The thyroid hormone, 3,3', 5-triiod-L-thyronine (T3) is critically important for growth, differentiation and development. The molecular signaling pathways mediated by T3 in cell proliferation are unknown. We used a rat cDNA microarray consisting of 4,400 genes to identify genes that contribute to T3-induced cell proliferation. About 60% of the 352 responsive genes were induced by T3 and the remainder was repressed by T3. Only 23% of the genes identified in this study were previously reported to be transcriptionally and/or functionally regulated by T3. Clustering of temporal patterns of expression and segregation of the known genes into functional classes indicated that activation of pathways of gluconeogenesis, oxidative phosphorylation, protein degradation and stress response/detoxification contributed to T3-induced cell proliferation. T3 rapidly repressed the expression of a host of key regulators of Wnt signaling pathway and the transcriptional activity of beta-catenin-Tcf complex. Furthermore, activation of Wnt signaling led to inhibition of cell proliferation. These results indicate that early silencing of this pathway is obligatory for the T3-induced cell proliferation. These novel results indicate that T3-induced cell proliferation requires a complex coordinated transcriptional reprogramming of many genes in different pathways. The biological activities of T3 are mediated by thyroid hormone nuclear receptors (TRs). Patients with mutations in the TRbeta (TRbeta) gene manifest resistance to thyroid hormone (RTH), resulting in a constellation of variable phenotypic abnormalities. We have generated mice with a targeted mutation in the TRbeta gene (TRbetaPV) using homologous recombination and the Cre/loxP system. Mice expressing a single PV allele showed the typical abnormalities of thyroid function found in heterozygous humans with RTH. Homozygous PV mice exhibit severe dysfunction of the pituitary-thyroid axis, impaired weight gains, abnormal bone development, hypercholesterolemia, loss of hearing and hyperactivity. This phenotype is distinct from that seen in mice with a null mutation in the TRbeta gene. Importantly, we identified abnormal expression patterns of several genes in tissues of TRbetaPV mice, demonstrating the interference of the mutant TR with the gene regulatory functions of the wild type TR in vivo. These results show that the actions of mutant and wild-type TRbeta in vivo are distinct. This model allows further study of the molecular action of T3 and mutant TR in vivo which could lead to better treatment for RTH patients.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Basic Sciences
United States
Zip Code
Araki, O; Ying, H; Zhu, X G et al. (2009) Distinct dysregulation of lipid metabolism by unliganded thyroid hormone receptor isoforms. Mol Endocrinol 23:308-15
Guigon, Celine J; Zhao, Li; Lu, Changxue et al. (2008) Regulation of beta-catenin by a novel nongenomic action of thyroid hormone beta receptor. Mol Cell Biol 28:4598-608
Ying, H; Willingham, M C; Cheng, S-Y (2008) The steroid receptor coactivator-3 is a tumor promoter in a mouse model of thyroid cancer. Oncogene 27:823-30
Lu, Changxue; Willingham, Mark C; Furuya, Fumihiko et al. (2008) Activation of phosphatidylinositol 3-kinase signaling promotes aberrant pituitary growth in a mouse model of thyroid-stimulating hormone-secreting pituitary tumors. Endocrinology 149:3339-45
Ying, Hao; Araki, Osamu; Furuya, Fumihiko et al. (2007) Impaired adipogenesis caused by a mutated thyroid hormone alpha1 receptor. Mol Cell Biol 27:2359-71
Furuya, Fumihiko; Lu, Changxue; Willingham, Mark C et al. (2007) Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer. Carcinogenesis 28:2451-8
Furuya, Fumihiko; Guigon, Celine J; Zhao, Li et al. (2007) Nuclear receptor corepressor is a novel regulator of phosphatidylinositol 3-kinase signaling. Mol Cell Biol 27:6116-26
Kim, Caroline S; Ying, Hao; Willingham, Mark C et al. (2007) The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer. Carcinogenesis 28:932-9
Owen, P J D; Ying, H; Lang, D et al. (2007) Endothelial dysfunction in a murine model of thyroid hormone resistance. Eur J Clin Invest 37:390-5
O'Shea, Patrick J; Guigon, Celine J; Williams, Graham R et al. (2007) Regulation of fibroblast growth factor receptor-1 (FGFR1) by thyroid hormone: identification of a thyroid hormone response element in the murine Fgfr1 promoter. Endocrinology 148:5966-76

Showing the most recent 10 out of 41 publications