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

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... peroxidase and sodium-iodide symporter promoters in a manner at least comparable with wildtype 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. (Endocrinology 147: 367-376, 2006) First Published Online September 22, 2005 * A.Y.M.A. and C.M. contributed equally to this work.