A DIRECT PROTEIN-PROTEIN INTERACTION IS INVOLVED IN THE COOPERATION BETWEEN THYROID-HORMONE AND RETINOIC ACID RECEPTORS AND THE TRANSCRIPTION FACTOR GHF-1

The nuclear receptors for thyroid hormone (TRs) and retinoic acid (RAR s and RXRs) cooperate with the pituitary-specific transcription factor GHF-1 to activate the rat growth hormone (GH) gene, The GH promoter c ontains a hormone response element (HRE), which binds TR/RXR and RAR/R XR heterodimers, located close to two binding sites for GHF-1, GHF-1 i nhibits binding of TR/RXR and RAR/RXR heterodimers to an isolated HRE, Similarly, the receptors inhibit binding of GHF-1 to its cognate site . These results suggest the existence of direct protein to protein int eractions between the receptors and the pituitary transcription factor . This was confirmed by in vitro binding studies with GST fusion prote ins, which demonstrated a strong association of GHF-1 with RXR and a w eaker interaction with RAR and TR, GHF-1 and the receptor heterodimers form a ternary complex with a fragment of the rat GH promoter, which contains binding sites for both, and GHF-1 increases receptor binding to the promoter when present in limiting conditions. These results sug gest that the synergistic activation of the rat GH gene involves prote in-DNA interactions as well as a physical association between the nucl ear receptors and the pituitary-specific transcription factor GHF-1.-P alomino, T., Sanchez-Pacheco, A. Pena, P., Aranda, A. A direct protein -to-protein interaction is involved in the cooperation between thyroid hormone and retinoic acid receptors and the transcription factor GHF- 1.