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J. Biol. Chem., Vol. 276, Issue 20, 16810-16816, May 18, 2001
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From the Massachusetts General Hospital Cancer Center and Harvard
Medical School, Charlestown, Massachusetts 02129
The Wilms tumor gene WT1 encodes a
zinc finger transcription factor that is required for normal kidney
development. WT1 was identified as a transcriptional repressor, based
on its suppression of promoter reporters, but analysis of native
transcripts using high density microarrays has uncovered
transcriptional activation, rather than repression, of potential target
genes. We report here that WT1 binds to the transcriptional coactivator
CBP, leading to synergistic activation of a physiologically
relevant promoter. The physical interaction between WT1 and CBP is
evident in vitro and in vivo, and the two
proteins are co-immunoprecipitated from embryonic rat kidney cells. The
WT1-CBP association requires the first two zinc fingers of WT1 and the
adenovirus 5 E1A-binding domain of CBP. Overexpression of this domain
of CBP is sufficient to inhibit WT1-mediated transcriptional activation
of a promoter reporter, as is co-transfection of E1A. Retrovirally
driven expression of either the CBP fragment or of E1A in human
hematopoietic cells suppresses the induction by WT1 of its endogenous
target gene, p21Cip1. These observations support a model of
WT1 as a transcriptional activator of genes required for cellular differentiation.
A Functional Interaction with CBP Contributes to
Transcriptional Activation by the Wilms Tumor Suppressor
WT1*
*
This work was supported by National Institutes of Health
Grant CA58596 (to D. A. H.) and the National Foundation for
Cancer Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: MGH Cancer Center, CNY
7, Bldg. 149, 13 Street, Charlestown, MA 02129. Tel.: 617-726-7805; Fax: 617-724-6919; E-mail: Haber@helix.mgh.harvard.edu.
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