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• W2100086304 abstract "β-catenin (encoded by CTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signal transducer in the WNT signaling pathway; alterations in its activity have been associated with the development of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signaling pathways also can converge at β-catenin. β-catenin also interacts with transcription factors such as T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α to regulate the expression of target genes. We discuss the role of β-catenin in metabolic zonation of the adult liver. β-catenin also regulates the expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in its activity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in β-catenin signaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatic tumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations in CTNNB1 that result in constitutive activation of β-catenin, so this molecule could be a therapeutic target. We discuss how alterations in β-catenin activity contribute to liver disease and how these might be used in diagnosis and prognosis, as well as in the development of therapeutics. β-catenin (encoded by CTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signal transducer in the WNT signaling pathway; alterations in its activity have been associated with the development of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signaling pathways also can converge at β-catenin. β-catenin also interacts with transcription factors such as T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α to regulate the expression of target genes. We discuss the role of β-catenin in metabolic zonation of the adult liver. β-catenin also regulates the expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in its activity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in β-catenin signaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatic tumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations in CTNNB1 that result in constitutive activation of β-catenin, so this molecule could be a therapeutic target. We discuss how alterations in β-catenin activity contribute to liver disease and how these might be used in diagnosis and prognosis, as well as in the development of therapeutics. β-catenin is expressed throughout the adult liver. In hepatocytes, it is observed at the cell surface throughout the hepatic lobule, although it has cytoplasmic and nuclear localization in the hepatocytes that surround the central vein. In the normal adult liver, β-catenin signaling is always active in hepatocytes in the pericentral region, although it forms part of intercellular junctions elsewhere. Upon injury to the liver (surgical resection, toxic insult, infection, metabolic insult, or tumor growth), β-catenin localization and signaling change. These changes can contribute to reparative responses or to disease development. How is β-catenin signaling regulated in the healthy liver and how does it change during the development of specific diseases? We discuss its roles in WNT signaling and WNT-independent pathways. β-catenin is a component of the WNT signaling pathway; it usually is bound to a multiprotein degradation complex comprising casein kinase I, glycogen synthase kinase 3β (GSK3β), adenomatous polyposis coli gene product (APC), diversin, and axin (Figure 1). When WNT signaling is off as a result of the presence of WNT inhibitors such as WNT inhibitory factor, soluble frizzled-related proteins (sFRPs), Dickkopf and cerberus,1Cruciat C.M. Niehrs C. Secreted and transmembrane wnt inhibitors and activators.Cold Spring Harb Perspect Biol. 2013; 5: a015081Crossref PubMed Scopus (374) Google Scholar β-catenin is phosphorylated first at serine-45 (S45) by casein kinase I, followed by phosphorylation at S33, S37, and threonine-41 by GSK3β2Behrens J. Jerchow B.A. Wurtele M. et al.Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta.Science. 1998; 280: 596-599Crossref PubMed Scopus (1080) Google Scholar, 3Liu C. Li Y. Semenov M. et al.Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.Cell. 2002; 108: 837-847Abstract Full Text Full Text PDF PubMed Scopus (1572) Google Scholar, 4Amit S. Hatzubai A. Birman Y. et al.Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway.Genes Dev. 2002; 16: 1066-1076Crossref PubMed Scopus (569) Google Scholar (Figure 1). Once phosphorylated, β-catenin is recognized by β-transducin repeat-containing protein, which also requires intact lysine-19 and lysine-49 in β-catenin, for ubiquitination and proteosomal degradation of β-catenin5Aberle H. Bauer A. Stappert J. et al.Beta-catenin is a target for the ubiquitin-proteasome pathway.EMBO J. 1997; 16: 3797-3804Crossref PubMed Scopus (2090) Google Scholar, 6Winer I.S. Bommer G.T. Gonik N. et al.Lysine residues Lys-19 and Lys-49 of beta-catenin regulate its levels and function in T cell factor transcriptional activation and neoplastic transformation.J Biol Chem. 2006; 281: 26181-26187Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar (Figure 2).Figure 2β-catenin structure and role in adherens junctions. (A) Specific amino acids in β-catenin regulate its stability, activity, and interactions with other proteins. (B) In a normal liver, β-catenin acts as a bridge between the intracytoplasmic tail of E-cadherin and the actin cytoskeleton to regulate cell adhesion. Molecules such as HGF, EGF, FER kinase, and SRC can affect this complex negatively through tyrosine phosphorylation of β-catenin at specific residues. The end result of dissociation of the complex in some cases can result in nuclear translocation and activation of β-catenin. Left: in the absence of β-catenin, γ-catenin is able to maintain AJs by binding to E-cadherin and actin cytoskeleton. γ-Catenin did not compensate for nuclear β-catenin function. EGF, epidermal growth factor; JAM-A, junctional adhesion molecule-A; jxns, junctions.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Binding of active WNT to its cell surface receptor (frizzled) and co-receptor (low-density lipoprotein–related protein 5 or 6 [LRP5/6]) in an autocrine or paracrine manner inactivates the β-catenin degradation complex. For WNT proteins to be bioactive, they must be glycosylated and acylated, which is, mediated by porcupine.7Barrott J.J. Cash G.M. Smith A.P. et al.Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.Proc Natl Acad Sci U S A. 2011; 108: 12752-12757Crossref PubMed Scopus (113) Google Scholar After acylation, WNT proteins become hydrophobic and require a cargo receptor, Wntless (also called Evenness interrupted), for cellular transport and secretion.8Banziger C. Soldini D. Schutt C. et al.Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells.Cell. 2006; 125: 509-522Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, 9Bartscherer K. Pelte N. Ingelfinger D. et al.Secretion of Wnt ligands requires Evi, a conserved transmembrane protein.Cell. 2006; 125: 523-533Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar Upon inhibition of degradation complex, β-catenin is released and undergoes nuclear translocation, where it acts as a co-factor for the T-cell factor/lymphoid enhancement factor (TCF/LEF) family of transcription factors to regulate target gene expression (Figure 1). It is important to note that WNT can activate or sometimes inhibit β-catenin as well. An example worth noting is that of WNT5a, which has been considered a prototypical noncanonical WNT. However, its ability to activate β-catenin or inhibit it through activation of the WNT/calcium pathway was shown to be dependent on the form of frizzled available at the time for ligand binding10Mikels A.J. Nusse R. