Wilms Tumor Suppressor, WT1, Suppresses Epigenetic Silencing of the β-Catenin Gene

Akpa, Murielle M.; Iglesias, Diana M.; Chu, Lee Lee; Cybulsky, Marta; Bravi, Cristina; Goodyer, Paul

doi:10.1074/jbc.m114.573576

Cited by 27 publications

(26 citation statements)

References 41 publications

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“…In the nucleus of renal progenitors, we previously found that the WT1(ϪKTS) isoform suppresses transcription of a Polycomb histone methyltransferase, EZH2 (6). This event is likely to be essential if the differentiation cascade is to be released by inductive WNT signals from ureteric bud.…”

Section: Discussionmentioning

confidence: 99%

“…3B). In previous studies, we noted that the WT1(ϩKTS) isoforms suppress EZH2 protein levels in mesenchymal stem cells (6). If this effect is due to transcriptional inhibition, there should be no effect of WT1(ϩKTS) on the CMV-driven EZH2 expression in fibroblasts.…”

Section: Wt1 Induces An Array Of Mirnas In Mesenchymal Stemmentioning

confidence: 99%

“…Wilms tumors retain a chromatin pattern resembling embryonic stem cells in which genes of the differentiation cascade are broadly silenced by tri-methylated lysine 27 residues in the H3 histone associated with their promoter regions (5). We recently showed that the WT1 isoforms lacking the three amino acid insertion lysine-threonine-serine between zinc fingers 3 and 4 (ϪKTS), inhibits transcription of the histone methyltransferase (Enhancer of Zeste Homolog 2, EZH2) that epigenetically silences ␤-catenin gene (CTNNB1) expression in mesenchymal stem cells and facilitates the canonical WNT/␤-catenin pathway response to WNT9b (6).…”

Section: Wilms Tumor (Wt)mentioning

confidence: 99%

“…These 12 included miR26a and miR101, previously shown to suppress translation of EZH2 in myocytes, lung tissue, and breast epithelia, respectively (12-15). We decided to focus on these latter two miRNAs as representative of the putative concerted mechanism by which WT1 suppresses epigenetic silencing in stem cells (6). To validate these two miRNAs, we performed quantitative RT-PCR on mesenchymal stem cells stably transfected with WT1(ϪKTS) or WT1(ϩKTS) isoforms.…”

Section: Wt1 Induces An Array Of Mirnas In Mesenchymal Stemmentioning

confidence: 99%

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Wilms Tumor Suppressor, WT1, Cooperates with MicroRNA-26a and MicroRNA-101 to Suppress Translation of the Polycomb Protein, EZH2, in Mesenchymal Stem Cells

Akpa

Iglesias

Chu

et al. 2016

Journal of Biological Chemistry

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Hereditary forms of Wilms arise from developmentally arrested clones of renal progenitor cells with biallelic mutations of WT1; recently, it has been found that Wilms tumors may also be associated with biallelic mutations in DICER1 or DROSHA, crucial for miRNA biogenesis. We have previously shown that a critical role for WT1 during normal nephrogenesis is to suppress transcription of the Polycomb group protein, EZH2, thereby de-repressing genes in the differentiation cascade. Here we show that WT1 also suppresses translation of EZH2. All major WT1 isoforms induce an array of miRNAs, which target the 3 UTR of EZH2 and other Polycomb-associated transcripts. We show that the WT1(؉KTS) isoform binds to the 5 UTR of EZH2 and interacts directly with the miRNA-containing RISC to enhance post-transcriptional inhibition. These observations suggest a novel mechanism through which WT1 regulates the transition from resting stem cell to activated progenitor cell during nephrogenesis. Our findings also offer a plausible explanation for the fact that Wilms tumors can arise either from loss of WT1 or loss of miRNA processing enzymes.In 1879, William Osler reported two pediatric patients from Montreal with massive kidney tumors containing bands of muscle-like tissue mixed with epithelial elements (35). Twenty years later, Max Wilms published his celebrated monograph recognizing the malignancy as a unique "mischgeschwulste der Niere" (mixed tumor of the kidney), composed of mixed stromal, epithelial, and undifferentiated mesenchymal cells. This "triphasic" histology suggests that Wilms tumors arise from developmentally arrested stem cells of the metanephric mesenchyme that occasionally exhibit abortive differentiation toward a stromal or an epithelial cell fate. It follows that a disturbance of molecular events governing the transition from renal progenitor cells into these differentiated lineages must be central to the pathogenesis of Wilms tumor. Wilms tumor (WT)2 is the most common form of pediatric kidney cancer and affects about 1:10,000 children in North America (1). In a subset of these patients, a germline deletion of the transcription factor, WT1, is accompanied by a somatic mutation of the second WT1 allele, giving rise to clones of incompetent stem cells adjacent to the malignant tumor (2). These "nephrogenic rests" are thought to represent embryonic renal progenitors that have failed to respond to inductive WNT signals during embryogenesis. The pre-malignant cell clusters may persist within the normal kidney (3) until a constitutively activating mutation of the ␤-catenin gene (CTNNB1) (17, 18) bypasses the need for a normal WNT signal and drives un-regulated rapid cell growth (4). Wilms tumors retain a chromatin pattern resembling embryonic stem cells in which genes of the differentiation cascade are broadly silenced by tri-methylated lysine 27 residues in the H3 histone associated with their promoter regions (5). We recently showed that the WT1 isoforms lacking the three amino acid insertion lysine-threonine-serine b...

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Section: Discussionmentioning

confidence: 99%

Section: Wt1 Induces An Array Of Mirnas In Mesenchymal Stemmentioning

confidence: 99%

Section: Wilms Tumor (Wt)mentioning

confidence: 99%

Section: Wt1 Induces An Array Of Mirnas In Mesenchymal Stemmentioning

confidence: 99%

See 2 more Smart Citations

Wilms Tumor Suppressor, WT1, Cooperates with MicroRNA-26a and MicroRNA-101 to Suppress Translation of the Polycomb Protein, EZH2, in Mesenchymal Stem Cells

Akpa

Iglesias

Chu

et al. 2016

Journal of Biological Chemistry

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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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