DNA RECOGNITION BY SPLICING VARIANTS OF THE WILMS-TUMOR SUPPRESSOR, WT1

被引:142
作者
DRUMMOND, IA
RUPPRECHT, HD
ROHWERNUTTER, P
LOPEZGUISA, JM
MADDEN, SL
RAUSCHER, FJ
SUKHATME, VP
机构
[1] HARVARD UNIV,SCH MED,BOSTON,MA 02215
[2] BETH ISRAEL HOSP,DEPT MED,DIV RENAL,BOSTON,MA 02215
[3] UNIV CHICAGO,HOWARD HUGHES MED INST,CHICAGO,IL 60637
[4] UNIV CHICAGO,DEPT MOLEC GENET & CELL BIOL,CHICAGO,IL 60637
[5] UNIV CHICAGO,DEPT MED,CHICAGO,IL 60637
[6] WISTAR INST ANAT & BIOL,PHILADELPHIA,PA 19104
关键词
D O I
10.1128/MCB.14.6.3800
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Wilms' tumor suppressor, WT1, is a zinc finger transcriptional regulator which exists as multiple forms owing to alternative mRNA splicing. The most abundant splicing variants contain a nine-nucleotide insertion encoding lysine, threonine, and serine (KTS) in the H-C link region between the third and fourth WT1 zinc fingers which disrupts binding to a previously defined WT1-EGR1 binding site. We have identified WT1[+KTS] binding sites in the insulin-like growth factor II gene and show that WT1[+KTS] represses transcription from the insulin-like growth factor II P3 promoter. The highest affinity WT1[+KTS] DNA binding sites included nucleotide contacts involving all four WT1 zinc fingers. We also found that different subsets of three WT1 zinc fingers could bind to distinct DNA recognition elements. A tumor-associated, WT1 finger 3 deletion mutant was shown to bind to juxtaposed nucleotide triplets for the remaining zinc fingers 1, 2, and 4. The characterization of novel WT1 DNA recognition elements adds a new level of complexity to the potential gene regulatory activity of WT1. The results also present the possibility that altered DNA recognition by the dominant WT1 zinc finger 3 deletion mutant may contribute to tumorigenesis.
引用
收藏
页码:3800 / 3809
页数:10
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