The predominant WT1 isoform (+KTS) encodes a DNA-binding protein targeting the planar cell polarity gene Scribble in renal podocytes.
WT1 encodes a tumor suppressor first identified by its inactivation in Wilms' Tumor. Although one WT1 splicing variant encodes a well-characterized zinc finger transcription factor, little is known about the function of the most prevalent WT1 isoform, whose DNA binding domain is disrupted by a three-amino acid (KTS) insertion. Using cells that conditionally express WT1(+KTS), we undertook a genome-wide chromatin immunoprecipitation and cloning analysis to identify candidate WT1(+KTS)-regulated promoters. We identified the planar cell polarity gene Scribble (SCRB) as the first WT1(+KTS) target gene in podocytes of the kidney. WT1 and SCRB expression patterns overlap precisely in developing renal glomeruli of mice, and WT1(+KTS) binds to a 33-nucleotide region within the Scribble promoter in mouse and human cell lines and kidneys. Together, our results support a role for the predominant WT1(+KTS) isoform in transcriptional regulation and suggest a link between the WT1-dependent tumor suppressor pathway and a key component of the planar cell polarity pathway.
Wells
Julie
J
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, USA.
Rivera
Miguel N
MN
Kim
Woo Jae
WJ
Starbuck
Kristen
K
Haber
Daniel A
DA
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D050199:Podocytes / Q000378:metabolism; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; D025721:WT1 Proteins; C480591:SCRIB protein, human; C508433:scrib protein, mouse