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This version published online on September 22, 2005
Endocrinology, doi:10.1210/en.2005-0147
A more recent version of this article appeared on January 1, 2006
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Submitted on February 4, 2005
Accepted on September 13, 2005

PAX8-PPAR{gamma} DISRUPTS NORMAL PAX8 OR PPAR{gamma} TRANSCRIPTIONAL FUNCTION AND STIMULATES FOLLICULAR THYROID CELL GROWTH

Amy Y. M. Au, Claire McBride, Kenneth G. Wilhelm Jr, Ronald J. Koenig, Bridget Speller, Linda Cheung, Marinella Messina, John Wentworth, Vitomir Tasevski, Diana Learoyd, Bruce G. Robinson, and Roderick J. Clifton-Bligh*

Cancer Genetics Unit, Kolling Institute of Medical Research, University of Sydney, N. S. W., Australia 2065, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0678 and the Department of Endocrinology, Royal North Shore Hospital, St Leonards, N. S. W., Australia 2065

* To whom correspondence should be addressed. E-mail: jclifton{at}med.usyd.edu.au.

Follicular thyroid carcinomas are associated with a chromosomal translocation that fuses the thyroid-specific transcription factor PAX8 with the nuclear receptor peroxisome proliferator-activated receptor {gamma}(PPAR{gamma}). This study investigated the transcriptional mechanisms by which PAX8-PPAR{gamma} regulates follicular thyroid cells. In HeLa cells, rat follicular thyroid (FRTL-5) cells or immortalized human thyroid cells, PAX8-PPAR{gamma} stimulated transcription from PAX8-responsive thyroperoxidase (TPO) and sodium-iodide symporter (NIS) promoters in a manner at least comparable with wild-type PAX8. In contrast, PAX8-PPAR{gamma} failed to stimulate transcription from the thyroglobulin (Tg) promoter and blocked the synergistic stimulation of this promoter by wild-type PAX8 and thyroid transcription factor-1 (TITF1). Unexpectedly, PAX8-PPAR{gamma} transcriptional function on a PPAR{gamma}-responsive promoter was cell-type dependent; in HeLa cells, PAX8-PPAR{gamma} dominantly inhibited expression of the PPAR{gamma}-responsive promoter, whereas in FRTL-5 and immortalized human thyroid cells PAX8-PPAR{gamma} stimulated this promoter. In gel shift analyses, PAX8-PPAR{gamma} bound a PPAR{gamma}-response element suggesting that its transcriptional function is mediated via direct DNA contact. A biological model of PAX8-PPAR{gamma} function in follicular thyroid cells was generated via constitutive expression of the fusion protein in FRTL-5 cells. In this model, PAX8-PPAR{gamma} expression was associated with enhanced growth as assessed by soft agar assays and thymidine uptake. Therefore, PAX8-PPAR{gamma} disrupts normal transcriptional regulation by stimulating some genes and inhibiting others, the net effect of which may mediate follicular thyroid cell growth and loss of differentiation that ultimately leads to carcinogenesis.




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