A Novel Wilms Tumor 1 (WT1) Target Gene Negatively Regulates the WNT Signaling Pathway

Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2010; 285(19):14585-93. DOI: 10.1074/jbc.M109.094334
Source: PubMed


Mammalian kidney development requires the functions of the Wilms tumor gene WT1 and the WNT/β-catenin signaling pathway. Recent studies have shown that WT1 negatively regulates WNT/β-catenin signaling, but the molecular mechanisms by which WT1 inhibits WNT/β-catenin signaling are not completely understood. In this study, we identified a gene, CXXC5, which we have renamed WID (WT1-induced Inhibitor of Dishevelled), as a novel WT1 transcriptional target that negatively regulates WNT/β-catenin signaling. WT1 activates WID transcription through the upstream enhancer region. In the developing kidney, Wid and Wt1 are coexpressed in podocytes of
maturing nephrons. Structure-function analysis demonstrated that WID interacts with Dishevelled via its C-terminal CXXC zinc finger and Dishevelled binding domains and potently inhibits WNT/β-catenin signaling in vitro and in vivo. WID is evolutionarily conserved, and ablation of wid in zebrafish embryos with antisense morpholino oligonucleotides perturbs embryonic kidney development. Taken together, our
results demonstrate that the WT1 negatively regulates WNT/β-catenin pathway via its target gene WID and further suggest a role for WID in nephrogenesis.

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Available from: Sean Bong Lee, Jan 22, 2014
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    • "The molecular mechanisms behind the proapoptotic activity of CXXC5/RINF silencing in AML cells are not known. Observations in neuronal cells and developing kidney have suggested that WT1 induce RINF expression and thereby downregulate signaling through the WNT-betacathenin pathway[27,28]. The correlation between WT1 and CXXC5/RINF expression may suggest that there is a crosstalk between these two molecules also in primary AML cells. However, the WNT-beta-cathenin pathway can be constitutively activated in AML cells[29]and this activation seems to mediate antiapoptotic effects[30,31]. "
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    ABSTRACT: The retinoid-responsive gene CXXC5 localizes to the 5q31.2 chromosomal region and encodes a retinoid-inducible nuclear factor (RINF) that seems important during normal myelopoiesis. We investigated CXXC5/RINF expression in primary human acute myeloid leukemia (AML) cells derived from 594 patients, and a wide variation in CXXC5/RINF mRNA levels was observed both in the immature leukemic myeloblasts and in immature acute lymphoblastic leukemia cells. Furthermore, patients with low-risk cytogenetic abnormalities showed significantly lower levels compared to patients with high-risk abnormalities, and high RINF/CXXC5/ mRNA levels were associated with decreased overall survival for patients receiving intensive chemotherapy for newly diagnosed AML. This association with prognosis was seen both when investigating (i) an unselected patient population as well as for patients with (ii) normal cytogenetic and (iii) core-binding factor AML. CXXC5/RINF knockdown in AML cell lines caused increased susceptibility to chemotherapy-induced apoptosis, and regulation of apoptosis also seemed to differ between primary human AML cells with high and low RINF expression. The association with adverse prognosis together with the antiapoptotic effect of CXXC5/RINF suggests that targeting of CXXC5/RINF should be considered as a possible therapeutic strategy, especially in high-risk patients who show increased expression in AML cells compared with normal hematopoietic cells.
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    • "Wnt/β-catenin downstream signaling is also negatively regulated by the product of the recently identified WT1 target gene CXXC5 (syn. WID), which interacts with the immediate downstream effector of the frizzled receptor, Disheveled (Kim et al., 2010). The local oxygen environment controls the Notch pathway and the expression of TGF-β (Scheid et al., 2002; Schäffer et al., 2003; Chen et al., 2007; Sahlgren et al., 2008; Zheng et al., 2008), which is also regulated by WT1 (Dey et al., 1994; Jin et al., 1999). "
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    • "Thus, PAWR compromises the WNT signalling pathway, which may explain some of the findings by Wang et al (2008). CXXC5 (also upregulated by MLL-AFF1) encodes the 'WT1-induced Inhibitor of Dishevelled' (WID; Kim et al, 2010). WID directly binds to the Dishevelled protein and abrogates WNT signalling, thus simulating the absence of FRIZZLED ligands. "
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