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.PLoS Biol. 2006; 4: e115Crossref PubMed Scopus (960) Google Scholar (Figure 1C). β-catenin is a component of the adherens junctions (AJs). It forms a bridge between the cytoplasmic domain of the cadherins and the actin cytoskeleton11Knudsen K.A. Soler A.P. Johnson K.R. et al.Interaction of alpha-actinin with the cadherin/catenin cell-cell adhesion complex via alpha-catenin.J Cell Biol. 1995; 130: 67-77Crossref PubMed Scopus (556) Google Scholar, 12Nieset J.E. Redfield A.R. Jin F. et al.Characterization of the interactions of alpha-catenin with alpha-actinin and beta-catenin/plakoglobin.J Cell Sci. 1997; 110: 1013-1022Crossref PubMed Google Scholar, 13Wheelock M.J. Knudsen K.A. Cadherins and associated proteins.In Vivo. 1991; 5: 505-513PubMed Google Scholar (Figure 2). Specific β-catenin binding sites on the cytoplasmic domain of cadherins have been characterized.14Huber A.H. Weis W.I. The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin.Cell. 2001; 105: 391-402Abstract Full Text Full Text PDF PubMed Scopus (578) Google Scholar, 15Jou T.S. Stewart D.B. Stappert J. et al.Genetic and biochemical dissection of protein linkages in the cadherin-catenin complex.Proc Natl Acad Sci U S A. 1995; 92: 5067-5071Crossref PubMed Scopus (301) Google Scholar Interactions between β-catenin and E-cadherin are regulated by tyrosine phosphorylation in the carboxy terminal of β-catenin. Phosphorylation of β-catenin destabilizes the cadherin–β-catenin bond and promotes loss of intracellular adhesion.16Ozawa M. Kemler R. Altered cell adhesion activity by pervanadate due to the dissociation of alpha-catenin from the E-cadherin.catenin complex.J Biol Chem. 1998; 273: 6166-6170Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 17Roura S. Miravet S. Piedra J. et al.Regulation of E-cadherin/catenin association by tyrosine phosphorylation.J Biol Chem. 1999; 274: 36734-36740Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar Conversely, dephosphorylation of β-catenin at tyrosine residues increases the activity of E-cadherin, and β-catenin and α-catenin reassembly.18Hu P. O'Keefe E.J. Rubenstein D.S. Tyrosine phosphorylation of human keratinocyte beta-catenin and plakoglobin reversibly regulates their binding to E-cadherin and alpha-catenin.J Invest Dermatol. 2001; 117: 1059-1067Abstract Full Text Full Text PDF PubMed Google Scholar After tyrosine phosphorylation of β-catenin, its cytosolic pool is increased, and may increase the transcriptional activity of the β-catenin–TCF complex.19Piedra J. Martinez D. Castano J. et al.Regulation of beta-catenin structure and activity by tyrosine phosphorylation.J Biol Chem. 2001; 276: 20436-20443Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Nonreceptor kinases such as sarcoma family kinase and Fps/fes (Feline sarcoma) related kinase phosphorylate β-catenin at tyrosine residues, leading to its dissociation from E-cadherin (Figure 2).20Rosato R. Veltmaat J.M. Groffen J. et al.Involvement of the tyrosine kinase fer in cell adhesion.Mol Cell Biol. 1998; 18: 5762-5770Crossref PubMed Google Scholar, 21Behrens J. Vakaet L. Friis R. et al.Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene.J Cell Biol. 1993; 120: 757-766Crossref PubMed Scopus (836) Google Scholar The epidermal growth factor receptor and epidermal growth factor receptor 2 are associated with β-catenin.22Hoschuetzky H. Aberle H. Kemler R. Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor.J Cell Biol. 1994; 127: 1375-1380Crossref PubMed Scopus (661) Google Scholar, 23Kanai Y. Ochiai A. Shibata T. et al.c-erbB-2 gene product directly associates with beta-catenin and plakoglobin.Biochem Biophys Res Commun. 1995; 208: 1067-1072Crossref PubMed Scopus (0) Google Scholar, 24Takahashi K. Suzuki K. Tsukatani Y. Induction of tyrosine phosphorylation and association of beta-catenin with EGF receptor upon tryptic digestion of quiescent cells at confluence.Oncogene. 