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Molecular and Cellular Biology, July 2008, p. 4598-4608, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.02192-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of β-Catenin by a Novel Nongenomic Action of Thyroid Hormone β Receptor{triangledown}

Celine J. Guigon,1 Li Zhao,1 Changxue Lu,1 Mark C. Willingham,2 and Sheue-yann Cheng1*

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,1 Department of Pathology, Wake Forest University, Winston-Salem, North Carolina2

Received 11 December 2007/ Returned for modification 1 February 2008/ Accepted 29 April 2008

We previously created a knock-in mutant mouse harboring a dominantly negative mutant thyroid hormone receptor β (TRβPV/PV mouse) that spontaneously develops a follicular thyroid carcinoma similar to human thyroid cancer. We found that β-catenin, which plays a critical role in oncogenesis, was highly elevated in thyroid tumors of TRβPV/PV mice. We sought to understand the molecular basis underlying aberrant accumulation of β-catenin by mutations of TRβ in vivo. Cell-based studies showed that thyroid hormone (T3) induced the degradation of β-catenin in cells expressing TRβ via proteasomal pathways. In contrast, no T3-induced degradation occurred in cells expressing the mutant receptor (TRβPV). In vitro binding studies and cell-based analyses revealed that β-catenin physically associated with unliganded TRβ or TRβPV. However, in the presence of T3, β-catenin was dissociated from TRβ-β-catenin complexes but not from TRβPV-β-catenin complexes. β-Catenin signaling was repressed by T3 in TRβ-expressing cells through decreasing β-catenin-mediated transcription activity and target gene expression, whereas sustained β-catenin signaling was observed in TRβPV-expressing cells. The stabilization of β-catenin, via association with a mutated TRβ, represents a novel activating mechanism of the oncogenic protein β-catenin that could contribute to thyroid carcinogenesis in TRβPV/PV mice.

* Corresponding author. Mailing address: Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Dr., Room 5128, Bethesda, MD 20892-4264. Phone: (301) 496-4280. Fax: (301) 402-1344. E-mail: chengs{at}mail.nih.gov

{triangledown} Published ahead of print on 12 May 2008.

Molecular and Cellular Biology, July 2008, p. 4598-4608, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.02192-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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