Regulation of -catenin by a Novel Nongenomic Action of Thyroid Hormone Receptor

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute National Institutes of Health, Bethesda, MD; and Department of Pathology, Wake Forest University, Winston-Salem, NC

^* To whom correspondence should be addressed. Email: chengs{at}mail.nih.gov.

	Abstract

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