1997; 15: 71-78Crossref PubMed Google Scholar Epidermal growth factor signaling can induce tyrosine phosphorylation of β-catenin at Y654 to decrease the association between β-catenin and E-cadherin, leading to enhanced β-catenin activity in the nuclei if its degradation by the proteasome is simultaneously inhibited.25Bonvini P. An W.G. Rosolen A. et al.Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription.Cancer Res. 2001; 61: 1671-1677PubMed Google Scholar Hepatocyte growth factor (HGF) induces phosphorylation of β-catenin at tyrosine residues 654 (Y654) and Y670 through direct interactions with MET (Figure 2).26Monga S.P. Mars W.M. Pediaditakis P. et al.Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes.Cancer Res. 2002; 62: 2064-2071PubMed Google Scholar, 27Shibamoto S. Hayakawa M. Takeuchi K. et al.Tyrosine phosphorylation of beta-catenin and plakoglobin enhanced by hepatocyte growth factor and epidermal growth factor in human carcinoma cells.Cell Adhes Commun. 1994; 1: 295-305Crossref PubMed Google Scholar, 28Zeng G. Apte U. Micsenyi A. et al.Tyrosine residues 654 and 670 in beta-catenin are crucial in regulation of Met-beta-catenin interactions.Exp Cell Res. 2006; 312: 3620-3630Crossref PubMed Scopus (0) Google Scholar In fact, β-catenin is required for liver growth in response to HGF in vivo.29Apte U. Zeng G. Muller P. et al.Activation of Wnt/beta-catenin pathway during hepatocyte growth factor-induced hepatomegaly in mice.Hepatology. 2006; 44: 992-1002Crossref PubMed Scopus (85) Google Scholar Hepatoblastomas, which frequently have deletions or missense mutations in exon 3 of the gene that encodes β-catenin (CTNNB1), express high levels of Y654 β-catenin, induced by HGF signaling via MET.30Purcell R. Childs M. Maibach R. et al.HGF/c-Met related activation of beta-catenin in hepatoblastoma.J Exp Clin Cancer Res. 2011; 30: 96Crossref PubMed Scopus (0) Google Scholar Fibrolamellar variants of hepatocellular cancers (HCCs) have higher levels of β-catenin phosphorylation at Y654 than nontumor liver tissues.31Cieply B. Zeng G. Proverbs-Singh T. et al.Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene.Hepatology. 2009; 49: 821-831Crossref PubMed Scopus (113) Google Scholar WNT signaling interacts with the transforming growth factor β (TGF-β) pathways. Complexes of β-catenin–TCF and SMAD4 interact with SMAD2 and SMAD3 after TGF-β signaling.32Nishita M. Hashimoto M.K. Ogata S. et al.Interaction between Wnt and TGF-beta signalling pathways during formation of Spemann's organizer.Nature. 2000; 403: 781-785Crossref PubMed Scopus (390) Google Scholar Subsets of HCC tissues have signs of activation of β-catenin after that of TGF-β.33Hoshida Y. Nijman S.M. Kobayashi M. et al.Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.Cancer Res. 2009; 69: 7385-7392Crossref PubMed Scopus (680) Google Scholar Intriguingly, the WNT target BMP and activin membrane-bound inhibitor inhibit the ability of TGF-β to inhibit proliferation, and could be involved in the development of HCC.34Sekiya T. Adachi S. Kohu K. et al.Identification of BMP and activin membrane-bound inhibitor (BAMBI), an inhibitor of transforming growth factor-beta signaling, as a target of the beta-catenin pathway in colorectal tumor cells.J Biol Chem. 2004; 279: 6840-6846Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar β-catenin forms a complex with the p65 subunit of the nuclear factor-κB (NF-κB) in hepatocytes to inhibit this transcription factor.35Nejak-Bowen K. Kikuchi A. Monga S.P. Beta-catenin-NF-kappaB interactions in murine hepatocytes: a complex to die for.Hepatology. 