 colon tumors associated with ulcerative colitis and induced with methylazoxymethanol acetate and 1-hydroxyanthraquinone [9].
• To allow a study of beta-catenin mutations in hepatocellular carcinomas (HCCs) induced by exogenous and endogenous carcinogens, we induced tumors in male Fischer 344 rats with N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet [10].
• Different frequencies and patterns of beta-catenin mutations in hepatocellular carcinomas induced by N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet in rats [10].
• Groups 1 - 3 were administered azoxymethane (AOM) s.c. at a dose of 15 mg / kg body weight, once weekly for 3 weeks to induce beta-catenin-accumulated crypts [11].

Biological context of Ctnnb1

• Based on the newly acquired knowledge of the primary sequence, more than a dozen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced rat liver tumors were screened for the presence or absence of mutations in all 14 exons of rat Ctnnb1 [12].
• We found the rat Ctnnb1 gene to contain 14 exons, ranging in size from 61 to 356 bp, and 13 introns ranging in size from 76 to 2524 bp [12].
• Mutations in the region corresponding to the N-terminal phosphorylation sites (codons 1-51) of the rat beta-catenin gene (Ctnnb1) were investigated in rat colon tumors induced by 1-hydroxyanthraquinone (1-HA) plus methylazoxymethanol (MAM) acetate, by using polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis [3].
• Thus, changes in the wnt pathway during regulated growth seem to tightly regulate cytosolic beta-catenin levels and may be contributing to induce cell proliferation and target gene expression [13].
• Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration [13].

Anatomical context of Ctnnb1

• We found wnt-1 and beta-catenin proteins to be predominantly localized in hepatocytes [13].
• In the present study, we examined the expression of beta-catenin in rat colon tumors induced by azoxymethane in comparison with adjacent normal colon mucosa by immunostaining and immunoblotting [14].
• Thus, beta-catenin was stably retained at the lateral cell membrane in tuberin-null renal cells lacking membrane-localized polycystin-1 and E-cadherin [15].
• (3) The cadherin-linked molecule beta-catenin, absent in fibrocytes, was detected in all epithelial cell membranes and was prominent in the E-cad-rich modiolar extremity of Kölliker's organ [16].
• In skeletal muscle, both insulin and exercise decrease GSK-3beta activity, and we tested the hypothesis that these two stimuli regulate beta-catenin [17].

Associations of Ctnnb1 with chemical compounds

• To determine the possible involvement of such mutations during chemically induced colon carcinogenesis, we examined the corresponding region of Ctnnb1 in colon tumors induced in the F344 rat by two cooked meat heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) [1].
• Such frequent mutations of the beta-catenin gene in azoxymethane-induced rat colon tumors suggest that consequent alterations in the stability and localization of the protein may play an important role in this colon carcinogenesis model [14].
• We show this increase to be the result of decreased degradation of beta-catenin (decrease in serine phosphorylated beta-catenin) as seen by immunoprecipitation studies [13].
• Glycogen Synthase Kinase-3 Inactivation and Stabilization of beta-Catenin Induce Nephron Differentiation in Isolated Mouse and Rat Kidney Mesenchymes [18].
• Retention of membrane-localized beta-catenin in cells lacking functional polycystin-1 and tuberin [15].
• These findings suggest an indirect pathway for Bcl-2 over-expression in PhIP-induced colon tumors involving beta-catenin, c-Myc and E2F1 [19].

Physical interactions of Ctnnb1

• We observed activation of beta-catenin degradation complex comprising of adenomatous polyposis coli gene product (APC) and serine-phosphorylated axin protein, beginning at 5 minutes after hepatectomy, leading to its decreased levels after this time [13].
• In some cell types, but not in others, activated beta-catenin interacts with members of the lymphoid enhancer-binding factor (LEF)/T-cell factor (TCF) family of transcription factors and induces gene expression [20].
• We previously reported that beta-catenin binds S-SCAM and recruits it to synapses [21].
• Overexpression of either Wnt-4 or a stabilized form of beta-catenin promoted growth plate chondrocyte terminal differentiation [22].

Regulatory relationships of Ctnnb1

• Furthermore, Axil enhanced GSK-3beta-dependent phosphorylation of beta-catenin [23].
• HGF induces dose-dependent nuclear translocation of beta-catenin in primary hepatocyte cultures that is Wnt independent [24].
• To investigate one aspect of the mechanisms, we focused on the role of tenascin C in regulating the migratory mobility of the progenitor cells via beta-catenin [25].
• In addition, the overexpression of Wnt-4 and beta-catenin promoted the cell cycle and increased the promoter activity and protein expression of cyclin D1 in LLC-PK1 cells [26].
• In vitro prolactin treatment induced even greater expression of beta-catenin in islet cells [27].

Other interactions of Ctnnb1

• In conclusion, exercise in vivo, but not insulin, increases the association between Dvl and GSK-3beta in skeletal muscle, an event paralleled by beta-catenin dephosphorylation [17].
• Comparative expression patterns of T-, N-, E-cadherins, beta-catenin, and polysialic acid neural cell adhesion molecule in rat cochlea during development: implications for the nature of Kölliker's organ [16].
• Immunoblotting demonstrated that Dvl, Axin, GSK-3beta, and beta-catenin proteins are expressed in rat red and white gastrocnemius muscles [17].
• By contrast, significantly stronger beta-catenin and Cyclin D1 mRNA expressions and protein levels were found in CsA-treated rats than controls by RT-PCR and immunohistochemistry at week 4, whereas PCNA production was stronger at both times [28].
• Stabilization and accumulation of cytoplasmic beta-catenin, which result from mutations in either the adenomatous polyposis coli or beta-catenin genes, are causatively associated with colon carcinogenesis [14].

Analytical, diagnostic and therapeutic context of Ctnnb1

• In addition, using immunoprecipitation, we observe elevated levels of tyrosine-phosphorylated beta-catenin at 6 hours onward [13].
• Immediately following partial hepatectomy, we observed an initial increase in beta-catenin protein during the first 5 minutes with its translocation to the nucleus [13].
• The expression and distribution of neural cell adhesion molecule (NCAM), cadherins and beta-catenin were investigated in the CG-4 cell line and primary rat oligodendrocyte progenitor cells (O-2A) by immunofluorescence and Western blotting [29].
• Western blot and RT-PCR demonstrated that dexamethasone up-regulated beta-catenin protein and transcript expression and nearly ablated beta-catenin phosphorylation under conditions that led to a significant increase in monolayer transepithelial resistance [30].
• Indirect immunofluorescence revealed that dexamethasone treatment also caused beta-catenin to localize predominantly at the cell membrane rather than the nucleus [30].

References