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

Celine J. Guigon, Li Zhao, Changxue Lu, Mark C. Willingham, Sheue Yann Cheng

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)4598-4608
Number of pages11
JournalMolecular and Cellular Biology
Volume28
Issue number14
DOIs
StatePublished - Jul 2008
Externally publishedYes

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Catenins
Thyroid Hormone Receptors
Thyroid Gland
Carcinogenesis
Follicular Adenocarcinoma
Triiodothyronine
Thyroid Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Regulation of β-catenin by a novel nongenomic action of thyroid hormone β receptor. / Guigon, Celine J.; Zhao, Li; Lu, Changxue; Willingham, Mark C.; Cheng, Sheue Yann.

In: Molecular and Cellular Biology, Vol. 28, No. 14, 07.2008, p. 4598-4608.

Research output: Contribution to journalArticle

Guigon, Celine J. ; Zhao, Li ; Lu, Changxue ; Willingham, Mark C. ; Cheng, Sheue Yann. / Regulation of β-catenin by a novel nongenomic action of thyroid hormone β receptor. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 14. pp. 4598-4608.
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