WT1-mediated transcriptional activation is inhibited by dominant negative mutant proteins

J. C. Reddy, J. C. Morris, J. Wang, M. A. English, D. A. Haber, Y. Shi, J. D. Licht

Research output: Contribution to journalArticle

146 Scopus citations

Abstract

The WT1 tumor suppressor gene encodes four isoforms of a zinc finger transcription factor with both activation and repression functions which are dependent upon promoter architecture. Using a simple HSV-tk promoter containing 5'-Egr-1/WT1-binding sites, we found that WT1 isoforms (A) and (B) strongly activated transcription. WT1(A) and (B) bound equally well to the Egr-1/WT1-binding site, but WT1(B), which contains a 17 amino acid insertion compared to WT1(A), was a consistently stronger activator of transcription than WT1(A). Transcriptional activation by wild-type WT1 was inhibited by coexpression of WT(PM) or WT(AR), genetically defined dominant negative alleles of WT1. In vitro, as well as in the yeast two-hybrid system, WT1 protein associated with itself and with dominant negative mutant proteins. The major domain required for self-association and inhibition of transcriptional activation mapped to the first 182 amino acids of WT1. Dominant negative WT1 alleles may play a role in tumorigenesis by associating with wild-type WT1 proteins and decreasing their transcriptional activity.

Original languageEnglish
Pages (from-to)10878-10884
Number of pages7
JournalJournal of Biological Chemistry
Volume270
Issue number18
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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