Regulation of beta-catenin by a novel nongenomic action of thyroid hormone beta receptor.

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.

• Authors: Celine J Guigon, Li Zhao, Changxue Lu, Mark C Willingham, Sheue-Yann Cheng
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 28 Issue 14 Pg. 4598-608 (Jul 2008) ISSN: 1098-5549 [Electronic] United States
• PMID: 18474620 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Ligands
• Nuclear Proteins
• Thyroid Hormone Receptors beta
• beta Catenin
• Ubiquitin-Protein Ligases
• seven in absentia proteins
• Glycogen Synthase Kinase 3
• Proteasome Endopeptidase Complex

Topics

• Adenomatous Polyposis Coli (metabolism)
• Animals
• Carcinoma (metabolism)
• Glycogen Synthase Kinase 3 (metabolism)
• HeLa Cells
• Humans
• Ligands
• Metabolic Networks and Pathways
• Mice
• Nuclear Proteins (metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Signal Transduction
• Thyroid Gland (metabolism)
• Thyroid Hormone Receptors beta (genetics, metabolism)
• Thyroid Neoplasms (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• beta Catenin (metabolism)