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Volume 272, Number 37, Issue of September 12, 1997 pp. 23334-23339
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Transcriptional Control of the Forkhead Thyroid Transcription Factor TTF-2 by Thyrotropin, Insulin, and Insulin-like Growth Factor I

(Received for publication, April 22, 1997, and in revised form, June 23, 1997)

Lourdes Ortiz , Mariastella Zannini ^§ , Roberto Di Lauro ^¶ and Pilar Santisteban

From the  Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid, Spain, ^§ Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universitá degli Studi di Napoli Federico II, via Pansini, 5, 80131 Naples, Italy, and ^¶ Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy

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.

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