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

Abstract

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.

Figure 1. Schematic comparison of TRβ1 and TRβPV structure

The TRβPV mutation was identified in a patient with resistance to thyroid hormone. The TRβPV mutation is a frameshift mutation due to a C-insertion at codon 448 of TRβ1. The carboxyl-terminal sequences of the wild-type TRβ and the TRβPV mutant are indicated.

Figure 2. Proposed model for the overactivation of PI3K signaling by TRβPV in the thyroid cancer of TRβ^PV/PV mice

TRβPV physically interacts with the regulatory subunit of PI3K, p85α, to activate PI3K signaling, thereby affecting cell proliferation, motility, migration, and apoptosis (Furuya et al., 2006). TRβPV competes with NCoR to interact with p85α, but in thyroid cancer of TRβ^PV/PV mice, NCoR protein abundance is lower than in normal thyroid, thus favoring the physical interaction of TRβPV and p85α and the overactivation of PI3K signaling (Furuya et al., 2007b).

Figure 3. TRβPV, via protein-protein interaction, interferes with proteasomal pathway regulatory function

A) A proposed molecular model for the accumulation of PTTG protein in the thyroid cancer of TRβ^PV/PV mice(a) The direct interaction of TRβ with SRC-3 induced by the binding of T3 induces the formation of TRβ/PTTG/SRC3/PA28γ complexes that activate the degradation of PTTG and lead to timely separation of sister chromatids at anaphase. (b) TRβPV physically interacts with PTTG but as it does not bind T3, it does not interact with SRC-3/PA28γ to activate PTTG degradation. The absence of degradation leads to PTTG accumulation and inhibition of mitotic progression (Ying et al., 2006). B) A proposed molecular model for the accumulation of β-catenin in the thyroid cancer of TRβ^PV/PV mice. (a) The physical interaction of TRβ with β-catenin is weakened by T3 binding and favors the degradation of β-catenin by proteasomal pathways. (b) TRβPV strongly interacts with β-catenin and the loss of its T3 binding activity inhibits the release of β-catenin from TRβPV/β-catenin complexes in the presence of T3, thereby preventing β-catenin degradation. The absence of β-catenin degradation leads to β-catenin accumulation and constitutive activation of its oncogenic signaling (Guigon et al., 2008).