Guigon Celine J, Cheng Sheue-yann
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4264, USA.
Mol Cell Endocrinol. 2009 Sep 24;308(1-2):63-9. doi: 10.1016/j.mce.2009.01.007. Epub 2009 Jan 21.
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.
甲状腺激素受体（TRs）是介导甲状腺激素T3多种效应的转录因子。由THRA和THRB两个基因编码产生四种T3结合异构体，即TRα1、TRβ1、TRβ2和TRβ3。在人类癌症中已报道了TRs的突变和表达改变。小鼠中Thrβ基因的靶向种系突变会导致滤泡性甲状腺癌自发发生（TRβ（PV/PV）小鼠）。TRβPV突变体丧失了T3结合活性，并表现出强大的显性负性活性。TRβ（PV/PV）小鼠所表现出的显著甲状腺癌表型最近导致了对TRβPV新型非基因组作用的发现，这些作用有助于甲状腺癌的发生。这些作用涉及TRβPV与细胞蛋白的直接物理相互作用，这些细胞蛋白即磷脂酰肌醇3激酶（p85α）的调节亚基、垂体肿瘤转化基因（PTTG）和β-连环蛋白，它们在细胞增殖、运动、迁移和转移中起关键作用。因此，一种TRβ突变体（TRβPV）通过一种新型的非基因组作用模式，在甲状腺癌发生过程中充当癌基因。
