Repression of the retinoic acid receptor-alpha gene by the Wilms' tumor suppressor gene product, wt1.
The Wilms' tumor (WT) suppressor gene, WT1, encodes a zinc finger DNA binding protein (wt1) which functions as a transcriptional regulator. Germline WT1 mutations predispose to WTs and in many cases are associated with urogenital anomalies. Identification of wt1 downstream targets is essential to understanding regulatory processes involved in development of this system. In this study, we demonstrate that wt1 can repress transcription of the retinoic acid receptor-alpha 1 (RAR-alpha 1) promoter. Transient transfection, deletion mutagenesis, and mobility shift assays suggest that wt1 mediates repression of the human RAR-alpha 1 promoter through a GC-rich DNA binding motif (5'-GCGGGGGCG-3'), at positions -111 to -120 bp (relative to the transcription initiation site). In contrast, the murine RAR-alpha 1 promoter contains a cryptic binding motif and is not responsive to wt1. These results indicate that some wt1-regulatory pathways are not conserved across species, suggesting a molecular basis for differences in phenotypes between humans and mice harboring WT1 lesions.
Goodyer
P
P
Department of Experimental Medicine, Montreal Children's Hosptial, Quebec, Canada.
Dehbi
M
M
Torban
E
E
Bruening
W
W
Pelletier
J
J
D001483:Base Sequence; D002460:Cell Line; D004247:DNA; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000235:genetics*; D025721:WT1 Proteins; D009396:Wilms Tumor / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics*
D004268:DNA-Binding Proteins; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025721:WT1 Proteins; D004247:DNA