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J. Biol. Chem., Vol. 280, Issue 52, 43100-43108, December 30, 2005

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WOX1 Is Essential for Tumor Necrosis Factor-, UV Light-, Staurosporine-, and p53-mediated Cell Death, and Its Tyrosine 33-phosphorylated Form Binds and Stabilizes Serine 46-phosphorylated p53^*

From the Guthrie Research Institute, Laboratory of Molecular Immunology, Sayre, Pennsylvania 18840

WW domain-containing oxidoreductase WOX1, also named WWOX or FOR, undergoes Tyr³³ phosphorylation at its first N-terminal WW domain and subsequent nuclear translocation in response to sex steroid hormones and stress stimuli. The activated WOX1 binds tumor suppressor p53, and both proteins may induce apoptosis synergistically. Functional suppression of WOX1 by antisense mRNA or a dominant negative abolishes p53-mediated apoptosis. Here, we determined that UV light, anisomycin, etoposide, and hypoxic stress rapidly induced phosphorylation of p53 at Ser⁴⁶ and WOX1 at Tyr³³ (phospho-WOX1) and their binding interactions in several tested cancer cells. Mapping by yeast two-hybrid analysis and co-immunoprecipitation showed that phospho-WOX1 physically interacted with Ser⁴⁶-phosphorylated p53. Knockdown of WOX1 protein expression by small interfering RNA resulted in L929 fibroblast resistance to apoptosis by tumor necrosis factor, staurosporine, UV light, and ectopic p53, indicating an essential role of WOX1 in stress stimuli-induced apoptosis. Notably, UV light could not induce p53 protein expression in these WOX1 knockdown cells, although p53 mRNA levels were not reduced. Suppression of WOX1 by dominant negative WOX1 (to block Tyr³³ phosphorylation) also abolished UV light-induced p53 protein expression. Time course analysis showed that the stability of ectopic wild type p53, tagged with DsRed, was decreased in WOX1 knockdown cells. Inhibition of MDM2 by nutlin-3 increased the binding of p53 and WOX1 and stability of p53. Together, our data show that WOX1 plays a critical role in conferring cellular sensitivity to apoptotic stress and that Tyr³³ phosphorylation in WOX1 is essential for binding and stabilizing Ser⁴⁶-phosphorylated p53.

Received for publication, May 23, 2005 , and in revised form, September 30, 2005.

^* This work was supported in part by the American Heart Association, Department of Defense Grant DAMD17-03-1-0736, and the Guthrie Foundation for Education and Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

² Supported by Ministry of Education, Taiwan, Republic of China, Grant 91-B-FA09-1-4.

¹ To whom correspondence should be addressed: Guthrie Research Institute, 1 Guthrie Square, Sayre, PA 18840. Fax: 570-882-4643; E-mail: chang_nanshan{at}guthrie.org.

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