Article

Caught up in a Wnt storm: Wnt signaling in cancer.

Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 07/2003; 1653(1):1-24. DOI: 10.1016/S0304-419X(03)00005-2
Source: PubMed

ABSTRACT The Wnt signaling pathway, named for its most upstream ligands, the Wnts, is involved in various differentiation events during embryonic development and leads to tumor formation when aberrantly activated. Molecular studies have pinpointed activating mutations of the Wnt signaling pathway as the cause of approximately 90% of colorectal cancer (CRC), and somewhat less frequently in cancers at other sites, such as hepatocellular carcinoma (HCC). Ironically, Wnts themselves are only rarely involved in the activation of the pathway during carcinogenesis. Mutations mimicking Wnt stimulation-generally inactivating APC mutations or activating beta-catenin mutations-result in nuclear accumulation of beta-catenin which subsequently complexes with T-cell factor/lymphoid enhancing factor (TCF/LEF) transcription factors to activate gene transcription. Recent data identifying target genes has revealed a genetic program regulated by beta-catenin/TCF controlling the transcription of a suite of genes promoting cellular proliferation and repressing differentiation during embryogenesis, carcinogenesis, and in the post-embryonic regulation of cell positioning in the intestinal crypts. This review considers the spectra of tumors arising from active Wnt signaling and attempts to place perspective on recent data that begin to elucidate the mechanisms prompting uncontrolled cell growth following induction of Wnt signaling.

2 Bookmarks
 · 
146 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Previously, we found that brain expressed X-linked gene 2 (Bex2) regulates the invasion/migration ability of glioma cells. However, the mechanism of this effect remains unknown. In current study, we reported that Bex2 down-regulation inhibited glioma cell migration and invasion by decreasing the nucleus and cytoplasm protein level of β-catenin. We found that the protein levels of Bex2 and β-catenin were up-regulated and showed direct correlation in glioma tissues. Bex2 down-regulation significantly decreased β-catenin protein levels but not its mRNA levels. Furthermore, the decreased protein level of β-catenin was located in the nucleus and cytoplasm but not in the cell membrane. Further study found that the effects of Bex2 down-regulation on the invasion and migration of glioma cell could be reversed by β-catenin over-expression. Taken together, Bex2 affects the invasion and migration ability of glioma cells by regulating β-catenin. Copyright © 2014 Elsevier Inc. All rights reserved.
    Biochemical and Biophysical Research Communications 01/2015; 456(1):494-9. · 2.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nephronophthisis-related ciliopathies (NPHP-RC) are recessive diseases characterized by renal dysplasia or degeneration. We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy. DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner. Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations. We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors. Mutations detected in human NPHP-RC lack these effects. A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis. Knockdown of dcdc2 in zebrafish recapitulates NPHP-RC phenotypes, including renal cysts and hydrocephalus, which is rescued by a Wnt inhibitor and by WT, but not by mutant, DCDC2. We thus demonstrate a central role of Wnt signaling in the pathogenesis of NPHP-RC, suggesting an avenue for potential treatment of NPHP-RC. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 12/2014; · 10.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract β-catenin is the key component of the canonical Wnt pathway and plays a crucial role in a multitude of developmental and homeostatic processes. The different tasks of β-catenin are orchestrated by its subcellular localization and participation in multiprotein complexes. To gain a better understanding of β-catenin's role in living cells we have generated a new set of single domain antibodies, referred to as nanobodies, derived from heavy chain antibodies of camelids. We selected nanobodies recognizing the N-terminal, core or C-terminal domain of β-catenin and applied these new high-affinity binders as capture molecules in sandwich immunoassays and co-immunoprecipitations of endogenous β-catenin complexes. In addition, we engineered intracellularly functional anti-β-catenin chromobodies by combining the binding moieties of the nanobodies with fluorescent proteins. For the first time, we were able to visualize the subcellular localization and nuclear translocation of endogenous β-catenin in living cells using these chromobodies. Moreover, the chromobody signal allowed us to trace the accumulation of diffusible, hypo-phosphorylated β-catenin in response to compound treatment in real time using High Content Imaging. The anti-β-catenin nanobodies and chromobodies characterized in this study are versatile tools that enable a novel and unique approach to monitor the dynamics of subcellular β-catenin in biochemical and cell biological assays. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Molecular &amp Cellular Proteomics 01/2015; · 7.25 Impact Factor

Full-text (2 Sources)

Download
64 Downloads
Available from
Jun 3, 2014