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

Kim, Myoung Shin; Yoon, Seung Kew; Bollig, Frank; Kitagaki, Jirouta; Hur, Wonhee; Whye, Nathan J.; Wu, Yiming; Rivera, Miguel N.; Park, Jik Young; Kim, Ho-Shik; Malik, Karim; Bell, Daphne W.; Englert, Christoph; Perantoni, Alan O.; Lee, Sean Bong

doi:10.1074/jbc.m109.094334

Cited by 97 publications

(95 citation statements)

References 34 publications

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“…Wnt inhibition by CXXC5 has been described in nontumorous tissue, and interaction of CXXC5 with Dvl proteins was identified as an underlying mechanism. 4,5 Here, we did not observe interaction of CXXC5 with Dvl proteins. This might be explained by the fact that in the leukemic cell lines tested, CXXC5 (EGFP-tagged and endogenous protein) was predominantly localized in the nucleus, in accordance with in silico analyses and results in NB4, HeLa, and MCF7 cells.…”

mentioning

confidence: 69%

“…4,5 However, we did not observe colocalization of EGFP-tagged CXXC5 with endogenous Dvl1, Dvl2, or Dvl3 in confocal microscopy or binding in immunoprecipitation experiments in K562 (data not shown).…”

Section: Cxxc5 Impairs the Canonical Wnt Pathwaymentioning

confidence: 92%

“…3 In addition, CXXC5 has been demonstrated to negatively regulate the canonical Wnt/b-catenin signaling pathway in nontumorous tissues. 4,5 Wnt activation has been implicated in leukemic transformation 6,7 and was shown to promote proliferation and survival of leukemic cells in vitro. 8 The CXXC motif is found in a small number of proteins, most of which are involved in epigenetic modification, like the DNA methyltransferase DNMT1 (CXXC9), histone methyltransferases (MLL [CXXC7], MLL2 [CXXC12]), the methylcytosine dioxygenase TET1 (CXXC6), and histone demethylases (KDM2A [CXXC8], KDM2B [CXXC2]).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

Kühnl

Valk

Sanders

et al. 2015

Blood

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Key Points• CXXC5 inhibits Wnt signaling and is a candidate tumor suppressor in AML.• Low CXXC5 expression is an independent prognostic factor in AML.The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P 5 .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and codownregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome. (Blood.

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mentioning

confidence: 69%

Section: Cxxc5 Impairs the Canonical Wnt Pathwaymentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

Kühnl

Valk

Sanders

et al. 2015

Blood

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“…Multiple signaling pathways have been reported to regulate the balance between self-maintenance and differentiation in NPCs, including FGF, BMP and canonical WNT signals (Barak et al, 2012;Blank et al, 2009;Brown et al, 2011Brown et al, , 2013Carroll et al, 2005;Park et al, 2012), all of which interact with or are activated by WT1 (Akpa et al, 2014;Hartwig et al, 2010;Kim et al, 2010;Motamedi et al, 2014). The FGF ligand FGF20 is transcriptionally activated by WT1 in NPCs (Motamedi et al, 2014) and is connected to NPC proliferation through activation of PI3K-AKT (Barak et al, 2012;Brown et al, 2011), whereas Bmp7 is a WT1 target gene (Hartwig et al, 2010) that promotes NPC proliferation by activation of JNK MAPK (Blank et al, 2009;Motamedi et al, 2014).…”

Section: Gas1 Selectively Modulates the Akt Branch Of The Fgf Signalimentioning

confidence: 99%

WT1 targetsGas1to maintain nephron progenitor cells by modulating FGF signals

et al. 2015

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Development of the metanephric kidney depends on tightly regulated interplay between self-renewal and differentiation of a nephron progenitor cell (NPC) pool. Several key factors required for the survival of NPCs have been identified, including fibroblast growth factor (FGF) signaling and the transcription factor Wilms' tumor suppressor 1 (WT1). Here, we present evidence that WT1 modulates FGF signaling by activating the expression of growth arrest-specific 1 (Gas1), a novel WT1 target gene and novel modulator of FGF signaling. We show that WT1 directly binds to a conserved DNA binding motif within the Gas1 promoter and activates Gas1 mRNA transcription in NPCs. We confirm that WT1 is required for Gas1 expression in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs. Although kidney development in Gas1 knockout mice progresses normally until E15.5, NPCs show decreased rates of proliferation at this stage and are depleted as of E17.5. Lastly, we show that Gas1 is selectively required for FGF-stimulated AKT signaling in vitro. In summary, our data suggest a model in which WT1 modulates receptor tyrosine kinase signaling in NPCs by directing the expression of Gas1.

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“…CXXC5 (renamed WID) has also independently been identified as a target of WT1. 39 (3) Erk1 (gene name: Mapk3), a major component of the MAP Kinase pathway was identified as a target. Additionally, RSK2 (gene name: Rps6ka3) is a member of the RSK family that acts downstream of Erk MAP kinases and also has a role in the regulation of mRNA translation 40 was identified as a strong target and validated in the morpholino assay.…”

Section: A Re-evaluation Of Wt1 Spatial and Gene Expression Relationsmentioning

confidence: 99%

WT1 and kidney progenitor cells

Kreidberg

2010

Organogenesis

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

Cited by 97 publications

References 34 publications

Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

WT1 targetsGas1to maintain nephron progenitor cells by modulating FGF signals

WT1 and kidney progenitor cells

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