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J Biol Chem, Vol. 275, Issue 14, 10202-10211, April 7, 2000

Physical Interaction between Wilms Tumor 1 and p73 Proteins Modulates Their Functions^*

Volkher Scharnhorst, Patrick Dekker, Alex J. van der Eb, and Aart G. Jochemsen

From the Laboratory of Molecular Carcinogenesis and Centre for Biomedical Genetics, Leiden University Medical Center, P. O. Box 9503, 2300 RA Leiden, The Netherlands

The WT1 gene, which is heterozygously mutated or deleted in congenital anomaly syndromes and homozygously mutated in about 15% of all Wilms tumors, encodes tissue-specific developmental regulators. Through alternative mRNA splicing, four main WT1 protein isoforms are synthesized. All isoforms can bind to DNA via their zinc fingers, albeit with different affinities and specificities, and thereby modulate the transcriptional activity of their target genes. Several proteins bind to and alter the transcription regulatory properties of the WT1 proteins, including the product of the tumor suppressor gene p53. Interaction between WT1 and p53 was shown to modulate their ability to regulate the transcription of their respective target genes. Here, we report that all four isoforms of WT1 bind to p73, a recently cloned homologue of p53. p73 binds to the zinc finger region of WT1 and thereby inhibits DNA binding and transcription activation by WT1. Similarly, WT1 inhibits p73-induced transcription activation in reporter assays and counteracts p73-induced expression of endogenous Mdm2. This, taken together with our finding that WT1 also interacts with p63/KET, another p53 homologue, suggests that association between WT1 and the members of the p53 family of proteins may be an important determinant of their functions in cell growth and differentiation.

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^* This work was supported by the Dutch Cancer Society Grant RUL 95-1044.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. Tel.: 31-71-5276136; Fax: 31-71-5276284; E-mail: A.G.Jochemsen@lumc.nl.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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