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PAX8-Peroxisome Proliferator-Activated Receptor (PPAR) Disrupts Normal PAX8 or PPAR Transcriptional Function and Stimulates Follicular Thyroid Cell Growth

Cancer Genetics Unit (A.Y.M.A., C.M., B.S., L.C., M.M., J.W., V.T., D.L., B.G.R., R.J.C.-B.), Kolling Institute of Medical Research, University of Sydney, and Department of Endocrinology (D.L., B.G.R., R.J.C.-B.), Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia; and Division of Metabolism (K.G.W., R.J.K.), Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Roderick Clifton-Bligh, Cancer Genetics Unit, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. E-mail address: jclifton{at}med.usyd.edu.au.

Follicular thyroid carcinomas are associated with a chromosomal translocation that fuses the thyroid-specific transcription factor paired box gene 8 (PAX8) with the nuclear receptor peroxisome proliferator-activated receptor (PPAR). This study investigated the transcriptional mechanisms by which PAX8-PPAR regulates follicular thyroid cells. In HeLa cells, rat follicular thyroid (FRTL-5) cells, or immortalized human thyroid cells, PAX8-PPAR stimulated transcription from PAX8-responsive thyroperoxidase and sodium-iodide symporter promoters in a manner at least comparable with wild-type PAX8. In contrast, PAX8-PPAR failed to stimulate transcription from the thyroglobulin promoter and blocked the synergistic stimulation of this promoter by wild-type PAX8 and thyroid transcription factor-1. Unexpectedly, PAX8-PPAR transcriptional function on a PPAR-responsive promoter was cell-type dependent; in HeLa cells, PAX8-PPAR dominantly inhibited expression of the PPAR-responsive promoter, whereas in FRTL-5 and immortalized human thyroid cells PAX8-PPAR stimulated this promoter. In gel shift analyses, PAX8-PPAR bound a PPAR-response element suggesting that its transcriptional function is mediated via direct DNA contact. A biological model of PAX8-PPAR function in follicular thyroid cells was generated via constitutive expression of the fusion protein in FRTL-5 cells. In this model, PAX8-PPAR expression was associated with enhanced growth as assessed by soft agar assays and thymidine uptake. Therefore, PAX8-PPAR 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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