ROLE OF GHF-1 IN THE REGULATION OF THE RAT GROWTH-HORMONE GENE PROMOTER BY THYROID-HORMONE AND RETINOIC ACID RECEPTORS

In non-pituitary HeLa cells the unliganded thyroid hormone or retinoic acid receptors cause a strong activation of the rat growth hormone pr omoter that is repressed by their ligands, In contrast, after expressi on of the pituitary-specific transcription factor GHF-1, thyroid hormo ne and retinoic acid produce a stimulation similar to that found in pi tuitary cells. Therefore, GHF-1 changes a ligand-dependent inhibition into a ligand-dependent activation. The essential role of GHF-1 on the rat growth hormone promoter was also demonstrated with AF-2-defective T-3 receptor mutants that show a normal activation of this promoter i n the presence of GHF-1. Furthermore, a truncated T-3 receptor, which lacks the N-terminus and the DNA binding domain, was able to stimulate this promoter in the presence of GHF-1 and exogenous RXR receptors, s uggesting the importance of protein to protein interactions in this re gulation, This study shows that the final transcriptional effect depen ds not only on the type of regulatory promoter response elements but a lso on the presence of other transcriptional activators, in the case o f the growth hormone promoter, the tissue-specific transcription facto r GHF-1, which plays a coactivator-like role in this promoter.