2013; 57: 763-774Crossref PubMed Scopus (43) Google Scholar Loss of β-catenin leads to NF-κB activation of genes that regulate cell survival. Mice with hepatocyte-specific disruption of β-catenin have reduced liver injury in response to tumor necrosis factor-α. Expression of NF-κB target genes increases when β-catenin is inhibited, and decreases when β-catenin is overexpressed.36Du Q. Zhang X. Cardinal J. et al.Wnt/beta-catenin signaling regulates cytokine-induced human inducible nitric oxide synthase expression by inhibiting nuclear factor-kappaB activation in cancer cells.Cancer Res. 2009; 69: 3764-3771Crossref PubMed Scopus (87) Google Scholar Studies are needed to determine whether interactions between NF-κB and β-catenin co-factor could be targeted by therapeutic agents. Prostaglandin E1 (PGE1) and isoproterenol activate protein kinase A (PKA) and also can activate β-catenin. PKA phosphorylates β-catenin at S675 to help stabilize and activate it.37Hino S. Tanji C. Nakayama K.I. et al.Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination.Mol Cell Biol. 2005; 25: 9063-9072Crossref PubMed Scopus (311) Google Scholar Cyclic adenosine monophosphate–dependent activation of PKA leads to phosphorylation of β-catenin at S552 and S675 to promote its ability to regulate transcription38Taurin S. Sandbo N. Qin Y. et al.Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase.J Biol Chem. 2006; 281: 9971-9976Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar (Figure 2A). PGE2 activates β-catenin via cyclic adenosine monophosphate and PKA during induction and engraftment of hematopoietic stem cells. PGE2 might cooperate with WNT to induce β-catenin activation during liver regeneration.39Goessling W. North T.E. Loewer S. et al.Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration.Cell. 2009; 136: 1136-1147Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar PKA activation was required for triiodothyronine-induced activation of β-catenin, expression of cyclin D1, and proliferation of hepatocytes.40Fanti M. Singh S. Ledda-Columbano G.M. et al.Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent beta-catenin activation in rodents.Hepatology. 2014; 59: 2309-2320Crossref PubMed Scopus (43) Google Scholar Recently, phosphorylation of β-catenin at S675 was shown to mediate fibrocystin-defective congenital hepatic fibrosis in mice.41Spirli C. Locatelli L. Morell C.M. et al.Protein kinase A-dependent pSer(675) -beta-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis.Hepatology. 2013; 58: 1713-1723Crossref PubMed Scopus (0) Google Scholar β-catenin does not bind DNA directly, but it interacts with and regulates the activities of transcription factors. For example, β-catenin activates gene expression by interacting with the TCF/LEF family of transcription factors. β-catenin binds other transcription factors under different conditions. The interactions between β-catenin with various transcription factors allows it to control many different functions of liver cells. In the nucleus, β-catenin co-activates the high mobility group box containing the DNA binding protein TCF/LEF family of transcription factors42Riese J. Yu X. Munnerlyn A. et al.LEF-1, a nuclear factor coordinating signaling inputs from wingless and decapentaplegic.Cell. 1997; 88: 777-787Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar, 43Brannon M. Gomperts M. Sumoy L. et al.A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus.Genes Dev. 1997; 11: 2359-2370Crossref PubMed Google Scholar (see Stadeli et al44Stadeli R. Hoffmans R. Basler K. Transcription under the control of nuclear Arm/beta-catenin.Curr Biol. 2006; 16: R378-R385Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar for a full description). Once the TCF-β–catenin complex is formed in the nucleus, expression of target genes is stage- and tissue-specific (Table 1).Table 1Genes Regulated by WNT Signaling to β-Catenin in the LiverTarget genesLiver modelCo-factor for TFReferenceAxin-2HCA, hepatoblastoma, and HCCTCF4142Lopez-Terrada D. Gunaratne P.H. Adesina A.M. et al.Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors.Hum Pathol. 2009; 40: 783-794Crossref PubMed Scopus (108) Google Scholar, 153Yan D. Wiesmann M. Rohan M. et al.Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/beta -catenin signaling is activated in human colon tumors.Proc Natl Acad Sci U S A. 2001; 98: 14973-14978Crossref PubMed Scopus (0) Google ScholarMYCHBTCF4142Lopez-Terrada D. Gunaratne P.H. Adesina A.M. et al.Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors.Hum Pathol. 2009; 40: 783-794Crossref PubMed Scopus (108) Google Scholar, 154Ranganathan S. Tan X. Monga S.P. beta-Catenin and met deregulation in childhood hepatoblastomas.Pediatr Dev Pathol. 2005; 8: 435-447Crossref PubMed Scopus (0) Google ScholarCyclin-D1Normal liver, LD, LR, hepatoblastoma, HCCTCF453Tan X. Behari J. Cieply B. et al.Conditional deletion of beta-catenin reveals its role in liver growth and regeneration.Gastroenterology. 2006; 131: 1561-1572Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 142Lopez-Terrada D. Gunaratne P.H. Adesina A.M. et al.Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors.Hum Pathol. 2009; 40: 783-794Crossref PubMed Scopus (108) Google Scholar, 154Ranganathan S. Tan X. Monga S.P. beta-Catenin and met deregulation in childhood hepatoblastomas.Pediatr Dev Pathol. 2005; 8: 435-447Crossref PubMed Scopus (0) Google Scholar, 155Gotoh J. Obata M. Yoshie M. et al.Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis.Carcinogenesis. 2003; 24: 435-442Crossref PubMed Scopus (0) Google Scholar, 156Sekine S. Gutierrez P.J. Lan B.Y. et al.Liver-specific loss of beta-catenin results in delayed hepatocyte proliferation after partial hepatectomy.Hepatology. 2007; 45: 361-368Crossref PubMed Scopus (106) Google Scholar, 157Tan X. Yuan Y. Zeng G. et al.Beta-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development.Hepatology. 2008; 47: 1667-1679Crossref PubMed Scopus (141) Google ScholarEpidermal growth factor receptorNormal liver and hepatoblastomaTCF4123Tan X. Apte U. Micsenyi A. et al.Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver.Gastroenterology. 2005; 129: 285-302Abstract Full Text Full Text PDF PubMed Scopus (189) Google ScholarG-protein–coupled receptor 49HCCTCF4158Yamamoto Y. Sakamoto M. Fujii G. et al.Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations.Hepatology. 2003; 37: 528-533Crossref PubMed Scopus (176) Google ScholarGlutamate transporter-1Normal liverTCF4159Cadoret A. Ovejero C. Terris B. et al.New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism.Oncogene. 2002; 21: 8293-8301Crossref PubMed Scopus (303) Google ScholarGlutamine synthetaseNormal liver, HCC, hepatoblastoma, HCATCF451Benhamouche S. Decaens T. Godard C. et al.Apc tumor suppressor gene is the “zonation-keeper” of mouse liver.Dev Cell. 2006; 10: 759-770Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar, 52Sekine S. Lan B.Y. Bedolli M. et al.Liver-specific loss of beta-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice.Hepatology. 2006; 43: 817-825Crossref PubMed Scopus (195) Google Scholar, 89Bioulac-Sage P. Rebouissou S. Thomas C. et al.Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry.Hepatology. 2007; 46: 740-748Crossref PubMed Scopus (428) Google Scholar, 96Zucman-Rossi J. Benhamouche S. Godard C. et al.Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas.Oncogene. 2007; 26: 774-780Crossref PubMed Scopus (186) Google Scholar, 142Lopez-Terrada D. Gunaratne P.H. Adesina A.M. et al.Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors.Hum Pathol. 2009; 40: 783-794Crossref PubMed Scopus (108) Google Scholar, 159Cadoret A. Ovejero C. Terris B. et al.New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism.Oncogene. 2002; 21: 8293-8301Crossref PubMed Scopus (303) Google Scholar, 160Loeppen S. Schneider D. Gaunitz F. et al.Overexpression of glutamine synthetase is associated with beta-catenin-mutations in mouse liver tumors during promotion of hepatocarcinogenesis by phenobarbital.Cancer Res. 2002; 62: 5685-5688PubMed Google ScholarOrnithine aminotransferaseNormal liverTCF4159Cadoret A. Ovejero C. Terris B. et al.New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism.Oncogene. 