The Wnt antagonist DICKKOPF-1 gene is a downstream target of β-catenin/TCF and is downregulated in human colon cancer

Universidad Autónoma de Madrid, Madrid, Madrid, Spain
Oncogene (Impact Factor: 8.56). 03/2005; 24(6):1098-103. DOI: 10.1038/sj.onc.1208303
Source: PubMed

ABSTRACT Wnt glycoproteins regulate homeostasis and development by binding to membrane Frizzled-LRP5/6 receptor complexes. Wnt signaling includes a canonical pathway involving cytosolic beta-catenin stabilization, nuclear translocation and gene regulation, acting as a co-activator of T-cell factor (TCF) proteins, and noncanonical pathways that activate Rho, Rac, JNK and PKC, or modulate Ca(2+) levels. DICKKOPF-1 (DKK-1) encodes a secreted Wnt antagonist that binds to LRP5/6 and induces its endocytosis, leading to inhibition of the canonical pathway. We show that activation of canonical signaling by Wnt1 or ectopic expression of active beta-catenin, TCF4 or LRP6 mutants induces transcription of the human DKK-1 gene. Multiple beta-catenin/TCF4 sites in the DKK-1 gene promoter contribute to this activation. In contrast, Wnt5a, which signals through noncanonical pathways, does not activate DKK-1. Northern and Western blot studies show that activation of the Wnt/beta-catenin pathway by treatment with lithium or Wnt3a-conditioned medium, or by stable expression of either Wnt1 or beta-catenin, increases DKK-1 RNA and protein, thus initiating a negative feedback loop. However, we found that DKK-1 expression decreases in human colon tumors, which suggests that DKK-1 acts as a tumor suppressor gene in this neoplasia. Our data indicate that the Wnt/beta-catenin pathway is downregulated by the induction of DKK-1 expression, a mechanism that is lost in colon cancer.

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    • "Wnt/β-catenin signaling is a key regulator of both normal development and tumorigenesis, and its deregulation is involved in various human cancers, such as colon cancer, breast cancer, prostate cancer and glioma [1] [2] [3] [4]. The canonical Wnt pathway includes Wnt protein ligands, the Frizzled and LRP membrane receptors, the key transcriptional factor β-catenin, the GSK-3/APC/Axin degradation complex, LEF/TCF coactivators and downstream targets such as cyclinD1 [5]. "
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    ABSTRACT: Inhibitor of β-catenin and T-cell factor (ICAT) is a key component of Wnt/β-catenin signaling. ICAT blocks the formation of the β-catenin/TCF complex and has been demonstrated to be involved in embryonic development and carcinogenesis. As an inhibitor of canonical Wnt signaling, ICAT was presumed to be a tumor-suppressor gene. However, the ICAT functions in human glioma remain unknown. In this study, we evaluated the expression of ICAT in 305 human glioma tissues and found that negative ICAT expression correlated with higher grade glioma and poor survival in patients with glioma. Then we transfected glioma cells with ICAT plasmid. Western blotting showed an increased ICAT protein expression level in glioma cells. MTT assay, flow cytometry and cell invasion assay were used to detect cell proliferation, cell cycle distribution, apoptosis and invasion. Our studies confirmed that ICAT inhibits glioma cell proliferation and invasion, and it induces cell apoptosis and cell cycle progression arrest. Besides, ICAT slowed down tumor growth in a glioblastoma xenograft model. Therefore, our study demonstrates that ICAT may serve as a tumor-suppressor in human glioma suggesting a promising direction for targeting therapy in glioma. Copyright © 2014. Published by Elsevier Ireland Ltd.
    Cancer Letters 11/2014; 357(1). DOI:10.1016/j.canlet.2014.11.047 · 5.02 Impact Factor
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    • "To address this issue, additional biochemical methods are required. In other systems, Axin2 (Jho et al., 2002), DRAPC (Takahashi et al., 2002), Dkk1 (Chamorro et al., 2005; González-Sancho et al., 2005), c-myc (He et al., 1998), and TCF1 (Roose et al., 1999) have been shown to be direct targets of Wnt/b-catenin signaling. Similarly, in cortical neural progenitor cells, Ngn1 and Ngn2 are direct targets of Wnt/ b-catenin signaling (Hirabayashi et al., 2004; Israsena et al., 2004). "
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    ABSTRACT: Loss of midbrain dopaminergic (mDA) neurons underlies the motor symptoms of Parkinson's disease (PD). Towards cell replacement, studies have focused on mechanisms underlying embryonic mDA production, as a rational basis for deriving mDA neurons from stem cells. We will review studies on β-catenin, an obligate component of the Wnt cascade that is critical for mDA specification and neurogenesis. mDA neurons have a unique origin - the midbrain floor plate (FP). Unlike the hindbrain and spinal cord FP, the midbrain FP is highly neurogenic and Wnt/β-catenin signaling is critical for this difference in neurogenic potential. In β-catenin loss-of-function experiments, the midbrain FP resembles the hindbrain FP, and key mDA progenitor genes such as Otx2, Lmx1a, Msx1, and Ngn2 are downregulated whereas Shh is maintained. Accordingly, the neurogenic capacity of the midbrain FP is diminished, resulting in fewer mDA neurons. Conversely, in β-catenin gain-of-function experiments, the hindbrain FP expresses key mDA progenitor genes, and is highly neurogenic. Interestingly, when excessive β-catenin is supplied to the midbrain FP, less mDA neurons are produced suggesting that the dosage of Wnt/β-catenin signaling is critical. These studies on β-catenin have facilitated new protocols to derive mDA neurons from stem cells.
    Journal of Molecular Cell Biology 11/2013; 6(1). DOI:10.1093/jmcb/mjt043 · 8.43 Impact Factor
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    • "Eight candidate genes were amplified using a polymerase chain reaction (PCR) with AmpliTaq Gold DNA polymerase (Applied Biosystems) and specific primers (available on request). The genes examined included DKK1, DKK2, WNT3A, WNT10B, AXIN1, SOST, TPH1, 5-HTR1B and the DKK1 promoter [15]. Samples were screened for mutations using conformation-sensitive gel electrophoresis (CSGE) [16]. "
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    ABSTRACT: Childhood-onset primary osteoporosis is manifested as reduced bone mineral density, peripheral fractures and/or vertebral compression fractures. Until now, only mutations in LRP5 have been shown to cause the disorder. Candidate gene analyses were performed on 15 patients with primary osteoporosis and 80 healthy controls using CSGE and sequencing. The genes studied included DKK1, DKK2, WNT3A, WNT10B, AXIN1, SOST, TPH1 and 5-HTR1B. Two rare variants in WNT3A (c.152A > G, p.K51R) and DKK1 (c.359G > T, p.R120L) were identified in two patients and their affected family members, but not in control subjects, suggesting a significance for the skeletal phenotype. The in vitro studies of variants showed reduced signaling activity in p.K51R-Wnt3a, while no differences were observed between the WT and variant forms of DKK1. This study addresses the role of other components of the canonical Wnt signaling pathway besides LRP5 in primary osteoporosis, and putatively associates WNT3A and DKK1 variants with the disorder. Future functional studies are needed to elucidate the functional effects of the variants.
    European journal of medical genetics 07/2012; 55(10):515-9. DOI:10.1016/j.ejmg.2012.06.011 · 1.49 Impact Factor
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