Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1.
The Wilms tumor suppressor gene wt1 encodes a zinc finger DNA binding protein, WT1, that functions as a transcriptional repressor. The fetal mitogen insulin-like growth factor II (IGF-II) is overexpressed in Wilms tumors and may have autocrine effects in tumor progression. The major fetal IGF-II promoter was defined in transient transfection assays as a region spanning from nucleotides -295 to +135, relative to the transcription start site. WT1 bound to multiple sites in this region and functioned as a potent repressor of IGF-II transcription in vivo. Maximal repression was dependent on the presence of WT1 binding sites on each side of the transcriptional initiation site. These findings provide a molecular basis for overexpression of IGF-II in Wilms tumors and suggest that WT1 negatively regulates blastemal cell proliferation by limiting the production of a fetal growth factor in the developing vertebrate kidney.
Drummond
I A
IA
Howard Hughes Medical Institute, University of Chicago, IL 60637.
Madden
S L
SL
Rohwer-Nutter
P
P
Bell
G I
GI
Sukhatme
V P
VP
Rauscher
F J
FJ
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016162:Genes, Wilms Tumor / Q000502:physiology*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007668:Kidney / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D014162:Transfection; D025721:WT1 Proteins; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D025721:WT1 Proteins; D007335:Insulin-Like Growth Factor II; D004247:DNA; D003850:Deoxyribonuclease I