Two N-terminal self-association domains are required for the dominant negative transcriptional activity of WT1 Denys-Drash mutant proteins

Biochemical and Biophysical Research Communications
G HolmesM H Little

Abstract

Patients with Denys-Drash syndrome (DDS) have been shown to be constitutionally heterozygous for mutations of the WT1 gene. Almost all DDS mutations inactivate or remove the DNA-binding zinc finger region of WT1 and the resulting mutant proteins appear to act in a dominant negative manner. This may occur via WT1 self-association, which has been shown to involve the first 180 amino acids. By creating a series of N-terminal deletions, we have further investigated WT1 self-association using a yeast di-hybrid system and an in vitro protein binding assay. Our results suggest that there are two distinct domains within the N-terminal region facilitating self-association, residing from amino acids 1-45 and 157-253. Co-transfection of WT1 with progressively shorter N-terminal constructs demonstrates that both of these sites are required for a dominant negative activity as assessed by activation of a reporter construct.

Citations

Aug 23, 2000·Leukemia & Lymphoma·P SpinsantiG Ragona
Mar 10, 2001·Experimental Cell Research·S B Lee, D A Haber
Jun 26, 2002·Oncogene·Edmund U-H SimMelissa H Little
Sep 7, 2002·International Journal of Hematology·Leif W Ellisen
Oct 27, 2004·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Suzanne LittleKathy Pritchard-Jones
May 20, 1999·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·M LittleP Walsh
Mar 13, 2009·Organogenesis·Kaisa PulkkinenSeppo Vainio
Sep 7, 2000·The Journal of Biological Chemistry·P Stanhope-Baker, B R Williams
Aug 9, 2008·American Journal of Medical Genetics. Part a·Miriam RegevOrit Reish
Jun 14, 2014·The Biochemical Journal·Eneda Toska, Stefan G E Roberts
Oct 12, 2001·Gene·V ScharnhorstA G Jochemsen

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