Regulation of beta-catenin by a novel nongenomic action of thyroid hormone beta receptor.
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.
Guigon
Celine J
CJ
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Zhao
Li
L
Lu
Changxue
C
Willingham
Mark C
MC
Cheng
Sheue-Yann
SY
D011125:Adenomatous Polyposis Coli / Q000378:metabolism; D000818:Animals; D002277:Carcinoma / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D053858:Metabolic Networks and Pathways; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
D008024:Ligands; D009687:Nuclear Proteins; D037042:Thyroid Hormone Receptors beta; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex