The biological activities of thyroid hormone (T3) are mediated by the thyroid hormone receptors (TRs). There are two TR genes, a and b, which yield TRa1, TRb1, TRb2 and TRb3 by alternative splicing of the primary transcripts. We have been generating mouse models not only to understand the molecular mechanisms of thyroid hormone action in vivo, but to delineate the molecular basis of diseases due to mutations of receptors. Generation of a mouse model of thyroid hormone resistance syndrome (RTH). RTH is a disease due to mutations of the TRb gene. TRbPV mice were generated by knocking in PV mutation into the TRb gene locus by homologous recombination. PV mutation was derived from an RTH patient with severe dysfunction of the pituitary-thyroid axis, growth abnormality, hypercholesterolemia and attention-deficit hyperactivity disorder. TRbPV mouse is the first mouse model which faithfully recapitulates RTH in humans. Using TRbPV mice, we can now address clinically related issues at the molecular level, which was not achievable previously. TRbPV mouse as a model to elucidate the role of TR mutants in carcinogenesis. The role of TRs in carcinogenesis is unknown. However, we have identified high frequencies of mutations of the TRa and/or TRb genes in human hepatocellular carcinoma, renal clear cell carcinoma and thyroid papillary carcinoma. Importantly, we discovered that homozygous TRbPV mice developed anaplastic variant of thyroid carcinoma with metastasis to the lung and heart. We also found primary tumors in the pituitary, lung, pericardium and the thymus of homozygous TRbPV mice. Thus, the TRbPV mouse is a new mouse model to study the genetic basis of thyroid carcinogenesis and could potentially be used for testing drugs to treat thyroid cancer. Their novel findings open a new paradigm to understand the role of mutant TRs in carcinogenesis. Generation of a novel mouse model (TRaPV mice) for the identification of the genetic basis of human dwarfism. No mutations of the TRa gene have ever been found in RTH patients. We therefore knocked in the same PV mutation to the TRa gene locus by homologous recombination to ask the question as to whether mutations of the TRa gene lead to diseases. TRaPV mice are not embryonic lethal and exhibit phenotypes distinct from those of TRbPV mice, indicating isoform-dependent action of mutant TRs. One prominent phenotype of TRaPV mice is dwarfism. This mouse model is being used as a tool to uncover human diseases, including cancers, which could be associated with mutations in the TRa gene. Discovery of the critical role of TR co-activators in the pathogenesis of RTH and thyroid carcinogenesis. The transcriptional activity of TRs is activated by co-activators such as the steroid hormone receptor co-activator-1 (SRC-1). We crossed the TRbPV mice with SRC-1 knockout mice and found that the lack of SRC-1 intensifies the resistance of tissues in RTH. These results demonstrate the important in vivo role of TR co-activators in the pathogenesis of RTH. Importantly, for the first time, we discovered that the progression of thyroid carcinogenesis is accelerated by the lack of SRC-1, suggesting that SRC-1 could potentially act as a tumor suppressor in thyroid carcinogenesis. The possible role of SRC-1 as a tumor suppressor is currently being investigated. These novel findings have important clinical implications.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC008752-21
Application #
6559019
Study Section
(LMB)
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
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
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
Pemberton, H N; Franklyn, J A; Boelaert, K et al. (2007) Separase, securin and Rad21 in neural cell growth. J Cell Physiol 213:45-53
Furuya, Fumihiko; Ying, Hao; Zhao, Li et al. (2007) Novel functions of thyroid hormone receptor mutants: beyond nucleus-initiated transcription. Steroids 72:171-9
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

Showing the most recent 10 out of 41 publications