title: An unliganded thyroid hormone beta receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis.
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 knock-in mouse harboring a mutated thyroid hormone receptor (TR) beta (PV; TRbeta(PV/PV) mouse) spontaneously developed TSH-omas. TRbeta(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 (TRalpha1(-/-) TRbeta(-/-)) 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 TRbeta(PV/PV) but not in TRalpha1(-/-) TRbeta(-/-) mice. Overexpression of cyclin D1 protein led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway only in TRbeta(PV/PV) mice. The liganded TRbeta 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 TRbeta(PV/PV) mice. The present study revealed a novel molecular mechanism by which an unliganded TRbeta mutant acts to contribute to pituitary tumorigenesis in vivo and provided mechanistic insights into the understanding of pathogenesis of TSH-omas in patients.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive, Rm. 5128, Bethesda, MD 20892-4264, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Furumoto
authors.forename: Hao
authors.initials: H
authors.lastname: Ying
authors.forename: G V R
authors.initials: GV
authors.lastname: Chandramouli
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D047468:Immunoprecipitation; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D010902:Pituitary Gland / Q000378:metabolism; D010907:Pituitary Hormones / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000209:etiology* / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037042:Thyroid Hormone Receptors beta; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D008024:Ligands; D010907:Pituitary Hormones; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D016160:Retinoblastoma Protein; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D014284:Triiodothyronine; D019938:Cyclin D1; D012313:RNA; D000242:Cyclic AMP; D005982:Glutathione Transferase; D018844:Cyclin-Dependent Kinases