Inhibition of the Wnt Signaling Pathway by Idax, a Novel Dvl-Binding Protein

Hino, Shinjiro; Kishida, Shosei; Michiue, Tatsuo; Fukui, Akimasa; Sakamoto, Ikuo; Takada, Shinji; Asashima, Makoto; Kikuchi, Akira

doi:10.1128/mcb.21.1.330-342.2001

Cited by 111 publications

(106 citation statements)

References 77 publications

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“…Idax also suppresses the Wnt-induced accumulation of b-catenin and activation of T-cell factor (Hino et al, 2001;Michiue et al, 2004). To our knowledge, we have provided the first evidence of a functional role of CXXC4 in cancer.…”

Section: Discussionmentioning

confidence: 68%

“…We focused on CXXC4 for further analyses as it encodes Idax, which is a negative regulator of Dishevelled (Dvl) in the Wnt signaling pathway (Hino et al, 2001;Michiue et al, 2004). To confirm the relative DNA quantity between the cancerous region and corresponding normal tissue in this case, we performed quantitative realtime-PCR (qRT-PCR) using primer sets for the regions indicating two (D4S1587), one (STS64905 and STS55593) and zero copies (CXXC4 and STS70240) in the SNP array analysis (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

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Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

et al. 2008

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The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P ¼ 0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P ¼ 0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of b-catenin. Knockdown of CXXC4 induced the nuclear translocation of b-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

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Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

et al. 2008

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“…Disruption of the CXXC5 gene in mESCs was confirmed by Southern blot analysis (Supplementary Figure S2A), and the CXXC5 deletion was confirmed in mice by PCR analysis of tail genomic DNA (Supplementary Figure S2B). CXXC5 knockout was also confirmed by immunohistochemical analysis of adult mouse tissues including kidney tissue; the level of CXXC4, the CXXC5 analog known as Idax, 10 was not altered in CXXC5 − / − mice (Supplementary Figure S2C).…”

Section: Cxxc5mentioning

confidence: 73%

“…8 Meanwhile, CXXC5 localized at the cytosol of neural stem cells and interacts with Dishevelled (Dvl) to inhibit the Wnt/ β-catenin pathway 9 similar to another CXXC-type zinc-finger protein lacking the KFGG motif, Idax (CXXC4). 10 However, most experiments were performed using in vitro cell culture systems, and no clear evidence for the in vivo function of CXXC5 has been suggested yet. In this study, we found that CXXC5 localizes to the cytosol of pre-osteoblasts.…”

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confidence: 99%

CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation

Yoon

Yun

et al. 2015

Cell Death Differ

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The positive roles of the Wnt/β-catenin pathway in osteoblast differentiation and bone mineral density (BMD) maintenance have been clearly demonstrated in both animal experiments and clinical investigations. CXXC finger protein 5 (CXXC5), a recently identified negative regulator of the Wnt/β-catenin pathway, showed altered cellular localization and function, which were dependent on the cell type in previous studies. However, the in vivo function of CXXC5 has not been clearly investigated yet. Here, we characterized CXXC5 as a negative regulator of osteoblast differentiation and bone formation. Deficiency of CXXC5 resulted in elevated BMD in mice without any severe gross developmental abnormalities. CXXC5 exerted a negative-feedback effect on the Wnt/β-catenin pathway via Wnt-dependent binding to Dishevelled (Dvl) during osteoblast differentiation. Suppression of the Dvl-CXXC5 interaction using a competitor peptide resulted in the activation of the Wnt/β-catenin pathway and osteoblast differentiation, and accelerated thickness growth of ex vivo-cultured calvariae. Overall, CXXC5 is a negative-feedback regulator induced by Wnt/β-catenin signaling that inhibits osteoblast differentiation and bone formation via interaction with Dvl. Cell Death and Differentiation (2015) 22, 912-920; doi:10.1038/cdd.2014.238; published online 30 January 2015Bone is an extremely dynamic tissue at the microscopic level. A dynamic process, called bone remodeling, takes place seamlessly in the bone to repair microdamage and to replace old bone with new bone. 1 The resorption of old bone and the formation of new bone must be in balance to maintain homeostasis and a constant mass of bone. Osteoblasts have been identified as an essential factor in regulation of the bone remodeling process, which produce bone matrix and differentiate into osteocytes for bone formation, as well as regulate differentiation and activation of osteoclasts for bone resorption. 2 The Wnt/β-catenin pathway is receiving increased attention as a main regulatory pathway for osteoblast differentiation. [2][3][4] Wnt-dependent nuclear accumulation of an effector protein of the pathway, β-catenin, is a major trigger of osteoblast differentiation and bone formation. 2 Many other intracellular and extracellular components of the Wnt/β-catenin pathway are known to regulate osteoblast differentiation. 4 Especially two negative regulators of this pathway, Dickkopf 1 and sclerostin, have been highlighted as osteoblast and osteocytespecific negative regulators of bone formation. 5 CXXC finger protein 5 (CXXC5) is a member of a small protein family in which the members contain CXXC-type zincfinger domain. 6 However, unlike other members of this family, CXXC5 lacks a KFGG motif, which is essential for non-methylated CpG recognition that regulates chromatin remodeling. 7 CXXC5 localizes to the cytosol or nucleus depending on particular cell type in different tissues. Localization of CXXC5 in the nucleus was observed in promyelocytic leukemia cells. 7 CXXC5 has a role as a nuclear t...

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“…Functional interaction between WWOX and Wnt pathway N Bouteille et al WWOX does not inhibit the interaction of Dvl-2 with the b-catenin-degradation complex In the b-catenin-degradation complex, Dvl-2 binds directly to Axin. This interaction seems to be crucial for Dvl-2 to inhibit glycogen synthase kinase 3b-dependent degradation of b-catenin (Kishida et al, 1999Smalley et al, 1999;Kadoya et al, 2000;Hino et al, 2001). WWOX would therefore inhibit the function of Dvl-2 in the Wnt/b-catenin pathway by disrupting Dvl-2-Axin association.…”

Section: Binding Domainsmentioning

confidence: 99%

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

et al. 2009

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The WWOX gene encodes a candidate tumor suppressor protein (WWOX) implicated in a variety of human diseases such as cancer. To better understand the molecular mechanisms of WWOX action, we investigated novel partners of this protein. Using the two-hybrid system and a coimmunoprecipitation assay, we observed a physical association between WWOX and the Dishevelled protein (Dvl) family signaling elements involved in the Wnt/b-catenin pathway. We found that enforced WWOX expression inhibited, and inhibition of endogenous WWOX expression stimulated the transcriptional activity of the Wnt/b-catenin pathway. Inhibition of endogenous WWOX expression also enhanced the effect of Wnt-3a on b-catenin stability. Moreover, we observed the sequestration of Dvl-2 wild type and Dvl-2NESm, a mutated form of Dvl-2 predominantly localized in the nucleus, in the cytoplasm compartment by WWOX. Our results indicate that WWOX is a novel inhibitor of the Wnt/b-catenin pathway. WWOX would act, at least in part, by preventing the nuclear import of the Dvl proteins.

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Inhibition of the Wnt Signaling Pathway by Idax, a Novel Dvl-Binding Protein

Cited by 111 publications

References 77 publications

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

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