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Molecular and Cellular Biology, January 2005, p. 124-135, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.124-135.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

An Unliganded Thyroid Hormone ß Receptor Activates the Cyclin D1/Cyclin-Dependent Kinase/Retinoblastoma/E2F Pathway and Induces Pituitary Tumorigenesis

Hiroko Furumoto,1,{dagger} Hao Ying,1,{dagger} G. V. R. Chandramouli,2 Li Zhao,1 Robert L. Walker,3 Paul S. Meltzer,3 Mark C. Willingham,4 and Sheue-Yann Cheng1*

Laboratory of Molecular Biology,1 Advanced Technology Center, Center for Cancer Research, National Cancer Institute,2 Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland,3 Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina4

Received 12 July 2004/ Returned for modification 12 August 2004/ Accepted 6 October 2004

Thyroid-stimulating hormone (TSH)-secreting tumors (TSH-omas) are pituitary tumors that constitutively secrete TSH. The molecular genetics underlying this abnormality are not known. We discovered that a knockin mouse harboring a mutated thyroid hormone receptor (TR) ß (PV; TRßPV/PV mouse) spontaneously developed TSH-omas. TRßPV/PV mice lost the negative feedback regulation with highly elevated TSH levels associated with increased thyroid hormone levels (3,3',5-triiodo-L-thyronine [T3]). Remarkably, we found that mice deficient in all TRs (TR{alpha}1–/– TRß–/–) had similarly increased T3 and TSH levels, but no discernible TSH-omas, indicating that the dysregulation of the pituitary-thyroid axis alone is not sufficient to induce TSH-omas. Comparison of gene expression profiles by cDNA microarrays identified overexpression of cyclin D1 mRNA in TRßPV/PV but not in TR{alpha}1–/– TRß–/– mice. Overexpression of cyclin D1 protein led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway only in TRßPV/PV mice. The liganded TRß repressed cyclin D1 expression via tethering to the cyclin D1 promoter through binding to the cyclic AMP response element-binding protein. That repression effect was lost in mutant PV, thereby resulting in constitutive activation of cyclin D1 in TRßPV/PV mice. The present study revealed a novel molecular mechanism by which an unliganded TRß mutant acts to contribute to pituitary tumorigenesis in vivo and provided mechanistic insights into the understanding of pathogenesis of TSH-omas in patients.

* Correspondending author. Mailing address: Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Dr., Rm. 5128, Bethesda, MD 20892-4264. Phone: (301) 496-4280. Fax: (301) 480-9676. E-mail: sycheng{at}helix.nih.gov.

{dagger} H.F. and H.Y. made equal contributions.

Molecular and Cellular Biology, January 2005, p. 124-135, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.124-135.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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