PMID: 9441865Jan 27, 1998Paper

Differential effects of Wilms tumor WT1 splice variants on the insulin receptor promoter

Biochemical and Molecular Medicine
Nicholas J G WebsterB L Seely

Abstract

The Wilms tumor gene WT1 has been implicated in the early development of the kidney. Mutations in WT1 are found in a small fraction of Wilms tumor, a pediatric nephroblastoma, and Denys-Drash syndrome, characterized by genitourinary abnormalities. The WT1 gene product functions as a transcriptional repressor of growth factor-related genes. The kidney is one of the major sites of insulin action in vivo and expresses high levels of insulin receptors (IR). IR expression has been detected during early embryogenesis, suggesting that it may play a role in development. We investigated whether two WT1 splice variants lacking or including a three-amino-acid (KTS) insertion between the third and fourth zinc finger in the DNA-binding domain could repress the IR promoter in vitro. We show that the +KTS variant effectively represses promoter activity under all conditions tested but the -KTS variant was only able to repress in the presence of cotransfected C/EBP beta or a dominant-negative p53 mutation. Deletional mapping indicated that distinct regions of the IR promoter mediated the effects of the two isoforms and DNaseI footprint analysis identified potential WT1 binding sites within these regions.

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Citations

May 20, 1999·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·M LittleP Walsh
Oct 12, 2001·Gene·V ScharnhorstA G Jochemsen
Aug 31, 2002·Journal of Hematotherapy & Stem Cell Research·Elizabeth Algar
May 29, 2014·The Journal of Clinical Investigation·María ElizaldeCarmen Berasain
Mar 16, 2007·Leukemia·L YangM D Minden
May 26, 2007·Expert Reviews in Molecular Medicine·Suzie Ariyaratana, David M Loeb
Nov 22, 2002·The Journal of Biological Chemistry·Gila IdelmanHaim Werner
Feb 15, 2007·The Journal of Pathology·Y LiS Xiao
Jun 14, 2014·The Biochemical Journal·Eneda Toska, Stefan G E Roberts
Jul 25, 2021·International Journal of Molecular Sciences·Nicole Wagner, Kay-Dietrich Wagner

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