Novel non-genomic signaling of thyroid hormone receptors in thyroid carcinogenesis

The thyroid hormone receptors (TRs) are transcription factors that mediate the pleiotropic activities of the thyroid hormone, T3. Four T3-binding isorforms, TR alpha 1, TR beta 1, TR beta 2, and TR beta 3, are encoded by two genes, THRA and THRB. Mutations and altered expression of TRs have been reported in human cancers. A targeted germ-line mutation of the Thr beta gene in the mouse leads to spontaneous development of follicular thyroid carcinoma (TR beta(PV/PV) mouse). The TR beta PV mutant has lost T3-binding activity and displays potent dominant negative activity. The striking phenotype of thyroid cancer exhibited by TR beta(PV/PV) mice has recently led to the discovery of novel non-genomic actions of TR beta PV that contribute to thyroid carcinogenesis. These actions involve direct physical interaction of TR beta PV with cellular proteins, namely the regulatory subunit of the phosphatidylinositol 3-kinase (p85 alpha), the pituitary tumor transforming gene (MG) and beta-catenin, that are critically involved in cell proliferation, motility, migration, and metastasis. Thus, a TR beta mutant (TR beta PV), via a novel mode of non-genomic action, acts as an oncogene in thyroid carcinogenesis. Published by Elsevier Ireland Ltd.