PAX8-peroxisome proliferator-activated receptor gamma (PPAR gamma) disrupts normal PAX8 or PPAR gamma transcriptional function and stimulates follicular thyroid cell growth

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 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 and sodium-iodide symporter promoters in a manner at least comparable with wildtype PAX8. In contrast, PAX8-PPAR gamma 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 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.