T3 inhibits transcription of the rat TSH β gene, and two T3 response elements have been identified that bind T3 receptors and that share sequence homology with the consensus sequence that is also recognized by retinoic acid receptors (RARs). We, therefore, asked whether RA was a regulator of TSH β gene expression in vivo. Using RNase protection analysis, we found that vitamin A deficiency led to a 2-fold increase in rat pituitary TSH β messenger RNA (mRNA) levels, which returned to normal 18 h after treatment with RA (20 μg/rat). Vitamin A deficiency had no effect on TSH β mRNA levels in hypothyroid rats. Coadministration of RA and T3 (10 μg/100g body wt) to either vitamin A-deficient or vitamin A-deficient, hypothyroid animals caused decreases in TSH β mRNA content that were indistinguishable from those seen with T3 alone. Surprisingly, vitamin A deficiency had no significant effect on GH mRNA levels in euthyroid or hypothyroid rats. Furthermore, treatment of vitamin A-deficient, hypothyroid animals with RA for either 18 or 72 h had no effect on GH mRNA levels, whereas T3 caused 11-fold and 18-fold increases in GH mRNA, respectively, at these times. We also used transient transfection to test for direct, retinoid receptor-mediated regulation of TSH β gene transcription by RA. A plasmid TSH β luciferase, containing 0.8 kilobases of rat TSH β gene 5'-flanking sequences, exon 1, and 150 base pairs of intron 1, was transfected into CV-1 cells. Cotransfection with RAR alpha and retinoid X receptor-β induced TSH β expression by 3.5-fold, and treatment with RA suppressed this induction by 46%. These results show that vitamin A levels play a significant role in regulating the expression of the TSH β gene, but not the GH gene, in vivo and suggest that RA may suppress TSH β gene transcription directly by an RAR-retinoid X receptor heterodimer-mediated mechanism.
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