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dc.contributor.authorKim, M. K.-H.
dc.contributor.authorMcGarry, T. J.
dc.contributor.authorO Broin, P.
dc.contributor.authorFlatow, J. M.
dc.contributor.authorGolden, A. A.-J.
dc.contributor.authorLicht, J. D.
dc.date.accessioned2018-09-20T16:13:16Z
dc.date.available2018-09-20T16:13:16Z
dc.date.issued2009-06-22
dc.identifier.citationKim, M. K.-H. McGarry, T. J.; O Broin, P.; Flatow, J. M.; Golden, A. A.-J.; Licht, J. D. (2009). An integrated genome screen identifies the wnt signaling pathway as a major target of wt1. Proceedings of the National Academy of Sciences 106 (27), 11154-11159
dc.identifier.issn0027-8424,1091-6490
dc.identifier.urihttp://hdl.handle.net/10379/12273
dc.description.abstractWT1, a critical regulator of kidney development, is a tumor suppressor for nephroblastoma but in some contexts functions as an oncogene. A limited number of direct transcriptional targets of WT1 have been identified to explain its complex roles in tumorigenesis and organogenesis. In this study we performed genome-wide screening for direct WT1 targets, using a combination of ChIP-ChIP and expression arrays. Promoter regions bound by WT1 were highly G-rich and resembled the sites for a number of other widely expressed transcription factors such as SP1, MAZ, and ZNF219. Genes directly regulated by WT1 were implicated in MAPK signaling, axon guidance, and Wnt pathways. Among directly bound and regulated genes by WT1, nine were identified in the Wnt signaling pathway, suggesting that WT1 modulates a subset of Wnt components and responsive genes by direct binding. To prove the biological importance of the interplay between WT1 and Wnt signaling, we showed that WT1 blocked the ability of Wnt8 to induce a secondary body axis during Xenopus embryonic development. WT1 inhibited TCF-mediated transcription activated by Wnt ligand, wild type and mutant, stabilized beta-catenin by preventing TCF4 loading onto a promoter. This was neither due to direct binding of WT1 to the TCF binding site nor to interaction between WT1 and TCF4, but by competition of WT1 and TCF4 for CBP. WT1 interference with Wnt signaling represents an important mode of its action relevant to the suppression of tumor growth and guidance of development.
dc.publisherProceedings of the National Academy of Sciences
dc.relation.ispartofProceedings of the National Academy of Sciences
dc.subjectchip-chip
dc.subjectmicroarray
dc.subjecttumor suppressor
dc.subjecttumor-suppressor gene
dc.subjectwilms-tumor
dc.subjectbeta-catenin
dc.subjectkidney development
dc.subjecttranscriptional activation
dc.subjectchromatin occupancy
dc.subjectgrowth suppression
dc.subjectctnnb1 mutations
dc.subjectcell-growth
dc.subjectc-myc
dc.titleAn integrated genome screen identifies the wnt signaling pathway as a major target of wt1
dc.typeArticle
dc.identifier.doi10.1073/pnas.0901591106
dc.local.publishedsourcehttp://www.pnas.org/content/106/27/11154.full.pdf
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