2002; 21: 8293-8301Crossref PubMed Scopus (303) Google ScholarSurvivinHCC161Zhang T. Otevrel T. Gao Z. et al.Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer.Cancer Res. 2001; 61: 8664-8667PubMed Google ScholarT-cell factor-1HCCTCF4162Roose J. Huls G. van Beest M. et al.Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1.Science. 1999; 285: 1923-1926Crossref PubMed Scopus (395) Google ScholarLect2Normal liver/HCCTCF496Zucman-Rossi J. Benhamouche S. Godard C. et al.Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas.Oncogene. 2007; 26: 774-780Crossref PubMed Scopus (186) Google Scholar, 163Okabe H. Delgado E. Lee J.M. et al.Role of leukocyte cell-derived chemotaxin 2 as a biomarker in hepatocellular carcinoma.PLoS One. 2014; 9: e98817Crossref PubMed Google Scholar, 164Ovejero C. Cavard C. Perianin A. et al.Identification of the leukocyte cell-derived chemotaxin 2 as a direct target gene of beta-catenin in the liver.Hepatology. 2004; 40: 167-176Crossref PubMed Scopus (94) Google ScholarVascular endothelial growth factor AHCC and ischemia-reperfusion injuryTCF4/HIF1α46Lehwald N. Tao G.Z. Jang K.Y. et al.Wnt-beta-catenin signaling protects against hepatic ischemia and reperfusion injury in mice.Gastroenterology. 2011; 141 (718 e1–5): 707-718Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 165Delgado E. Bahal R. Yang J. et al.β-Catenin knockdown in liver tumor cells by a cell permeable gamma guanidine-based peptide nucleic acid.Curr Cancer Drug Targets. 2013; 13: 867-878Crossref PubMed Scopus (25) Google Scholar, 166Zhang X. Gaspard J.P. Chung D.C. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia.Cancer Res. 2001; 61: 6050-6054PubMed Google ScholarRegucalcinNormal liver and HCCTCF4167Nejak-Bowen K.N. Zeng G. Tan X. et al.Beta-catenin regulates vitamin C biosynthesis and cell survival in murine liver.J Biol Chem. 2009; 284: 28115-28127Abstract Full Text Full Text PDF PubMed Scopus (39) Google ScholarConstitutive androstane receptorNormal liverTCF458Gougelet A. Torre C. Veber P. et al.T-cell factor 4 and beta-catenin chromatin occupancies pattern zonal liver metabolism in mice.Hepatology. 2014; 59: 2344-2357Crossref PubMed Scopus (90) Google ScholarCYP1A2Normal liverTCF458Gougelet A. Torre C. Veber P. et al.T-cell factor 4 and beta-catenin chromatin occupancies pattern zonal liver metabolism in mice.Hepatology. 2014; 59: 2344-2357Crossref PubMed Scopus (90) Google ScholarGlucose-6-phosphataseNormal liverFOXO50Liu H. Fergusson M.M. Wu J.J. et al.Wnt signaling regulates hepatic metabolism.Sci Signal. 2011; 4: ra6Crossref PubMed Scopus (127) Google ScholarPhosphoenol-pyruvate carboxykinaseNormal liverFOXO50Liu H. Fergusson M.M. Wu J.J. et al.Wnt signaling regulates hepatic metabolism.Sci Signal. 2011; 4: ra6Crossref PubMed Scopus (127) Google ScholarErythropoietinIschemia-reperfusion injuryHIF1α46Lehwald N. Tao G.Z. Jang K.Y. et al.Wnt-beta-catenin signaling protects against hepatic ischemia and reperfusion injury in mice.Gastroenterology. 2011; 141 (718 e1–5): 707-718Abstract Full Text Full Text PDF PubMed Scopus (85) Google ScholarClaudin-2Normal liverTCF453Tan X. Behari J. Cieply B. et al.Conditional deletion of beta-catenin reveals its role in liver growth and regeneration.Gastroenterology. 2006; 131: 1561-1572Abstract Full Text Full Text PDF PubMed Scopus (265) Google ScholarLD, liver development; LR, liver regeneration; TF, transcription factor. Open table in a new tab LD, liver development; LR, liver regeneratio" @default.
• W2100086304 created "2016-06-24" @default.
• W2100086304 creator A5082852521 @default.
• W2100086304 date "2015-06-01" @default.
• W2100086304 modified "2023-10-14" @default.
• W2100086304 title "β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis" @default.
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