1) The thyroid hormone-inducible expression of some genes has recently been shown to be enhanced by 9-cis retinoic acid receptor. This effect appears to be at least partially elicited by the ability of 9-cis retinoic acid receptor to heterodimerize with thyroid hormone receptor and enhance its binding to the cis-acting thyroid hormone responsive elements found within those genes. In the present study, we show that the thyroid hormone/thyroid hormone response element-inducible expression of the myelin basic protein gene is not enhanced by 9-cis retinoic acid receptor beta while expression of another target gene, malic enzyme, is further enhanced by addition of 9- cis retinoic acid receptor. We also demonstrate the 9-cis retinoic acid receptor s reverses the thyroid hormone/thyroid hormone response element- dependent down-regulation mediated by the negative thyroid hormone response element found within the promoter of the mouse thyroid stimulating hormone gene. The ligand for 9-cis retinoic acid receptor beta, either alone or in combination with thyroid hormone, did not alter the transcription mediated by any thyroid hormone response element studied. We concluded that the capacity of 9-cis retinoic acid receptor to modulate thyroid hormone- dependent transcriptional regulation depends upon the nature of the thyroid hormone response element. 2) Using the 5' and 3' deletion mutants, containing the thyroid hormone receptor alpha genomic sequences located upstream of the start of translation, we identified 3 genomic regions important for the expression of the rat thyroid hormone receptor alpha gene: 1. -137 to -60 (relative to the major start site of transcription) 2. 3 copies of AGG sequence located immediately downstream of the exon-intron junction; both these regions contribute positively to the promoter activity. 3. this element in the intron consists of two octamer binding motifs. They function as negative regulators. Thus tissue specific expression of the thyroid hormone receptor alpha gene can be governed by the relative tissue specific abundance of transcription factors binding to these regions.
