Supplemental Data Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases

F. M. Kirby Neurobiology Center, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Developmental Cell (Impact Factor: 9.71). 08/2009; 17(1):9-26. DOI: 10.1016/j.devcel.2009.06.016
Source: PubMed


Signaling by the Wnt family of secreted glycolipoproteins via the transcriptional coactivator beta-catenin controls embryonic development and adult homeostasis. Here we review recent progress in this so-called canonical Wnt signaling pathway. We discuss Wnt ligands, agonists, and antagonists, and their interactions with Wnt receptors. We also dissect critical events that regulate beta-catenin stability, from Wnt receptors to the cytoplasmic beta-catenin destruction complex, and nuclear machinery that mediates beta-catenin-dependent transcription. Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications.

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    • "The main effector in this pathway is β-catenin, which in the absence of Wnt signals is phosphorylated in its amino terminus by CK1α and GSK3β, events coordinated by the scaffold proteins Axin and APC. Phospho-β-catenin is ubiquitinated by TrCP-E3 ligase and thereby targeted to proteasomal degradation (Macdonald et al., 2009). Upon binding of Wnt ligands or misregulation of the degradation process, stabilized β-catenin import to the nucleus and activates transcription of many genes, which is a feature shared by different cancers, including colorectal (Bienz and Clevers, 2000), ovarian (Jamieson et al., 2004) and brain (Zhang et al., 2011). "
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    DESCRIPTION: The key protein in the canonicalWnt pathway is β-catenin, which is phosphorylated both in absence and presence ofWnt signals by different kinases. Upon activation in the cytoplasm, β-catenin can enter into the nucleus to transactivate target gene expression, many of which are cancer-related genes. The mechanism governing β- catenin's nucleocytoplasmic transport has been recently unvealed, although phosphorylation at its C-terminal end and its functional consequences are not completely understood. Serine 646 of β-catenin is a putative CK2 phosphorylation site and lies in a region which has been proposed to be important for its nucleocytoplasmic transport and transactivation activity. This residue was mutated to aspartic acid mimicking CK2- phosphorylation and its effects on β-catenin activity as well as localization were explored. β-Catenin S6464D did not show significant differences in both transcriptional activity and nuclear localization compared to the wild-type form, but displayed a characteristic granular nuclear pattern. Three-dimensional models of nuclei were constructed which showed differences in number and volume of granules, being those from β-catenin S646D more and smaller than the wild-type form. FRAP microscopy was used to compare nuclear export of both proteins which showed a slightly higher but not significant retention of β-catenin S646D. Altogether, these results show that C-terminal phosphorylation of β-catenin seems to be related with its nucleocytoplasmic transport but not transactivation activity.
    • "While many genetic mutations occur during the multi-step pathogenesis of CRC, among the earliest and most common events is the failure of the adenomatous polyposis coli (APC) tumor suppressor gene function (De Filippo et al., 2002). APC acts as a tumor suppressor by composing proteolytic destruction complex, which negatively regulates the Wnt signaling pathway (Stamos and Weis, 2013) by degradation of β-catenin, a transcriptional coactivator of the Wnt signaling pathway (MacDonald et al., 2009). Consequently, loss of APC stabilizes β-catenin and allows its subsequent translocation to the nucleus and activation of Wnt target genes by associating with LEF-1/TCF proteins (Clevers and Nusse, 2012; Stamos and Weis, 2013). "
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    ABSTRACT: In this study, we examined the effect of different fractions and components of Chaga mushroom (Inonotus Obliquus) on viability and apoptosis of colon cancer cells. Among them, one component showed the most effective growth inhibition and was identified as ergosterol peroxide by NMR analysis. We investigated the anti-proliferative and apoptosis mechanisms of ergosterol peroxide associated with its anticancer activities in human colorectal cancer (CRC) cell lines and tested its anti-tumor effect on colitis-induced CRC developed by Azoxymethane (AOM) / Dextran sulfate sodium (DSS) in a mouse model. We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, Western blot analysis, colony formation assays, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and AOM/DSS mouse models to study the molecular mechanism of metastatic activities in CRC cells. Ergosterol peroxide inhibited cell proliferation and also suppressed clonogenic colony formation in HCT116, HT-29, SW620 and DLD-1 CRC cell lines. The growth inhibition observed in these CRC cell lines was the result of apoptosis, which was confirmed by FACS analysis and Western blotting. Ergosterol peroxide inhibited the nuclear levels of β-catenin, which ultimately resulted in reduced transcription of c-Myc, cyclin D1, and CDK-8. Ergosterol peroxide administration showed a tendency to suppress tumor growth in the colon of AOM/DSS-treated mice, and quantification of the IHC staining showed a dramatic decrease in the Ki67-positive staining and an increase in the TUNEL staining of colonic epithelial cells in AOM/DSS-treated mice by ergosterol peroxide for both prevention and therapy. Our data suggest that ergosterol peroxide suppresses the proliferation of CRC cell lines and effectively inhibits colitis-associated colon cancer in AOM/DSS-treated mice. Ergosterol peroxide down-regulated β-catenin signaling, which exerted anti-proliferative and pro-apoptotic activities in CRC cells. These properties of ergosterol peroxide advocate its use as a supplement in colon cancer chemoprevention. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Journal of ethnopharmacology 07/2015; 173. DOI:10.1016/j.jep.2015.07.030 · 3.00 Impact Factor
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    • "In general, activation of Foxo1 has been associated with lifespan extension in animal models by facilitating defense against oxidative and other cellular stressors (Murakami, 2006). This effect appears mediated by the interaction of FoxO proteins with b-catenin, with the latter being diverted from TCF and therefore attenuating the canonical Wnt pathway (MacDonald et al., 2009). On the other hand, this FoxO-driven molecular switch has also been found to mediate a pathogenic mechanism for osteoporosis by decreasing the number of matrix-synthesizing osteoblasts and the amount of bone mass. "
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    ABSTRACT: Recent evidence demonstrates that serum levels of specific miRNAs significantly change with age. The ability of circulating sncRNAs to act as signaling molecules and regulate a broad spectrum of cellular functions implicates them as key players in the aging process. To discover circulating sncRNAs that impact aging in the long-lived Ames dwarf mice, we conducted deep sequencing of small RNAs extracted from serum of young and old mice. Our analysis showed genotype-specific changes in the circulating levels of 21 miRNAs during aging [genotype-by-age interaction (GbA)]. Genotype-by-age miRNAs showed four distinct expression patterns and significant overtargeting of transcripts involved in age-related processes. Functional enrichment analysis of putative and validated miRNA targets highlighted cellular processes such as tumor suppression, anti-inflammatory response, and modulation of Wnt, insulin, mTOR, and MAPK signaling pathways, among others. The comparative analysis of circulating GbA miRNAs in Ames mice with circulating miRNAs modulated by calorie restriction (CR) in another long-lived mouse suggests CR-like and CR-independent mechanisms contributing to longevity in the Ames mouse. In conclusion, we showed for the first time a signature of circulating miRNAs modulated by age in the long-lived Ames mouse. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 07/2015; DOI:10.1111/acel.12373 · 6.34 Impact Factor
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