HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kim, W. B. Articles by Kohn, L. D Search for Related Content PubMed PubMed Citation Articles by Kim, W. B. Articles by Kohn, L. D

¹ Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University, The Ridges, Athens, Ohio 45701, USA
² Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
³ The Howard Hughes Medical Institute and
⁴ The Department of Hematology, University of Washington, Seattle, Washington 98195, USA

(Requests for offprints should be addressed to L D Kohn; Email: lkohn1{at}rrohio.com, kohnl{at}ohio.edu)

Wnt binding to cell surface receptors can activate a ‘canonical’ pathway that increases cellular ß-catenin or a ‘noncanonical’ Ca⁺⁺ pathway which can increase protein kinase C (PKC) activity. Although components of both Wnt/ß-catenin-signaling pathways exist in thyrocytes, their biological role is largely unknown. In evaluating the biological role of Wnt signaling in differentiated FRTL-5 thyroid cells, we showed that TSH increased canonical Wnt-1 but, surprisingly, decreased the active form of ß-catenin. Transient overexpression of Wnt-1 or ß-catenin in FRTL-5 cells increased active ß-catenin (ABC), decreased thyroperoxidase (TPO) mRNA, and suppressed TPO-promoter activity. The target of ß-catenin suppressive action was a consensus T cell factor/lymphoid enhancing factor (TCF/LEF)-binding site 5'-A/T A/T CAAAG-3', –137 to –129 bp on the rat TPO promoter. ß-Catenin overexpression significantly increased complex formation between ß-catenin/TCF-1 and an oligonucleotide containing the TCF/LEF sequence, suggesting that the ß-catenin/TCF-1 complex acts as a transcriptional repressor of the TPO gene. Stable over-expression of Wnt-1 in FRTL-5 cells significantly increased the growth rate without increasing ß-catenin levels. Increased growth was blunted by a PKC inhibitor, staurosporin. Wnt-1 overexpression increased serine phosphorylation, without affecting tyrosine phosphorylation, of signal transducers and activators of transcription 3 (STAT3) protein. In addition, these final results suggest that TSH-induced increase in Wnt-1 levels in thyrocytes contributes to enhanced cellular growth via a PKC pathway that increases STAT3 serine phosphorylation and activation, whereas TSH-induced decrease in activation of ß-catenin simultaneously relieves transcriptional suppression of TPO. We hypothesize that Wnt signaling contributes to the ability of TSH to simultaneously increase cell growth and functional, thyroid-specific, gene expression.