Transcriptional control of the forkhead thyroid transcription factor TTF-2 by thyrotropin, insulin, and insulin-like growth factor I

The hormonal regulation of both thyroglobulin and thyroperoxidase promoter activity in FRTL-5 thyroid cells takes place, at least in part, through a hormone-responsive element to which the thyroid transcription factor TTF-2 binds. The TTF-2 cDNA, encoded by the titf2 locus, has recently been cloned and classified as a member of the forkhead transcription factor family. Here, we demonstrate that TTF-2 mRNA levels become undetectable in FRTL-5 thyroid cells cultured for 4 days in 0.2% serum and in the absent of thyrotropin (TSH) and insulin. Addition of TSH, insulin or insulin-like growth factor I (IGF-I) to the culture medium increases the levels of this transcription factor in a dose- and time-dependent manner and requires ongoing protein synthesis. The TSH effect is greater than that produced by insulin or IGF-I and is similar to the effect produced by the cAMP analog forskolin. The TSH and insulin effects are additive. In all cases, the mRNA levels increase is accompanied by an increase in transcription rate, as demonstrated by run-off assays. These data demonstrate that the TTF-2 mRNA is under tight hormonal control. This is consistent with an important role for TTF-2 as a mediator of the transcriptional activation of thyroid-specific genes (thyroglobulin and thyroperoxidase) by TSH via cAMP and by insulin through the IGF-I receptor.