The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity

doi:10.1073/pnas.0811349106

The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity

Massachusetts General Hospital Cancer Center, Harvard Medical School, 149 13th Street, Room 7-101, Charlestown, MA 20129

Edited by Webster K. Cavenee, University of California at San Diego School of Medicine, La Jolla, CA, and approved April 2, 2009
↵¹M.N.R. and W.J.K. contributed equally to this work. (received for review November 8, 2008)

Abstract

WTX encodes a tumor suppressor gene inactivated in Wilms tumor and recently implicated in WNT signaling through enhancement of cytoplasmic β-catenin (CTNNB1) degradation. Here, we report that WTX translocates to the nucleus, a property that is modified by an endogenous splicing variant and is modulated by a nuclear export inhibitor. WTX is present in distinct subnuclear structures and co-localizes with the paraspeckle marker p54NRB/NONO, suggesting a role in transcriptional regulation. Notably, WTX binds WT1, another Wilms tumor suppressor and stem cell marker that encodes a zinc-finger transcription factor, and enhances WT1-mediated transcription of Amphiregulin, an endogenous target gene. Together, these observations suggest a role for WTX in nuclear pathways implicated in the transcriptional regulation of cellular differentiation programs.

Footnotes

²To whom correspondence should be addressed. E-mail: haber{at}helix.mgh.harvard.edu
Author contributions: M.N.R., W.J.K., J.W., A.B., and D.A.H. designed research; M.N.R., W.J.K., J.W., A.S., A.B., E.J.C., and J.Z. performed research; M.N.R., W.J.K., J.W., A.B., and D.A.H. analyzed data; and M.N.R. and D.A.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0811349106/DCSupplemental.
Freely available online through the PNAS open access option.