The WWOX tumor suppressor is essential for postnatal survival and normal bone metabolism
Authors
Aqeilan, Rami I.Hassan, Mohammad Q.
de Bruin, Alain
Hagan, John P.
Volinia, Stefano
Palumbo, Titziana
Hussain, Sadiq
Lee, Suk Hee
Gaur, Tripti
Stein, Gary S.
Lian, Jane B.
Croce, Carlo M.
UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2008-05-20Keywords
AnimalsAnimals, Newborn
Bone and Bones
Cell Differentiation
Cell Line, Tumor
Chromatin
*Gene Expression Regulation
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Osteoblasts
Osteoclasts
Oxidoreductases
Phenotype
Tumor Suppressor Proteins
Cell Biology
Metadata
Show full item recordAbstract
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.Source
J Biol Chem. 2008 Aug 1;283(31):21629-39. Epub 2008 May 16. Link to article on publisher's siteDOI
10.1074/jbc.M800855200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/49618PubMed ID
18487609Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M800855200