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J. Biol. Chem., Vol. 283, Issue 31, 21629-21639, August 1, 2008
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1
2
From the
Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210 and the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655
The WW domain-containing oxidoreductase (WWOX) gene encodes a tumor suppressor. We have previously shown that targeted ablation of the Wwox gene in mouse increases the incidence of spontaneous and chemically induced tumors. To investigate WWOX function in vivo, we examined Wwox-deficient (Wwox-/-) mice for phenotypical abnormalities. Wwox-/- mice are significantly reduced in size, die at the age of 2-3 weeks, and suffer a metabolic disorder that affects the skeleton. Wwox-/- mice exhibit a delay in bone formation from a cell autonomous defect in differentiation beginning at the mineralization stage shown in calvarial osteoblasts ex vivo and supported by significantly decreased bone formation parameters in Wwox-/- mice by microcomputed tomography analyses. Wwox-/- mice develop metabolic bone disease, as a consequence of reduced serum calcium, hypoproteinuria, and hypoglycemia leading to increased osteoclast activity and bone resorption. Interestingly, we find WWOX physically associates with RUNX2, the principal transcriptional regulator of osteoblast differentiation, and on osteocalcin chromatin. We show WWOX functionally suppresses RUNX2 transactivation ability in osteoblasts. In breast cancer MDA-MB-242 cells that lack endogenous WWOX protein, restoration of WWOX expression inhibited Runx2 and RUNX2 target genes related to metastasis. Affymetrix mRNA profiling revealed common gene targets in multiple tissues. In Wwox-/- mice, genes related to nucleosome assembly and cell growth genes were down-regulated, and negative regulators of skeletal metabolism exhibited increased expression. Our results demonstrate an essential requirement for the WWOX tumor suppressor in postnatal survival, growth, and metabolism and suggest a central role for WWOX in regulation of bone tissue formation.
Received for publication, February 1, 2008 , and in revised form, May 5, 2008.
* This work was supported, in whole or in part, by National Institutes of Health Grants P01 CA082834 and P01 AR048818 (to G. S. S. and J. B. L.). This work was also supported by Ohio Cancer Research Associates and Kimmel Scholar Award (to R. I. A.). 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 Tables 2-4.
1 To whom correspondence may be addressed: Human Cancer Genetics Program, Ohio State University-Biomedical Research Tower, Rm. 1088, 460 West 12th Ave., Columbus, OH 43210. Tel.: 614-292-5906; Fax: 614-292-4097; E-mail: rami.aqeilan{at}osumc.edu. Present address: The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
2 To whom correspondence may be addressed. E-mail: jane.lian{at}umassmed.edu.
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