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

Abstract

ABSTRACT 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) β (PV; TR β PV/PV mouse) spontaneously developed TSH-omas. TR β PV/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 α 1 −/− TR β −/− ) 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 TR β PV/PV but not in TRα1 −/− TR β −/− mice. Overexpression of cyclin D1 protein led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway only in TR β PV/PV mice. The liganded TRβ 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 TR β PV/PV mice. The present study revealed a novel molecular mechanism by which an unliganded TR β mutant acts to contribute to pituitary tumorigenesis in vivo and provided mechanistic insights into the understanding of pathogenesis of TSH-omas in patients.