5'-FLANKING SEQUENCES IN THYROID-HORMONE RESPONSE ELEMENT HALF-SITES DETERMINE THE REQUIREMENT OF RETINOID-X-RECEPTOR FOR RECEPTOR-MEDIATEDGENE-EXPRESSION
Dp. Olson et Rj. Koenig, 5'-FLANKING SEQUENCES IN THYROID-HORMONE RESPONSE ELEMENT HALF-SITES DETERMINE THE REQUIREMENT OF RETINOID-X-RECEPTOR FOR RECEPTOR-MEDIATEDGENE-EXPRESSION, The Journal of biological chemistry, 272(15), 1997, pp. 9907-9914
Thyroid hormone receptors are ligand-inducible transcription factors t
hat can potentially interact with thyroid hormone response elements as
homodimers or heterodimers with the retinoid X receptor. It has gener
ally been felt, however, that the heterodimer is responsible for induc
tion of gene expression, We have demonstrated previously that the opti
mal thyroid hormone receptor binding sequence is not the consensus hex
amer half-site AGGTCA but is an octamer, TAAGGTCA. Based upon these fi
ndings, we hypothesize that thyroid hormone response elements composed
of optimal half-sites (TAAGGTCA) will bind thyroid hormone receptors
readily and activate gene expression independently of the retinoid X r
eceptor. In contrast, response elements composed of suboptimal half-si
tes (e.g. GCAGGTCA) will require the retinoid X receptor to facilitate
thyroid hormone receptor-mediated gene expression. To test this hypot
hesis, we have reconstituted thyroid hormone receptor mediated gene ex
pression in yeast. Our studies confirm the hypothesis that the retinoi
d X receptor is required for gene expression from response elements co
mposed of suboptimal half-sites, whereas thyroid hormone receptors are
sufficient to activate gene expression maximally from response elemen
ts containing optimal half sites. Furthermore, coexpression of steroid
receptor coactivator-1 is required for ligand-dependent gene activati
on from single response elements. Surprisingly, however, coexpression
of the retinoid X receptor decreases the steroid receptor coactivator-
1-dependent thyroid hormone induction. Overall these data demonstrate
that the architecture of the thyroid hormone response element dictates
the nuclear receptor requirements for gene activation. The studies su
ggest that different coactivators may be required for gene activation
depending upon the response element architecture and the nature of the
bound thyroid hormone receptor complex (homo- versus heterodimer).