Abstract
We previously created a knock-in mutant mouse harboring a dominantly negative mutant thyroid hormone receptor beta (TRbeta(PV/PV) mouse) that spontaneously develops a follicular thyroid carcinoma similar to human thyroid cancer. We found that beta-catenin, which plays a critical role in oncogenesis, was highly elevated in thyroid tumors of TRbeta(PV/PV) mice. We sought to understand the molecular basis underlying aberrant accumulation of beta-catenin by mutations of TRbeta in vivo. Cell-based studies showed that thyroid hormone (T3) induced the degradation of beta-catenin in cells expressing TRbeta via proteasomal pathways. In contrast, no T3-induced degradation occurred in cells expressing the mutant receptor (TRbetaPV). In vitro binding studies and cell-based analyses revealed that beta-catenin physically associated with unliganded TRbeta or TRbetaPV. However, in the presence of T3, beta-catenin was dissociated from TRbeta-beta-catenin complexes but not from TRbetaPV-beta-catenin complexes. beta-Catenin signaling was repressed by T3 in TRbeta-expressing cells through decreasing beta-catenin-mediated transcription activity and target gene expression, whereas sustained beta-catenin signaling was observed in TRbetaPV-expressing cells. The stabilization of beta-catenin, via association with a mutated TRbeta, represents a novel activating mechanism of the oncogenic protein beta-catenin that could contribute to thyroid carcinogenesis in TRbeta(PV/PV) mice.