An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1

Marianne K.H. Kim, Thomas J. McGarry, Pilib Ó Broin, Jared M. Flatow, Aaron A.J. Golden, Jonathan D. Licht

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

WT1, 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 studyweperformed 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 β-catenin by preventing TCF4 loading onto a promoter. This was neither due to direct binding ofWT1to the TCF binding site nor to interactionbetweenWT1and TCF4, but by competition ofWT1and TCF4 for CBP.WT1interference withWnt signaling represents an important mode of its action relevant to the suppression of tumor growth and guidance of development.

Original languageEnglish (US)
Pages (from-to)11154-11159
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number27
DOIs
StatePublished - Jul 7 2009

Keywords

  • ChIP-ChIP
  • Microarray
  • Tumor suppressor

ASJC Scopus subject areas

  • General

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