Regulation of the growth hormone gene by fish thyroid/retinoid receptors

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Abstract

Transcription of growth hormone (GH) genes in vertebrates depends, among other factors, on triiodothyronine (T3) and retinoic acid (RA), mediated by nuclear receptors. In vitro studies of carp (Cyprinus carpio) pituitary cells have shown that addition of T3and RA increase the steady state levels of the GH messenger RNA.

In this study various isomers of fish thyroid hormone and retinoic acid receptor genes were tested in carp pituitary primary cell culture for transcription stimulation of Atlantic salmon (Salmo salar) GH promoter and of a general thyroid hormone-dependent promoter (4TREpTK). Zebrafish (Danio rerio) thyroid hormone receptor (TR) and retinoic acid receptor (RAR), in the presence of their ligands, T3and RA respectively, increase synergistically expression of the reporter gene regulated by GH promoter, while only TR (and T3) is required for maximal stimulation from the 4TREpTK promoter. RA is essential for RAR mediated transcription from the GH promoter, while transcription stimulation by RAR from 4TREpTK promoter is ligand independent. Overexpression of the pituitary specific Japanese flounder (fl)TRβ isomer alone, or with either of the RAR isomers is more stimulatory than the TRα isomer in transcription from the pituitary specific endoTRE promoter element, while there is no preference among the TR or RAR isomers in stimulating transcription from the general consensus 4TREp. Furthermore, the recombinant TRα and TRα/RARα/γ heterodimers are shown to bind specifically to DNA elements. TRα binds specifically to endoTRE from Atlantic salmon GH promoter and to the consensus 4TREp. The zebrafish TRα and RAR(α/γ) preferentially heterodimerize on the consensus 4TREp, and the endoTRE successfully compete the complex formation. It would seem that the specific sequence of the promoter thyroid response elements controls the receptor isomer specificity, and the regulation of transcription by their ligands, thyroid hormone and RA.

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