title: Wnt-independent role of β-catenin in thyroid cell proliferation and differentiation.
abstract: The Wnt/β-catenin pathway has been associated with thyroid cell growth and tumorigenesis. However, little is known regarding its involvement in the response to the key regulators of thyroid cell proliferation and differentiation. Here we show that TSH and IGF-1 increase β-catenin nuclear accumulation and its transcriptional activity in differentiated thyroid cells. This effect takes place in a Wnt-independent manner because TSH and IGF-1, through the activation of protein kinase A and protein kinase B/Akt, phosphorylate β-catenin at S552 and S675, which results in β-catenin release from E-cadherin at the adherens junctions. Nuclear β-catenin regulates thyroid cell proliferation, because its silencing or the overexpression of a dominant-negative form of T-cell factor 4 resulted in reduced levels of cyclin D1 and DNA synthesis. Furthermore, the β-catenin silencing markedly reduced the expression of Pax8, the main transcription factor involved in epithelial thyroid cell differentiation. Finally, we observed that β-catenin physically interacts with the transcription factor Pax8, increasing its transcriptional activity on the sodium iodide symporter (NIS) gene, a critical gene required for thyroid cell physiology. Taken together, our findings show that β-catenin plays a not yet described role in thyroid function including a functional interaction with Pax8.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sastre-Perona
authors.forename: Pilar
authors.initials: P
authors.lastname: Santisteban
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000166:cytology* / Q000378:metabolism; D013972:Thyrotropin / Q000502:physiology; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000502:physiology*
chemical_list: C530106:Ccnd1 protein, rat; C495268:Ctnnb1 protein, rat; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499497:Pax8 protein, rat; D051176:beta Catenin; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin