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 isoforms, TRalpha1, TRbeta1, TRbeta2, and TRbeta3, 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 Thrbeta gene in the mouse leads to spontaneous development of follicular thyroid carcinoma (TRbeta(PV/PV) mouse). The TRbetaPV mutant has lost T3-binding activity and displays potent dominant negative activity. The striking phenotype of thyroid cancer exhibited by TRbeta(PV/PV) mice has recently led to the discovery of novel non-genomic actions of TRbetaPV that contribute to thyroid carcinogenesis. These actions involve direct physical interaction of TRbetaPV with cellular proteins, namely the regulatory subunit of the phosphatidylinositol 3-kinase (p85alpha), the pituitary tumor transforming gene (PTTG) and beta-catenin, that are critically involved in cell proliferation, motility, migration, and metastasis. Thus, a TRbeta mutant (TRbetaPV), via a novel mode of non-genomic action, acts as an oncogene in thyroid carcinogenesis.
Guigon
Celine J
CJ
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4264, USA.
Cheng
Sheue-yann
SY
D000595:Amino Acid Sequence; D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D064249:Securin; D015398:Signal Transduction / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D009363:Neoplasm Proteins; D011988:Receptors, Thyroid Hormone; D064249:Securin; D051176:beta Catenin; C578002:pituitary tumor-transforming protein 1, human; D019869:Phosphatidylinositol 3-Kinases