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.
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