SPECIFICITY AND MECHANISM OF THYROID-HORMONE INDUCTION FROM AN OCTAMER RESPONSE ELEMENT

Thyroid hormone response elements are specific DNA sequences that allo w thyroid hormone receptors to confer ligand-dependent regulation of g ene expression. The response elements characterized to date have been composed of varying arrangements of multiple copies of a conserved hex americ sequence. The traditional consensus half-site of these response elements is the sequence 5'-AGGTCA, although we have demonstrated rec ently that the optimal thyroid hormone receptor monomer binding site i s 2 base pairs larger, 5'-TAAGGTCA. Since other members of this family of nuclear receptors also have been shown to use varying arrangements of the traditional hexamer sequence as response elements, we examined whether the octamer sequence was specific as a thyroid hormone respon se element. The studies reported here demonstrate that only thyroid ho rmone receptors confer ligand responsiveness to a reporter gene contai ning a single copy of the octamer sequence as a response element and t hat qualitative and quantitative differences in the binding of related nuclear receptors to this sequence can account for this functional sp ecificity. We also have shown that thyroid hormone induction from the octamer response element occurs independently of retinoid X receptors, in contrast to the induction from traditional complex thyroid hormone response elements.